CBNS 2016 Annual Report, April 2017 by SCDesign

Annual Report 2016

CBNS Annual Report 2016 a

Collaborating Organisations

Partner Organisations

Feature photography of CBNS staff, students and laboratories throughout this report by Joe Vittorio. Other photographs and images courtesy of CBNS members and organisations, unless otherwise attributed. Content compiled and edited by Jason Murphy. Graphic design by Sophie Campbell, SCDesign.

Contents About the CBNS

Director’s Report

CBNS at a Glance

Research

Research Overview

Delivery Systems

Vaccines 20 Sensors and Diagnostics

Imaging Technologies

Signature Projects

Cross Centre Activity

Strategic Projects

Engagement 49 Collaborations and Partnerships

Events 53 Education Committee

CBNS Awards

Media 59 Governance

Overview 62 Governance Board – profiles

Scientific Advisory Board – profiles

Performance

Performance and KPIs

Financial Report 2016

Awards, Memberships and Grant Success 71 CBNS Personnel

Visitors 78 Publications 80

CBNS Annual Report 2016 1

2 CBNS Annual Report 2016

About the CBNS The Australian Research Council Centre of Excellence in Convergent Bio-Nano Science and Technology or, as we prefer to be known, ARC Centre for Bio-Nano Science (CBNS) was established in mid-2014 as a national innovator in bio-nano sciences. We bring together a diverse team of Australiaâ&#x20AC;&#x2122;s leading scientists with the aim of developing next generation bio-responsive nano-structured materials. The key scientific aim that underpins all the activities of the Centre is to fully understand, and then exploit, the interface between nano-engineered materials and biological systems. The CBNS research program is structured around the applications of understanding this interface: drug and gene delivery; vaccines; bio-imaging â&#x20AC;&#x201C; both cellular and whole body imaging; and sensors and diagnostics. CBNS research is integrated by overarching research activities to understand the social dimensions of bio-nanotechnology, to visualise bio-nano interactions, and by using a systems biology

Health and biomedical sector engagement

approach to fully describe the complex interactions that dictate success or failure of nanotechnology for therapeutic applications. In delivering the promise of bio-nano science, the CBNS has brought together Australiaâ&#x20AC;&#x2122;s leading scientists and engineers with expertise in nanotechnology, polymer science, cell biology, cancer biology, systems biology, chemical engineering, 3D computer generated imagery (CGI), immunology, chemistry and social science. The Centre consists of five primary nodes: Monash University (Monash); the University of Melbourne (Melbourne); the University

Centre for Bio-Nano Science

of Queensland (UQ); the University of New South Wales (UNSW); and the University of South Australia (UniSA), in addition to eight overseas partners and the Australian Nuclear Science and Technology Organisation. The CBNS is a seven-year program of research that is funded by the ARC ($27M) and the Australian collaborating universities ($9M) over this period. The universities also contribute in-kind, as do the partner organisations. In total the in-kind support for the CBNS is valued at more than $23M over the life of the program and we thank all of the contributors for this support.

Education and training

Delivery (delivery systems, vaccines)

Computational biology

Understanding and exploiting the bio-nano interface

Social dimensions

Detection (sensors and diagnostics, imaging technologies)

Community outreach

Visualisation

Industry and commercial engagement

CBNS Annual Report 2016 3

Director’s Report Welcome to the third annual report of the ARC Centre for Bio-Nano Science (CBNS). As you are about to read, we have seen another strong year of research, collaboration and engagement across all our nodes. The CBNS has continued to grow and be recognised for its impact. This report covers our research and activities in 2016 and looks forward to 2017. In 2015, the CBNS saw a consolidation of the Centre and 2016 has built on this and led to continued growth and positive outcomes. The Centre has continued to produce a high level of outputs, which have been underpinned by a refined research direction through the formation of our seven new ‘Signature Projects’. We have continued to engage with our communities through the delivery of events, outreach activities, industry collaboration and interaction with the media. This year has also seen continued recognition of our members, through a number of awards and accolades. Highlights are captured in this welcome message, while a comprehensive listing is available on pages 71-72 of this report.

Signature Projects While our CBNS Research Themes continue to underpin the majority of our research, in 2016 we have collaboratively formed seven new Signature Projects. These projects have been developed to address significant, unanswered questions that cannot be solved by small groups over short periods of time with comparatively narrow expertise. A detailed overview of these projects is available on pages 32-43.

Growth The CBNS has grown to be a collaborative and truly international centre. We are now home to over 300 members, the majority of whom are researchers. These researchers make an important contribution to the CBNS and add depth and breadth to our profile.

4 CBNS Annual Report 2016

Our international approach to collaboration also continues to yield exciting research. For example, CBNS researchers at the University of Queensland and the University of Nottingham in the UK have begun collaborating on a project with the goal of creating a single miniature biodegradable device that can detect, and treat disease. The detection of specific gene sequences is a vital step in diagnosing a wide range of diseases, including bacterial and viral infection, and in numerous cancers.

Engagement In 2016 CBNS members ran, supported, and contributed to events that engaged expert and general audiences alike. These included: • the International Nanomedicine Conference at Coogee, New South Wales, co-organised and chaired by CBNS researchers • a jointly run Polymer and Nanotechnology Conference organised at Warwick University • a meeting on molecular imaging jointly run by the CBNS and the School of Advanced Studies at the Warwick University Hospital in Coventry • the CBNS playing a leading role at the Australasian Polymer Symposium, held in the Victorian coastal town of Lorne, where two CBNS researchers (Professor Frank Caruso (Melbourne) and Professor Tom Davis (Monash)) delivered plenary lectures • the Emerging Medical Technologies Summit held in Melbourne where three CBNS researchers (Professor Maria Kavallaris (UNSW), Professor Justin Gooding (UNSW), and Professor Tom Davis (Monash)) delivered plenary lectures.

Our education committee continued its work in organising and delivering programs and events that build the capabilities of CBNS members, as well as undertake the important task of engaging the public by helping to increase awareness of the research being undertaken at the Centre. These activities included imaging workshops, a tour of the Australian Synchrotron and a highly successfully, National Science Week movie screening of the film, Contagion. After screening, there was a lively discussion panel around public perceptions of the work of science. The event resulted in an ABC radio interview with Dr Angus Johnston (Monash).

In July, the work undertaken within our Signature Project, journey to the centre of the cell, was featured in New Scientist, and went on to be featured on the ABC’s Catalyst program, aired during National Science Week (see page 59). In July, the work undertaken within our Signature Project, journey to the centre of the cell, was featured in New Scientist, and went on to be featured on the ABC’s Catalyst program, aired during National Science Week. The focus of the article and program was the team’s successful, immersive Virtual Reality (VR) visualisation of a breast cancer cell. This work provides a powerful platform that enhances researchers’ understanding of intracellular processes and is also a compelling vehicle for public outreach and education – with the team evaluating the educational impact of VR.

We also welcomed visiting Professor Vince Rotello from the University of Massachusetts at Amherst. Professor Rotello’s visit to the Centre in July and research into cancer detection, was featured in The Australian newspaper. We’ve included in-depth information about many of our engagement activities on pages 50–59 of this document. Many significant international exchanges were also instigated with our international partners including the visits of CBNS postdocs Dr Jeroen Goos (Monash) and Dr Simon Puttick (UQ) at Memorial Sloan Kettering Cancer Center in New York, and Dr Nghia Truong’s visit to The University of California, Santa Barbara. We also hosted Professor Raffaele Mezzenga from Eidgenössische Technische Hochschule Zürich on a sabbatical leading to significant joint publications and ongoing research collaboration.

Grant successes and research impact Numerous grants were awarded to CBNS members during 2016. In total, over $26M in additional funding was secured by our Chief Investigators and early career researchers. This funding will provide important support to further the research and advancement of key projects being undertaken by the Centre. A number of these successes are also tied to active industry projects – helping to realise direct, commercial applications of the Centre’s research. These successes also demonstrate the considerable expertise of our members and I wish to congratulate all who were successful in their bids.

Members of the CBNS Governance Board

In addition to our grant successes, our impact has continued to be recognised and this is demonstrated by our range of external memberships. This includes ten of our researchers performing roles as editors for some 19 national and international academic journals. More details of our successes are available on pages 71-72.

Awards and fellowships The year saw Centre members continuing to be recognised for their contribution to science. Particular highlights were the elections of Professor Maria Kavallaris (UNSW) as a Fellow of the Australian Academy of Health and Medical Sciences (AAHMS), Professor Justin Gooding (UNSW) as a Fellow of the Australian Academy of Science, and Professor Mark Kendall (UQ) as Fellow of the Queensland Academy of Arts and Science.

New staff While some of our staff have moved on to other projects and we thank them for their contribution, we have been fortunate to welcome some new outstanding staff to the Centre. These include our new University of South Australia node Chief Investigators, Professor Clive Prestidge and Associate Professor Benjamin Thierry, Centre Manager, Dr Natalie Jones, and Senior Communications and Events Advisor, Mr Jason Murphy. As we approach the mid-term review of the CBNS, we look forward to the development of a new year of strong research outputs and engagement. Professor Tom Davis Centre Director

Significantly, six of our early career researchers received fellowships to support their continued research, along with three fellowships for our established researchers. Our awards have been documented on page 71.

CBNS Annual Report 2016 5

CBNS at a Glance Timeline 30 months into 84 month program 2014 2015 2016

2017 2018 2019 2020 2021

Funding $9M in University funding

Partners and collaborators

$35M

over 7 years

$26M in ARC funding

Australian universities

partner organisations

Key data

24 publications in journals with impact factors >10

Our people

101

talks given

new fellowships awarded

Chief Investigators

19 Senior research fellows undertaking CBNS research

Post-doctoral researchers

302 people

Honours and Masters students

9 Management, administration and operational staff

6 CBNS Annual Report 2016

Diverse disciplines: bioimaging, cell biology, chemistry, engineering, immunology, pharmacology, sociology, systems biology, visual arts

Partner Investigators

137

Research assistants and technical staff

PhD students

Partner Organisations US Partner Organisations: Memorial Sloan Kettering Cancer Center (New York); University of California, Santa Barbara University of Wisconsin-Madison

European Partner Organisations: University of Nottingham University of Warwick Imperial College, London University College Dublin

Asian Partner Organisation: Sungkyunkwan University, Korea

Australian Partner Organisation: ANSTO (Sydney)

Collaborating Organisations

University of Queensland Delivery Systems, Imaging Technologies, Sensors and Diagnostics, Vaccines

University of New South Wales University of South Australia Delivery Systems, Sensors and Diagnostics

Delivery Systems, Imaging Technologies, Sensors and Diagnostics, Social Dimensions

Monash University (Administering Organisation) Delivery Systems, Imaging Technologies, Vaccines

University of Melbourne Delivery Systems, Computational and Systems Biology, Vaccines

CBNS Annual Report 2016 7

3D illustration of cell environment by Associate Professor John McGhee 8 CBNS Annual Report 2016

Research CBNS Annual Report 2016 9

Research overview The research focus of the CBNS is to understand the bio-nano interface in order to better predict, control and visualise the myriad of interactions that occur between nanomaterials and the biological environment.

Predict

Control

Visualise

We aim to accurately predict nanoparticle fate using laboratory based tools and analysis

We seek to precisely control the routes of uptake and interaction of nanomaterials into cells and their subsequent delivery to intracellular compartments

We develop visualisation methods that communicate the complexity of bio-nano interactions.

The research program and expertise within the CBNS are presented in more detail in the following pages.

Due to the overlap of our Research Themes and Signature Projects in 2016, this document reports on both areas.

In 2016 we restructured our research program â&#x20AC;&#x201C; focusing on Signature Projects, rather than the Research Themes as had been done previously.

The CBNS Signature Projects draw on the expertise of the Research Themes and the cross centre activities to solve the big questions in bio-nano research.

Research Themes

visualisation visualisationDelivery

Systems

social dimensions social dimensions

These problems couldnâ&#x20AC;&#x2122;t be solved by smaller groups over a shorter period of time, but the breadth and depth of expertise within the Centre and the five years available allow for the CBNS to address these challenges.

Signature Projects

visualisation

Social dimensions

visualisation

Social dimensions social dimensions

Social dimensions Visualisation

Visualisation

Social dimensions Visualisation

Visualisation

social dimensions

visualisation

visualisation Internalisation and trafficking visualisation social dimensions

visualisation

Vaccines

cell

Predictive bio-nano interactions

Imaging Technologies

blood

Imaging social dimensions

Drug delivery for solid cancer tumour

Quantifying in vivo targeting

Isolating single cells

Sensors and Diagnostics

protein / DNA

cell

ons social dimensivisualisation

visualisation

10 CBNS Annual Report 2016

visualisation

social dimensions

social dimensions visualisation

visualisation

cell cluster/ tumour

social dimensions

visualisation

social dimensions

ocial dimensions

s ns social dimensio visualisation social dimensions visualisation social dimensions

social dimensions visualisation visualisation social dimensions social dimensions

organ

visualisation

social dimensions visualisation

visualisation

lisation atn iiossnu visualise ioa ns social dimv visualisation social dimensions

visualisation

The Signature Projects cover a range of scales within the body, from the level of protein and DNA to organs. Each node of the Centre is involved in at least one of the Signature Projects and every project involves multiple nodes. The seven projects listed below form Phase I of activities. Internalisation and trafficking

Quantifying in vivo targeting

Drug delivery for cancer

A material scientist’s guide to the cell By understanding the internalisation and trafficking of nanoparticles inside cells, we aim to optimise the therapeutic response to drugs. See page 32.

Measuring the ‘magic bullet’: quantifying active targeting By targeting nanoparticles to cellular proteins to enhance drug accumulation in tumours we investigate whether therapeutic efficacy is increased. We seek to quantify the contribution that targeting ligands play in the accumulation and bio-distribution of these nanoparticles. See page 34.

Nanoparticles in cancer drug delivery We aim to use our understanding of nanoparticle properties, specifically the characteristics related to targeting, to improve therapy development for aggressive cancers and micrometastatic disease. See page 37.

Predictive bio-nano interactions

Isolating single cells

Visualisation

Developing predictive models of bio-nano interactions By studying the interactions of a range of nanoparticles in blood we aim to develop predictive models of nanoparticle properties. See page 33.

Isolating, capturing and releasing rare single cells for precision medicine By capturing rare migratory cancer cells we seek to understand the phenotype of these cells and the internalisation and trafficking of nanomedicines for therapeutic benefit. See page 36.

Journey to the centre of the cell We are studying whether the use of immersive 3D virtual reality, generated using CBNS scientific data, improves the comprehension of the complex cellular and subcellular processes we study. See page 40.

Social dimensions Into the panoply of precision and personalisation By studying collaborative bio-nano research we are exploring how new social and healthcare practices evolve. See page 42-43. The final Signature Project – Social dimensions: into the panoply of precision and personalisation – will use the other six projects as case studies for understanding how collaborative bio-nano research practices evolve.

Signature Project collaborations

A material scientist’s guide to the cell UQ

Co-leading

Measuring the ‘magic bullet’: quantifying active targeting

Actively involved

Leading

Actively involved

Leading

UNSW Melbourne

Actively involved

UniSA Monash

Co-leading

Isolating, capturing and releasing rare single cells for precision medicine

Developing predictive models of bio-nano interactions

Leading

Actively involved

We expect that over the typically two to three-year duration of the projects some aims will be met and in other cases new avenues for exploration will open up. The CBNS has already identified areas

Nanoparticles in cancer drug delivery

Visualisation: Journey to the centre of the cell

Social dimensions: Into the panoply of precision and personalisation Actively involved

Leading

Leading Actively involved

Actively involved

Co-leading

Actively involved

for focus in Phase II (such as imaging of bio-nano interactions) and expect that new challenges will result from the Phase I projects that will complete the suite of Phase II Signature Projects.

Further details of the Signature Projects, fundamental expertise of the Research Themes and cross centre activities are provided in the following pages.

CBNS Annual Report 2016 11

Delivery systems Leader: Professor Chris Porter (Monash) CBNS Chief Investigators involved in this research theme: The majority of work of the Delivery Systems theme presented here was undertaken by the following CBNS Chief Investigators and their teams: Professor Tom Davis (Monash); Professor Frank Caruso (Melbourne), Professor Maria Kavallaris (UNSW); Associate Professor Kris Thurecht (UQ), Dr Angus Johnston (Monash); Professor Nico Voelcker (UniSA); Professor Rob Parton (UQ) and Professor Ben Boyd (Monash), although wider contributions were made by many other individuals within CBNS.

2016 Summary CBNS activities in the Delivery Systems Theme in 2016 are organised into five major areas of activity. These are summarised below. As CBNS transitions into activities driven more significantly by the Signature Projects, aspects of the work described below will be subsumed into these cross cutting activities. For 2016, however, we summarise activity more broadly and signpost upcoming incorporation into the Signature Projects.

1. Mapping bio-nano interactions Our focus in 2016 was to better understand the patterns and mechanisms of nanoparticle uptake and trafficking into cells and to continue evaluating the ability of polymeric materials to interrupt (or report) protein aggregation. To this end CBNS researchers made progress in developing sensors that report on particle internalisation1 and in quantifying the relationship between nanomaterial structure and the ability to diffuse away from the blood supply and into the heart of a tumour2 We have previously identified that Rab5, and its effector EEA1 are critical regulators of endosomal trafficking. In 2016 we have now shown using state of the art electron microscopy that EEA1 forms long filaments that extend out from the surface of the endosome. These filaments bind Rab5 on incoming vesicles causing a conformational change in the EEA1 that allows vesicle fusion with the endosome.3 Significant progress has also been made in the development of methods that quantify particle transitions between the cytosol and organelle membrane boundaries such as the endosome.4 This method provides novel insight into the role of endosomes in particle trafficking and suggests that many more

12 CBNS Annual Report 2016

particle uptake mechanisms may be functioning than previously thought possible. These studies are reported in more detail in the Sensors and Diagnostics section of the report. A further aim in 2016 was to better understand the mechanisms of amylin aggregation and toxicity that are hallmarks of type 2 diabetes (T2D), a disease impacting over 360 million people worldwide (ref 5-8 below). Collaborations have been established between CBNS partners at Monash University, Melbourne University and the University of South Australia, and external partners at St Vincentâ&#x20AC;&#x2122;s Institute, Clemson University (USA), Tongji University (China) and the Swiss Institute of Technology (ETH), Zurich (Switzerland). Studies in 2016 found that effective inhibition of protein aggregation hinges on a balance between peptide-peptide interaction and peptide-exogenous ligand interaction. Furthermore, star polymers were found to shorten the lifetime of toxic amylin oligomers by accelerating amylin aggregation. The formation of a protein corona was also revealed as an essential step in modulating amylin toxicity. These findings point to a new route for the design of T2D therapeutics.

Figure: Protein corona, a new paradigm for elucidating amylin toxicity in type 2 diabetes. aLac: alpha lactalbumin, Lys: lysozyme. Top four panels: aLac and Lys interacting with amylin monomers. Bottom top panels: aLac and Lys interacting with amylin fibrils. Pharm. Res., 2016, 33, 2421-2432; Chem. Commun., 2016, 52, 9121-9124; 3 Nature, 2016, 537, 107-111; 4 Nature Nano., 2017, 12, 81â&#x20AC;&#x201C;89; 5 Small, 2016, 12, 1615-1626; 6 Sci. Rep., 2016, 6, 21274; 7 Sci. Rep., 2016, 6, 19463; 8 Phys. Chem. Chem. Phys., 2016, 18, 94-100. 1 2

2. The design of novel nanomaterials for targeted drug delivery In 2016 we focused on the development of novel materials that promote endosomal escape (thereby promoting access to the cytosol where many drugs and vaccines act); evaluation of metal phenolic networks as a platform for targeted drug delivery; the use of lipid-polymer hybrid materials for forming and controlling nanostructures; novel mechanisms of generating nanomaterials with high antifouling properties (rendering them invisible to the body’s defence mechanisms), methods to promote scale up of nanomaterial formation and the use of the antibody-functionalised diatom biosilica as a novel means of delivering poorly soluble drugs to tumours.

Engineering endosomal escape Endosomal escape remains a major barrier to therapeutic delivery, especially for the delivery of vaccines and nucleic acids for gene therapy. To overcome this hurdle, in 2016 CBNS scientists developed pH responsive nanoparticles that are designed to release their therapeutic cargo in the acidic

Nanocapsules from metal-phenolic networks for targeted drug delivery Capsules formed from metal-phenolic coordination networks (MPNs) have emerged as a versatile platform for drug delivery. In 2016, CBNS researchers formed MPN capsules from functional polymers (hyaluronic acid (HA)) to target the CD44 receptor that is overexpressed on certain cancer cells.1 Interaction between the targeting ligand on the capsule surface and a tumour-specific cell receptor increased cellular association and internalisation. At the same time, incorporation of a low-fouling polymer (polyethylene glycol (PEG)) into MPN capsules reduced non-specific binding to cells that did not express the receptor, allowing for optimisation of targeting efficiency.2 Anticancer drugs can be encapsulated into the capsules and released by the pH-responsive nature of the MPNs that disassemble at the slightly acidic intracellular environment pH but remain stable at neutral pH. Drug loaded MPN capsules with an optimised HA/PEG ratio showed higher cytotoxicity to a CD44 overexpressing cancer cell line compared with a cell line with low CD44 expression, demonstrating a potential application for targeted drug delivery.

endosomal compartments of the cell. We demonstrated that the molecular weight of the polymers used to assemble these particles plays a crucial role in the ability to induce endosomal escape. Nanoparticles assembled from polymers with a low molecular weight core showed significantly reduced endosomal escape compared to particles with a higher

Notably, the targeting ability of HAbased MPN capsules was maintained in the presence of physiologically relevant proteins that adsorb on nanoparticle surfaces and form a protein corona.3 Biomacromolecules, 2016, 17, 2268; Biomacromolecules, 2015, 16, 807; 3 ACS Appl. Mater. Interfaces, 2016, 8, 22914. 1 2

molecular weight core. All the particles in this study had similar size, surface change and disassembly pH, suggesting that interactions of the pH responsive polymer core with the endosomal membrane play an important role in endosomal escape.1 1 Macromol. Biosci., 2016 DOI: 10.1002/ mabi.201600248

Figure: Schematic illustration of a) the assembly of HA-PEG-based MPN capsules with different HA and PEG ratio in each capsule. b) Targeting to CD44+ (MDAMB-231, blue) cells and non-specific binding to CD44– (BT-474, red) cells can be controlled by tuning the ratio of HA and PEG incorporated into the MPN capsules. Reprinted with permission from Ju, Y. et al. Engineered Metal-Phenolic Capsules Show Tunable Targeted Delivery to Cancer Cells”. Biomacromolecules 2016, 17, 2268. Copyright © 2016 American Chemical Society.

CBNS Annual Report 2016 13

Responsive lipidic nanostructures for triggered drug release Lipidic materials and lipid-polymer hybrid nanomaterials continue to show promise as delivery systems and in 2016 efforts focused on the generation of materials that can be externally ‘activated’ to facilitate remote release. Systems that respond to light

on incorporation of graphene1 and gold nanorods2 were developed alongside peptide-responsive nanostructured materials for disease specific delivery and diagnostic applications.3 Our studies of lipid-polymer hybrid nanomaterials have also shown the potential to form nanomaterials where bioactive peptides are a key component of the structure,

Establishing a viable alternative to PEGylation for antifouling and drug delivery Polyethylene glycol (PEG) has been widely used as a grafting agent in biomedical and surface sciences. Despite its prevalent use, PEG in either linear or brushed form is not biodegradable and chronic administration has the potential to lead to accumulation of the polymer in vivo with unknown consequences. Repeated administration of PEG may also promote an antibody response and accelerated blood clearance of delivery systems, thereby compromising the circulation time and efficacy of PEGylated drugs and nanocarriers. In 2016 CBNS researchers developed a facile scheme for grafting superparamagnetic iron oxide nanoparticles (IONPs) with brushed phosphorylcholine (bPC), a biomimetic alternative to brushed PEG, and demonstrated the advantages of PC in affording water suspendibility and biocompatibility.1 CBNS researchers further examined the structures of both brushed PEG (bPEG)- and PC (bPC)-grafted IONPs and compared

their antifouling properties.2 Both brushed polymers were more rigid than linear PEG, while bPEG and bPC displayed distinct globular and cylindrical morphologies, respectively. Both bPEG- and bPC-grafted IONPs displayed antifouling properties against human serum albumin (HSA), and increased grafting density gave rise

Scaling-up manufacture of polymeric nanomaterials for drug delivery One of the challenges in developing nanomedicines is reproducibly scaling up the synthesis of complex nanostructured materials.1 CBNS researchers have therefore explored environmentally friendly techniques based on emulsion polymerisation to rapidly synthesise large quantities of complex polymers and polymeric nanoparticles. This research is the outcome of international collaborations between the Monash and Warwick nodes of the CBNS and was recently reported in Nature Chemistry.2

14 CBNS Annual Report 2016

Using this emulsion polymerisation technique, the Monash-Warwick team was also able to prepare a suite of polymeric nanoparticles with a variety of sizes, shapes, surface and core properties.3-5 This synthesis technique can also be used to produce nanoworms, an emerging nanostructured material with several advantages for cancer drug delivery such as long circulation time, high accumulation in tumours, deeper tumour penetration, and enhanced targeted delivery.6 This new synthesis technique provides great opportunities for the large-scale manufacture of complex nanomaterials for both bio-nano interaction studies, and drug delivery applications.

allowing for simultaneous control of structure and activity (in this case an antimicrobial effect).4 Nanoscale, 2017, 9, 341; J. Control. Release, 2016, 228, 67–73; Langmuir, 2016, 32, 5155−5161; 4 Appl. Mater. Interfaces, 2016, 8, 31321−31329. 1 2 3

to enhanced antifouling. With stronger repulsion to HSA and a capability of accommodating higher grafting density, bPC may therefore be advantageous when compared to linear and brushed PEG in rendering stealth capabilities to nanostructures for drug delivery. 1 2

Polym. Chem., 2016, 7, 1931-1944; Polym. Chem., 2016, 7, 6875-6879.

Figure: A three-dimensional illustration of a nanoworm, an emerging nanostructured material for both bio-nano interaction studies and cancer drug delivery applications. ACS Central Science, 2016, 2, 434-437; Nat. Chem., 2016, 10.1038/nchem.2634; 3 Polym. Chem., 2016, 7, 430-440; 4 Chem. Commun., 2016, 52, 4497-4500; 5 Polym. Chem., 2016, 7, 7325-7337; 6 Polym. Chem., 2016, 7, 4295-4312. 1 2

Antibody functionalised silicabased nanostructures for drug targeting Progress has also been made toward the development of a novel method for the (bio-)synthesis of a silica-based platform that can be utilised for the targeted delivery of poorly water soluble anti-cancer drugs to tumour sites.

The synthesis was accomplished by a two-step process. In the first step, single-celled diatom microalgae were genetically engineered to display an immunoglobulin G binding domain on their mesoporous biosilica cell walls. This allowed for the attachment of cancer cell-targeting antibodies to the biosilica surface. In the second step, the antibody-

functionalised diatom biosilica was loaded with hydrophobic drugs trapped in micelles or liposomes. Selective targeting and killing of tumour cells was demonstrated using drug-loaded biosilica that displayed the specific antibodies.1 1

Nat. Commun., 2015, 6, 8791.

3. Controlled and site specific delivery of therapeutics 2016 activities on site specific therapeutic delivery focused on the use of bispecific antibodies as a facile means of rapid development of targeted PEGylated nanomaterials, the development of nanomaterials that respond to gaseous neurotransmitters, the development of synthetic cationic peptide-based polymers as novel antimicrobials, the use of nanoparticles and lipid-conjugated delivery systems to target receptors that signal specifically from the endosome, the development of porous silicon nanoparticles as novel delivery vectors to target immune responses in dendritic cells and design of novel materials to allow the formation of tumour spheroids that provide the means for better in vitro testing of candidate drug delivery systems.

Bispecific antibodies to target PEGylated nanomaterials to tumours

Targeted nanomaterials promise improved therapeutic efficacy, however their application in nanomedicine is slowed by the complexities associated with protein conjugation to synthetic nanocarriers.

Gasotransmitter-reactive materials for regulation of cell signaling processes Gaseous signalling molecules or gasotransmitters (e.g. oxygen, nitric oxide, carbon monoxide and hydrogen sulphide) are a small family of gaseous molecules that are intimately involved in a host of cell signalling processes. For instance, nitric oxide (NO) is involved in pain perception, sleep control and regulation, vasodilation, and mucus production. Conversely, misregulation of NO is associated with pathologies including preeclampsia-related hypertension, Prinzmetal’s angina, transplant rejection and septic shock.

Materials capable of modulating physiological levels of NO are therefore of considerable benefit. In 2016 CBNS researchers explored polymers including o-phenylenediamine and p-phenylenediamine motifs as NOresponsive materials. In 2016, we demonstrated that p-phenylenediamine functional monomers (and polymers synthesised therefrom) react in the presence of NO to yield materials with a phenyldiazohydroxide moiety.1 Interestingly, the product formed decomposes under UV irradiation to yield phenol substituted polymers and nitrogen, providing a convenient method by which excess nitric oxide can be converted to a non-signalling molecule.

For further information about this activity, see the Signature Project: Measuring the “magic bullet”: Quantifying active targeting vs the EPR effect on pages 34–35.

Figure: Schematic representation of the chemical structure transitions of NO-reactive copolymers in the presence of NO followed by UV irradiation (λmax = 365 nm). The aniline residues are transformed into phenyldiazonium by NO, these moieties being further converted to phenol derivatives (with loss of nitrogen) when subjected to UV irradiation. 1

Macromolecules, 2016, 49, 2741-2749.

CBNS Annual Report 2016 15

Synthetic cationic polymers as novel antimicrobial peptide analogues Antibiotic-resistant bacteria represent a critical challenge to the health care system. Cationic antimicrobial peptides (AMPs), exhibit a broad spectrum of antibacterial activity, have lower susceptibility to resistance and represent one alternative class of antibiotic agents. AMPs owe their activity to a combination of ionisable nitrogenous moieties (which allow for the binding to the outer surface of the bacteria) and lipophilic groups (which insert into the cell membrane

causing cell death through osmotic swelling and lysis). Despite their promise, AMPs have many limitations: they are costly to manufacture in large quantities and have short in vivo half-lives due to degradation by proteases. CBNS researchers have recently reported the use of wholly synthetic cationic polymers to mimic the structure and function of AMPs, and have demonstrated their efficacy against a range of resistant and susceptible bacteria.1,2 In contrast to AMPs, these materials can be produced cheaply and on a large scale, and can be easily modified.

Figure: Synthesis of antimicrobial peptide (AMP) analogues using Cu(0) mediated polymerisation. 1 2

RSC Adv., 2016, 6, 15469-15477; J Mater. Chem. B., 2017,5, 531-536.

Endosomal drug delivery systems: Targeting pain at the source G protein-coupled receptors (GPCRs) are dynamic cell surface receptors that control most physiological processes by initiating intracellular signalling pathways that are both spatially and temporally controlled. GPCRs are conventionally thought to bind ligands and initiate signalling pathways from the cell surface, and this signalling can be subsequently “arrested” via GPCR interactions with β-arrestin adaptor proteins that recruit receptors into the endosomal network and away from the cell surface. However, new evidence suggests that GPCR internalisation is not only important for switching off cell surface signalling, but that, endosomes are now considered a platform for generating spatially and temporally distinct signalling outputs. Importantly, CBNS researchers demonstrated that GPCR-mediated “endosomal signalling” in spinal neurons is associated with pathophysiological processes such as sustained pain transmission. The selective delivery of GPCR inhibitors directly to endosomes is a unique and novel strategy for effective and selective inhibition of chronic pain or other conditions. Two endosomal delivery strategies are currently being investigated: A) Conjugation of inhibitors to a lipid anchor (cholestanol) to promote endosomal targeting and retention; B) pH-sensitive soft nanoparticles for delivery of antagonists into endosomes. Lipid-anchored inhibitors: Using realtime fluorescence confocal microscopy and pharmacological analyses in cells and animals, our data demonstrates that cholestanol conjugates can bind GPCRs at the cell surface and in endosomes, and are very effective at selectively

16 CBNS Annual Report 2016

blocking endosomal signals thereby providing long-term analgesia that is not observed with a non-lipidated drug equivalent (manuscript under review). Importantly, in 2016 these findings were extended to multiple cholestanol conjugates that target different GPCRs, to demonstrate that endosomal inhibition could be applied to many trafficking proteins. pH-responsive nanoparticles: Developing a nanoparticle that carefully “tunes” cell signalling without affecting cell viability poses a significant challenge. In particular, cytotoxicity can be caused by protonation of pHresponsive monomers in the hydrophobic portion of the diblock copolymer

when particles disassemble within the acidic environment of early and late endosomes. To reduce this toxicity, we have incorporated non-charged monomers units by RAFT to “shield” the cell from protonated polymers. Fluorescence microscopy has confirmed these particles remain within endosomes (i.e. do not promote endosomal escape). Most importantly, for the first time we have observed improved analgesia with spinal administration of drugloaded nanoparticles when compared to the drug alone or empty particles. These studies are ongoing. Future cell signalling assays will provide a clearer understanding of how these particles are regulating endosomal signalling.

Porous silicon nanoparticles to target immune cells Dendritic cells are the most potent antigen-presenting cells and are fundamental to the establishment of transplant tolerance. The DC-SIGN receptor is a potential target for dendritic cell therapy of graft-versus-host disease. Biodegradable and high-surface area porous silicon (pSi) nanoparticles displaying DC-SIGN antibodies and loaded with the immunosuppressant rapamycin provide a unique platform to target and modify dendritic cells (DC). In 2016 CBNS scientists fabricated rapamycin-loaded DC-SIGN displaying pSi nanoparticles and assessed uptake efficiency into dendritic cells and the extent of nanoparticle-induced modulation of phenotype and function. DC-SIGN antibody displaying pSi nanoparticles favourably targeted and

were phagocytised by monocyte-derived and myeloid DCs in whole blood in a time and dose-dependent manner. DC preconditioning with rapamycinloaded nanoparticles, resulted in a maturation resistant phenotype and significantly suppressed allogeneic T-cell proliferation (publication in preparation). Tumour spheriod design Novel tumour spheroids have been designed using a chemically welldefined 3D cell culture matrix based on self-assembled peptides. In 2016 CBNS scientists showed that this 3D cell culture can support the growth of SK-N-BE(2)-luc neuroblastoma multicellular tumour spheroids for up to 72 hours without any detectable adverse reaction.1 The advantage of this approach is that it moves away from the use of chemically complex and heterogeneous biological (e.g. MatrigelÂŽ)

and synthetic polymer-based 3D cell culture matrix materials which are less reproducible and therefore complicate interpretation of in vitro drug efficacy and delivery studies.

Figure: A SK-N-BE(2)-luc neuroblastoma multicellular tumour spheroid grown in the newly developed 3D peptide gel matrix. 1

ChemPlusChem., 2017, 82, 383â&#x20AC;&#x201C;389.

4. Gene silencing and gene therapy The primary goal in gene silencing delivery technologies in 2016 was to develop and validate more effective delivery vehicles for RNAi/chemotherapeutic delivery to tumour cells.

Star-polymers to deliver RNAi to pancreatic cancer

Pancreatic cancer is one of the most lethal of cancers as it is often diagnosed at an advanced stage. It can rarely be surgically removed and is poorly responsive to chemotherapy or radiotherapy.

In vivo efficacy of siRNA released from porous silicon nanoparticles Although the inhibition of multidrug resistance protein 1 (MRP1) in glioblastoma multiforme (GBM) has recently shown promise in drugsensitising GBM at the cellular level, the inhibition of MRP1 in vivo and the resulting phenotypic influence to the tumour and normal tissues that express MRP1 have not been illustrated. We have recently demonstrated that

MRP1 silencing using siRNA not only drug-sensitised, but also inhibited GBM cell proliferation by arresting the cell cycle at G1/S. The inhibition observed is independent of the siRNA delivery method. Functional inhibition of MRP1 indicates that the reduction in proliferation is mediated through transmembrane transporters. Through the use of porous silicon nanoparticle (pSiNP) delivery of siRNA, we established MRP1 silencing in GBM tumour-bearing mice. Consistently,

For further information about this activity, see the Signature Project: Nanoparticles in cancer delivery on pages 37â&#x20AC;&#x201C;39.

the GBM proliferation associated with MRP1 silencing in tumour. Non-targeted delivery of MRP1-siRNA has shown an extended silencing in other MRP1 expressing organs such as kidney and duodenum, however no adverse histopathology has been observed. These results highlight the potential that, apart from chemotherapeutics sensitising, MRP1 silencing itself may deliver therapeutic effect by attenuating the growth of GBM.

CBNS Annual Report 2016 17

5. Promoting transepithelial and transmucosal drug delivery In 2016 CBNS research on drug delivery across epithelial and mucosal barriers focused on delivery after oral administration across the GI tract.

Ionic liquids and lipid formulations to promote drug exposure after oral administration Lipid formulations are commonly used to promote the absorption of drugs that have intrinsically low water solubility and may be very effective.1 A limitation to their broader application, however, is lack of drug solubility in the formulation itself. By converting drugs to ionic liquids, the melting point of the complex is usually significantly reduced

and this facilitates enhanced solubility of the drug in lipid based formulations. Our focus in 2016 was to examine the broader application of the ionic liquid technology using a range of drugs and to better understand the chemical and physical stability of these ionic liquid – lipid hybrid formulations. We have also been developing improved methods of assessment of lipid-based formulations for oral delivery. Lipidic formulations are difficult to assess using

Targeting lymph lipoproteins to promote drug delivery Lipoproteins are endogenous nanomaterials that are synthesised in the intestine and liver and whose primary role is the distribution of lipids around the body. Lipoproteins that are synthesised in the intestine, in response to the absorption of fat in the diet are transported to the general blood circulation via the lymphatic system. This is in contrast to the majority of nutrients (and drugs) that are absorbed across the intestine and transported to the general circulation via the portal blood. Lymphatic transport rather than portal blood transport has two primary advantages for drug delivery. Firstly the portal blood must pass through the liver before reaching the general circulation and many drugs are highly metabolised before even reaching the general blood stream (so called ‘first pass’ metabolism). This can severely limit drug exposure to sites of action. Secondly, the lymphatics contain high concentrations of immune cells including T lymphocytes, that are a key component of the immune response. Targeting drugs to the lymphatic may therefore significantly benefit the delivery of drugs with immunomodulatory activity. In 2016 CBNS scientists worked on developing prodrugs that are structurally related to natural lipids and that ‘piggyback’ onto lipid transport pathways and become integrated into lipoprotein transport pathways.1 Most notably, the focus has

been on optimising prodrug structure so that the prodrug is stable in intestinal lumen, but rapidly hydrolysed when it reaches the blood stream. This has been achieved using testosterone (as an example of a drug with very high first pass metabolism) and the incorporation of ‘self immolative’ linkers in the prodrug structure to promote drug release.

18 CBNS Annual Report 2016

simple traditional approaches since their physical properties are dramatically changed by interaction with bile and digestive enzymes in the GI tract. To address these limitations in 2016 CBNS scientists have been developing laboratory models that simulate the GI environment to allow better understanding of the ideal formulation components to promote absorption.2 1 2

Adv. Drug Deliv. Rev., 2016, 101, 167-194; Pharm. Res., 2016, 33, 970–982.

For testosterone, this approach resulted in remarkable increases (up to 90-fold) in plasma exposure when compared to the current commercial product (testosterone undecanoate).2 Mol. Pharmaceut., 2016, 13, 3351-3361; Angew. Chem. Ind. Ed., 2016, 55, 1370013705. 1 2

Key goals for 2017 The major general goal for 2017 will be to expand the major areas of activity across nodes and to harness the collective problem solving power of the cross-centre Signature Projects where applicable to delivery systems projects. Specific goals will be:

1. To expand our understanding of

the role of bio-nano interactions in dictating the cellular and in vivo fate of nanomaterials. Aspects of this work will be concentrated in Signature Project 1 (Bio-nano visualisation) and 3 (Internalisation and trafficking of particles in cells) but will include focus around mechanisms of endocytosis, methods to engineer endosomal escape, a better understanding of the role of the protein corona and further progress in the potential for polymeric materials to inhibit (or mimic) the endogenous aggregation behaviour of amylin.

2. To design and develop novel

nanomaterials with delivery advantage. Specific areas of focus for 2017 will be in the development of i) NO-responsive materials for

potential applications in oral drug delivery and cancer biology; ii) synthetic antimicrobial peptide analogues aimed at increasing efficacy and reducing off-target effects such as haemolytic activity; iii) metal phenolic networks as a novel, flexible alternative to traditional polymeric delivery vehicles.

3. To develop responsive nanomaterials that control bioactive release and promote targeted drug delivery. Much of this work will be conducted as a centre wide activity under Signature Project 2 (Quantifying active targeting) and 5 (Drug delivery for cancer), but specific focus will also be directed to targeting intracellular organelles such as the endosome to manipulate the activity of G-protein coupled

receptors, and in using nanostructured lipid vehicles that are able to â&#x20AC;&#x2DC;reactâ&#x20AC;&#x2122; with metabolically labelled cells providing a novel means of in vitro and in vivo targeting.

4. To further refine delivery strategies for nuclei acids such as RNAi. The major focus of activity in RNAi delivery is in cancer and as such these efforts will be largely subsumed into Signature Project 5 (Drug delivery for cancer)

5. To promote oral drug delivery

using lipidic-mimetic conjugates (prodrugs) and complexes (ionic liquids) and to harness the benefits of drug delivery to the lymphatic system by targeting drug delivery to endogenous nanomaterials such as lipoproteins.

CBNS Annual Report 2016 19

vaccines Leader: Professor Stephen Kent (Melbourne) CBNS Chief Investigators involved in this research theme: The work of the Vaccines theme is undertaken primarily by the following CBNS Chief Investigators and their teams: Professor Rob Parton (UQ); Dr Angus Johnston (Monash); Associate Professor Kris Thurecht (UQ); Professor Frank Caruso (Melbourne); Professor Mark Kendall (UQ). The research within the vaccine theme is broad, interacts and overlaps with several of the other Research Themes, and contributions are made by several others in the CBNS. Working towards preventing illnesses is an important long-term global and Australian health goal. Vaccines are perhaps the most effective public health mechanism aimed at controlling infections and preventing cancers. Major opportunities exist for the design and delivery of more effective ‘smart’ vaccines through the use of nanoengineered materials. However, a much improved fundamental understanding of how nanoparticles interact with immune cells is needed to provide a rational basis for improving our designs and capitalise on advances in this field. For example, new generation vaccines are likely to be capable of both (a) avoiding degradation and non-specific clearance, as well as (b) targeting specific immune cells such as dendritic cells capable of orchestrating the most effective immunity and (c) activating specific immune cell components to provide long-lasting immunity.

Widespread human pathogens that cause a major global burden of disease for which highly effective vaccines do not exist include HIV, tuberculosis, hepatitis C and malaria. The CBNS research work in the Vaccine theme is complementary with aspects within the Delivery systems research since reaching specific cell types while avoiding nonspecific degradation is common to both applications. There is however a dearth of information about targeting immune cells with nanoengineered structures and we have initiated a major undertaking (a Signature Project) towards understanding the biological ‘rules’ by which nanoparticles interact with immune cells. Our many materials-scientist orientated Chief Investigators across the CBNS have the expertise that permits them to finely tune nanoengineered structures, and allows for comparisons of divergent nanoparticle systems in order to understand the most efficient mechanisms to deliver appropriate vaccine antigens to immune cells. Computational biology with Chief Investigator Crampin will be used to analyse the data, at the single cell and gene expression level, to develop

testable ‘rules’ that underpin how physical properties such as charge and size affect interaction with human immune cells. An over-arching understanding of these processes has become a key Signature Project of the CBNS and few multidisciplinary groups exist worldwide that have the necessary range of skills and collaborative environment to push this forward. In parallel, the Centre Chief Investigators are continuing to design and test improved vaccine concepts for advanced testing through the CBNS. The team are making headway in targeting nanoparticles to immune cells using surface-tethered antibodies. Caveospheres have developed into an exciting vaccine- particle system that is being exploited in a highly productive collaboration across UQ, Melbourne and Monash University CBNS nodes. Vaccines delivered by microinjection with an array of small needles that target skin dendritic cells (the Nanopatch™) continue to be exploited through the CBNS. Looking forward, an additional key goal will be to understand how targeting antibodies could affect nonspecific clearance of the particles.

The Nanopatch™ – non-invasive vaccine delivery to the skin An advanced concept in the Vaccine theme involves the NanopatchTM, developed by Chief Investigator Professor Mark Kendall and colleagues at UQ with important contributions from his colleague Chief Investigator Corrie now at Monash. This vaccine delivery system uses a small patch applied to the skin with micro-projections that can carry vaccines or other materials into the very superficial layers of the skin. Dendritic cells are rich in this epidermal layer of the skin. Further work is now on understanding how best to achieve this. Remarkably, application of the Nanopatch results in transudation of fluid beneath the patch. This unexpected finding provides two important opportunities: (a) an understanding of how this fluid can contribute to activating the immune system and improving

20 CBNS Annual Report 2016

vaccine effectiveness and (b) a relatively non-invasive means to sample body fluids as a marker of levels of various bioactive substances in the body. The overall goal is to deliver on the promise of nanotechnology to both improve the protective efficacy of a vaccine and at the same time reduce unwanted ‘off-target’ side effects.

Figure: The tips of Nanopatch’s microprojections are coated with a vaccine material and release this material directly to the large numbers of key immune cells immediately below the skin surface.

Caveolin nanospheres as a vaccine delivery agent Chief Investigators Professor Rob Parton and Dr Angus Johnston together with other CBNS researchers have been developing a novel biologically derived nanoparticle system based on the formation of caveolin-induced nanovesicles in bacteria. Expression of the caveolin protein in bacteria induces budding of 50 nm diameter caveospheres from the bacterial plasma membrane. These nanoparticles can be modified to use as vaccines or to deliver drugs to specific cells of the body. Specifically, the team has engineered the caveospheres using molecular cloning techniques to incorporate vaccine components and synthetic amino acids that allow for modification of the particles in a site specific way. The purified caveospheres contain lipids from the bacterial

cytoplasmic membrane and caveolin protein (approximately 150 copies per vesicle). The bacterial synthesis of the caveospheres means they are simple and economical to manufacture as the process can be easily scaled using industrial fermentation methods. In preliminary tests, the immunogenic caveospheres show significant promise as a vaccine delivery system, and the team is currently investigating the targeting and biodistribution of the caveospheres in vivo. Further experiments are underway to understand in molecular detail how caveospheres form and to use this understanding to nanoengineer the caveospheres. To further improve the caveospheres, a short polypeptide of caveolin has been identified – just 66 amino acids long – which can generate smaller ‘mini-

spheres’ containing just the minimal domain of caveolin. This allows the properties of the caveospheres to be tailored for specific needs. Work is now on the investigation of the use of different versions of the caveospheres with different properties to deliver agents specifically to cells of the immune system or to target tumour cells. Preliminary work of caveospheres expressing model antigens (ovalbumin protein) shows that these particles can stimulate dendritic cells and induce potent immune responses. We have now constructed caveospheres expressing part of influenza to test as improved influenza vaccines. J. Biol. Chem., 2015, 290(41), 24875.

Targeting of caveospheres to human immune cells During 2016 we made exciting advances on the ability to attach antibodies to caveospheres to target these vaccine particles to immune cells (Glass JJ et al). This joint effort across a team of three CBNS Chief Investigators (Parton, Johnston, and Kent) bringing complementary skills to the problem illustrates the power of the CBNS to tackle large problems. Attaching antibodies to caveospheres was achieved through the expression of a “z-domain” of staphylococcal Protein A, which then binds the Fc portion of antibodies. This allowed us to test multiple different targeting antibodies with the same particle. Indeed, we showed that we could target either B cell or T cells (types of immune cells) both in cells in tissue culture but also in the complex environment of human blood. Further, by targeting another molecule on T cells (the CCR5 receptor) we were able to show that particles can be internalised into T cells. The CCR5 receptor is critical in the entry of HIV into cells, meaning that we have a platform to target our particles to the same target cells as HIV. This opens up exciting possibilities in the delivery of novel anti-HIV therapeutics, as well as driving the development of novel vaccines.

Figure: Representative field of view showing caveospheres internalized by primary CD4 T cells from 2 independent experiments (>100 cells per condition). Scale bars: A. 5 μm, B. 2 μm, C. 6 μm.

CBNS Annual Report 2016 21

Figure: Caveospheres can be targeted to primary B and T cells within mixed human blood cell populations. PBMC were purified from healthy donors, phenotyped using a 6-antibody cocktail and incubated with caveospheres functionalized with or without anti-human Abs. (A) Gating strategy used to identify leukocyte populations. After gating on final populations, single cells were selected by FSC-A vs. FSC-H. (B) Targeting was examined in primary human PBMCs. Representative FACS plots from one donor showing caveosphere binding to cell subsets. (C) Binding is displayed as fold change of MFI over untargeted caveosphere, with mean ± SEM. n = 9 donors across independent experiments. * p < 0.05, ** p < 0.01. (D) Confocal microscopy of sorted primary immune cells confirmed the targeting of α-CD4 and α-CD20 caveospheres. Representative images displayed, showing brightfield and caveospheres (red). Scale bar = 2 μm.

22 CBNS Annual Report 2016

Stealth PEG particles for improved in vivo circulation and targeting The successful delivery of therapeutics or vaccines at the relevant target sites is heavily influenced by biological interactions, for example, the nonspecific uptake of drug carriers by the phagocytic cells of the immune system. Modifying the surface of nanoparticle drug carriers with polyethylene glycol (‘PEGylation’), has been the most widely used strategy to reduce non-specific clearance and to prolong circulating lifetimes.1 However, PEGylation is usually dependent on the PEG chain

architecture and PEG surface density, both of which are difficult to finely control and simulate. CBNS researchers circumvented the issues relating to PEG chain architecture and PEG density on the surface of particles and instead engineered particles composed entirely of PEG by infiltrating PEG into mesoporous silica templates.2,3 They also improved in vivo circulation times of the PEG particles by modifying the molecular weight, size and rigidity of the PEG polymer.

In 2016 we initiated another three-way collaboration amongst CBNS Chief Investigators Caruso, Thurecht and Kent where we have prepared our PEG particles with ‘bispecific’ antibodies (where one arm of the antibody binds to the PEG and one arm to a desired target). This has been promising for targeting cancer cell lines and we are now testing the same concept to target immune cells in blood.

2. Engineer antigens into complex

3. Use a matrix of nanoparticles to

Biomacromolecules, 2015, 16, 807; ACS Nano, 2015, 9(2), 1571; 3 ACS Nano, 2015, 9(2), 1294. 1 2

Key goals for 2017 1. Engineer next generation

nanomaterial-based vaccines to more efficiently target dendritic cells using surface-tethered antibodies.

nanomaterials to enable effective vaccination.

further guide how best to target nanoparticles to immune cells (see Signature Project “Developing predictive models of bio-nano interactions” on page 33).

Dr Frieda Mansfeld (UNSW)

CBNS Annual Report 2016 23

Sensors and diagnostics Leader: Professor Justin Gooding (UNSW) CBNS Chief Investigators involved in this research theme: The work of the Sensors and Diagnostics theme presented here is undertaken by the following CBNS Chief Investigators and their teams: Professor Nico Voelcker (UniSA); Professor Beatriz Prieto-Simón (UniSA); Dr Simon Corrie (Monash); Dr Angus Johnson (Monash); Professor Mark Kendall (UQ). The research of our Research Themes is broad and contributions are made by others in the CBNS.

2016 Summary Sensor activity in 2016 can be subdivided into two broad areas. The first is the application of sensors for the prevention and treatment of diseases in situations where performing diagnostic measurements away from a centralised laboratory are required. The long-term goal of such work is to develop commercial devices. The second area is to develop sensors for biological or chemical information to enhance our understanding of how chemical or biological systems work. Within the major goal of the CBNS to understand the bio-nano interface, considerable research has been undertaken to develop sensing systems, combined with fluorescence spectroscopy, to enhance our understanding of the entry and internal trafficking of nanomaterials within cells. We will discuss these two broad areas in turn.

Application of sensors for disease diagnosis The main application goals of the CBNS are to develop technologies for biomarkers and methods for the isolation and measurement of single cells. Three of the four goals outlined in the 2015 Annual Report pertained to the application of sensors. These goals were: demonstrating the isolation of single cells from biological fluids (now a Signature Project); use of sensors for detecting markers of infection and inflammation; and advancing the Micropatch™ technology for sampling blood markers. Demonstrating the isolation of single cells from biological fluids This interdisciplinary project aims to provide the first tools for the capture and release on single rare cells, such as circulating tumour cells, from complex samples. Such a strategy is vital for understanding cell heterogeneity in rare cells, an enduring challenge, and has relevance in understanding resistance of cancers to therapy, understanding the heterogeneity in uptake of nanoparticle drug delivery vehicles and in the detection and treatment of the spread of cancer. Because of the broad reaching nature of this project more detailed progress is outlined in the Signature Project: Isolating viable single diseased cells on page 36. Use of sensors for detecting markers of infection and inflammation Considerable progress has been made in this regard with both electrochemical1,2

24 CBNS Annual Report 2016

and optical sensors.3 Such sensors are vital for both detection of disease and the monitoring of patients that are undergoing aggressive therapies for other diseases. Important research in the CBNS in 2016 was the development of an electrochemical sensor for the detection of bacteriophage infections.1 This novel biosensor was based on an invention by CBNS researchers where porous silicon membranes were deposited on gold surfaces to give electrochemical nanopore sensors (see Figure). Modification of the pores with antibodies then allowed the electrochemical detection of the bacteriophage via the blocking of access of redox active species to the underlying gold electrode. The merits of this approach is an exceptionally broad detection range from 6 to 1010

Figure: Illustration of the sensing principle for the bacteriophage sensor where the capture of bacteriophage inside the pores of the porous silicon membrane blocks access of electroactive species to the electrode.

plaque forming units/mL and the fact that the nanoporous membrane provides incredible advantages in using the device in complex samples with regards to filtering our interferences. The application on sensors directly in complex samples, like blood was also the defining feature of another electrochemical biosensor developed in the CBNS for the detection of the inflammatory marker, the cytokine TNF-α. TNF-α is a 17.5 kDa proinflammatory cytokine that can mediate a variety of biological effects such as immune regulation, antitumor activity, viral replication, and infection resistance. Using unique surface chemistry specifically developed in the CBNS, electrochemical immunosensors were developed that have layers that provide

resistance to nonspecific adsorption of proteins but still allow electron transfer to occur to the underlying electrode.2 This unprecedented capability then allowed TNF-Îą to be detected in whole blood down to 10 pg/mL which is more than adequate for clinical application. Moving beyond in vitro sensors to in vivo sensors, using the biocompatible porous silicon, CBNS researchers have shown which surface chemistries maintain the biocompatibility of the material and which do not.3 This is an important step in using these materials in vivo. In the same papers it was demonstrated that when the porous silicon sensors were implanted subcutaneously that their optical signature was detectable through the skin. The development of sensors for the in vivo detection of infectious markers will be a major focus of 2017. Biosensors Bioelectronics, 2016, 80, 47; ACS Sensors, 2016, in press; 3 Biomaterials, 2016, 74, 217 1 2

Advancing the MicropatchTM technology for sampling blood markers The alternative to in vitro sensors that require the collection of blood samples and in vivo sensors that require implantation is the minimally invasive collection of biological fluids for in vitro sensing. This is an area where the CBNS holds a considerable strategic advantage through the development of microprojection technology. A major step forward in this goal was reported in 2016 where the ability of the microprojections to induce circulating protein markers. The important discovery in this paper was that in the process of applying the microprojection array patch, the pressure applied resulted in higher amounts of proteins being collected due to extravasation. Additionally, in this paper, it was shown that the length of the microprojections can then allow different regions below the skin to

be sampled (see Figure). This is an important development in the pain-free collection of biomarkers for in vitro analysis with the next major step being relating the levels of the biomarkers collected to levels in the blood.

Figure: Dynamic application of microprojection arrays to skin induces circulating protein extravasation for enhanced biomarker capture and detection. Biomaterials, 2016, 84, 130-43.

Sensors for biological discovery With the major goal of the CBNS being to understand the bio-nano interface and how to rationally design materials for bio-nanotechnology, a major shift in the Sensors and Diagnostics theme in 2016 has been to develop sensing tools to understand the bio-nano interface direction inside cells. This work pertains to Goal 2 of 2016, development of the first diagnostics for the detection of biomarkers from a single cell. There have been two major developments in this regard aimed at understanding the journey of nanoparticles into a cell and through the cell to the nucleus. These studies are important because they provide tools for understanding how to develop nanoparticle based sensor and nanoparticle based drug delivery vehicles and how to get the nanoparticles to go to a given organelle of interest. The first of these two studies is the development of a sensor for determining whether nanoparticles are internalised or not1. This sensor is a DNA based sensor that is anchored to a nanoparticle (See Figure). This is important as classical fluorescence imaging of a fluorophore on a membrane cannot show whether the fluorescent species is on the inside or the outside of the membrane. This is naturally important as a drug delivery vehicle that is stuck to the outside of the cell will not have the same therapeutic impact as one inside the cell. The way the sensor works is that attached to the nanoparticles for internalisation are single strands of DNA

that possess a fluorophore on them. The cell is then exposed to a complementary sequence of DNA which can bind to the single strand of DNA if it is outside the cell. If it is inside the cell, then no binding occurs. The presence of binding is determined from the complementary sequence possessing a quencher. Hence nanoparticles outside the cell are not fluorescent and nanoparticles inside the cell are. In this way the impact of particle design to promote internalisation by cells can be monitored. In a second study a new microscope method was exploited to understand how the shape of nanoparticles influenced their ability to transit through cells2. The new microscope method is called paircorrelation microscopy and also relies on the design of nanoparticles that have fluorescent tags. The main advance here is that pair-correlation microscopy is a form of fluctuation analysis that permits quantification of how many nanoparticles are in the cell, and how many are moving and their rate of movement. The method has the sensitivity to detect a change of a single nanoparticle within a volume yet tracks many millions of nanoparticle so gives statistically relevant data. The method uses standard confocal microscopy and looks at the fluctuations in fluorescence intensity at one pixel in the cell relative to another pixel. The correlation in fluctuations between this pair of pixels allows calculation of the speed of nanoparticle movement.

Figure: Design of the DNA sensor for determining whether nanoparticles are internalised or not.

If the two pixels are on either side of a barrier, such as the nuclear envelope, then the speed different particles go across the barrier can be determined. CBNS researchers found nanoparticles of different shapes but the same surface chemistry delivered different results; rod shaped nanoparticles were more effective at killing cancer cells than spherical shaped ones because they managed to travel into the nucleus before releasing their drug payload. Such information is vital to understand how to develop more effective drug delivery vehicles. 1 2

Pharm. Res., 2016, 33, 2421; Nature Nano., 2017, 12, 81.

CBNS Annual Report 2016 25

Key goals for 2017 1. Build collaborations between the UNSW, Monash, UQ and UniSA nodes through the development of the two main sensors and diagnostic Signature Projects.

2. Develop sensors for inflammation

and infection that have the potential to measure inflammatory and infection markers in vivo.

Professor Justin Gooding (UNSW)

26 CBNS Annual Report 2016

3. Develop cellular based biosensors

to monitor the impact of therapeutics on cell function.

4. Strengthen the collaboration between the Sensors and Diagnostics theme and the Imaging theme.

Imaging technologies Leader: Professor Andrew Whittaker (UQ) CBNS Chief Investigators involved in this research theme: The work of the Imaging Technologies theme presented here was undertaken by the following CBNS Chief Investigators and their teams: Associate Professor Kris Thurecht (UQ); Professor Tom Davis (Monash); Professor Rob Parton (UQ). The research of our themes is broad and contributions are made by others in the CBNS. The CBNS is developing new, ‘intelligent’ imaging agents with predicable and controlled behaviour in vivo and which respond to changes in local biochemical signals. This can facilitate early detection of disease, changes in tissue biology, and progression of disease such as metastatic spread. This CBNS research will lead to safer, more sensitive imaging agents for magnetic resonance imaging (MRI), positron emission tomography (PET), x-ray computed tomography (CT) and ultrasound. Imaging lies at the core of many of the research projects of the CBNS and so the Imaging Technologies research theme supports many of the activities. Importantly, the CBNS is connected to the national network of imaging capabilities, providing an outlet for commercial development and receipt of real-world feedback regarding design requirements. Fluorescence, MRI, X-ray CT and PET agents have led to major advances in our understanding of diseased tissue. Often these are blood flow agents that accumulate in the tissue of origin due to changes in details of circulation. For example, the ‘leaky vasculature’ within cancerous tissue can be taken advantage of to allow permeation and retention of imaging agents in tumours.

However, such agents often cannot be targeted to specific diseases or even specific tumours, and are poor at detecting the early stages of disease and/or small tissue volumes. The programs within the Imaging Technologies theme of the CBNS focus on these challenges, aiming to identify novel, safe and more effective imaging agents. The issues of selectivity, specificity, responsiveness and lifetime are tackled using polymer-based imaging agents. Using a macromolecular strategy allows, for example, superior relaxivity for paramagnetic MRI contrast agents (thereby addressing sensitivity issues) and also provides control over nanostructure and therefore in vivo lifetimes and clearance. Specificity can be achieved by modifying polymeric imaging agents with bio-recognition molecules such as antibodies in conjunction with other programs within the CBNS. In collaboration with the Delivery Systems theme, imaging particles are made responsive using molecular beacons which can be interrogated to provide information on cell function or local metabolic processes. Simple examples of this are agents that can

be designed to respond to changes in temperature, pH, redox potential, hypoxia, etc. Imaging agents responsive to oxygen tension, or specific ions, can be envisaged and polymeric architecture provides very distinct advantages in the design of these molecules. The key scientific goals of the Imaging Technologies theme are: • to develop imaging agents with high specificity for particular tissue types and diseases, specifically determining the most effective targeting strategies; • to design imaging agents that are responsive to biological triggers, so that certain pathologies, for example hypoxia, inflammation and cancerous tissue can be identified; • to investigate how the structure of imaging agents influences the lifetime in vivo, so that clearance of the imaging agent can be controlled to ensure appropriate cellular uptake and removal of the agent from the body; and • to investigate the design requirements to optimise sensitivity of imaging agents, to allow early detection of disease and to identify the margins of diseased tissue.

Nanoparticles for medical imaging In order to provide effective patient treatment, accurate imaging of disease physiology and biology is a necessity, particularly in the field of oncology. Currently, a variety of imaging modalities are available for disease staging and monitoring, including ultrasound, CT, MRI and PET. Whereas ultrasound and CT mainly focus on visualising anatomy, MRI also offers the possibility to provide physiological information. Likewise, PET is unprecedented in its ability to acquire biological information. As such, both MRI and PET – increasingly being combined into one apparatus – are emerging as multi-potent imaging modalities and offer great possibilities

for medical imaging and clinical research. Members of the CBNS Imaging Technologies team have published a major review on multimodal agents in 2016.1 To optimally benefit from the favourable features of both imaging techniques, CBNS researchers have been incorporating MRI and/ or PET functionalities into novel (radio) pharmaceutical nanoparticles. Nanoparticles are a highly desirable platform for the development of socalled ‘intelligent’ imaging agents. Intelligent imaging agents are sensitive to microenvironmental-dependent

stimuli, such as subtle changes in pH or temperature, and may have tuneable properties that enable disease- or tissue-specific targeting. Advantageous properties of nanoparticles include their ability to become functionalised with one or more targeting molecules (e.g. antibodies) at a wide range of densities, their potential to enhance imaging intensity by including a large number of imaging moieties within a single nanoparticle at predetermined ratios and their tuneable size and shape which optimises biodistribution and enhances accumulation via he enhanced permeability and retention effect in tumours.2

CBNS Annual Report 2016 27

Within CBNS, researchers are developing novel theranostic nanoparticles, in which both therapeutic (e.g. drugs) and diagnostic components (e.g. MRI contrast agents) are being combined. CBNS researchers have developed a novel multimodality imaging probe in collaboration with ANSTO (Sydney), in which the clinically applied contrast agent gadolinium is combined with radio-iodine using a nanogel star polymer as a platform. This probe aims at improving the sensitivity and specificity of current clinical imaging modalities and simultaneously enabling multimodality imaging using hybrid PET/MRI scanners. Furthermore, nanogel star polymers were used for the incorporation of the radionuclide copper-64, in order to investigate the benefits of applying nanoparticle-based systems in nuclear medicine. Linear polymers were synthesised for the controlled delivery of an existing, but suboptimal, hypoxia PET tracer. Using this approach, the signal-to-noise ratio could be improved by only releasing the PET tracer at the tumour site upon changes in microenvironmental pH, whereas the PET signal in unaffected tissue remains minimal. Such systems aim at improving clinical decision making, e.g. radiotherapy dose planning, based on tumour biology. This work is also performed in collaboration with ANSTO (Sydney) and our partner investigators at the Memorial Sloan Kettering Cancer Center (New York). Previously, CBNS researchers have designed intelligent hybrid imaging probes that facilitate monitoring of nanoparticle drug release via the incorporation of responsive elements.3 Responsiveness is based on the physiological changes in the tumour microenvironment (e.g. increased acidity or level of reactive oxygen species). Using silica-based nanoparticles, functionalised with a gadolinium component and grafted with polymers containing such pH-sensitive elements, CBNS researchers are focusing on monitoring these physiological changes. Furthermore, a class of inorganic materials, known as polyoxometalates, was also being investigated for their potential in responsive MR imaging. By tuning the properties of the polyoxometalates using polymers, such imaging agents form a new class of responsive imaging agents, which will offer new opportunities for clinical imaging.

28 CBNS Annual Report 2016

Figure: Gd-DOTA-labelled nanoparticles with various morphologies: micelle, worm-like micelle and vesicle.

MRI contrast is dependent on nanoparticle shape and architecture. Therefore, CBNS researchers have developed novel nanoparticles with different shapes and sizes containing MRI contrast agents. Depending on which architectural characteristics provide the best MRI properties, such nanoparticles are expected to benefit MR angiography and cancer theranostics.4 In a collaboration with CSIRO (Melbourne) and QIMR Berghofer (Brisbane), CBNS researchers have developed a novel imaging agent for the detection of high grade glioma. Glioma is the most lethal of primary brain tumours and disproportionately affects younger people compared with other malignancies. The nanoparticles combine an antibody to the EphA2 receptor, which is overexpressed in a number of cancers including glioma, and the PET radioisotope, 64Cu. We have shown that the imaging agent delineates tumour boundaries in primary xenograft mouse models of glioma and accumulates selectively in the tumour. Significantly, tumour-to-brain contrast is significantly higher using our agent compared with the current ‘gold standard’, 18F-FDOPA PET, and the boundary delineation is comparable to that obtained using Gd contrastenhanced MRI. Theranostic agents based on these nanoparticles are currently being developed.

Multimodal molecular imaging is having a profound effect on the diagnosis of disease and as an investigative tool in biomedical research. The team at the University of Queensland have engineered multifunctional hyperbranched polymers containing iodine and fluorine and demonstrated their application as CT/19F MRI bimodal imaging contrast agents. This is the first nanoparticle system to combine these two modalities. Hyperbranched iodopolymers (HBIP) composed of 2-(2’,3’,5’-triiodobenzoyl)ethyl methacrylate (TIBMA), oligoethylene glycol methyl ether methacrylate (OEGMA) and a degradable crosslinker were synthesised by reversible additionfragmentation chain transfer (RAFT) polymerisation. The resulting HBIPs were chain extended with OEGMA and 2,2,2-trifluoroethyl acrylate (TFEA) to form hyperbranched iodopolymers containing 19F (HBIPFs). The team was successfully able to acquire images of solutions of the polymers using both micro-CT and 19F MRI. These results suggest that the HBIPFs are attractive candidates for CT/19F MRI bimodal imaging.6 Nanoscale, 2016, 8, 10491; Adv. Drug. Deliv. Rev., 2010, 62, 1053; Adv Healthc. Mater., 2015, 4, 148; Chem. Sci. 2014, 5, 715; ACS Nano, 2013, 7, 10175; 4 Polym. Chem., 2016, 7, 7325-7337; 5 Molecular Imaging, 2015, 14, 1535; 6 Polym. Chem., 2016, 7, 1059. 1 2 3

Figure: Structure of unique 19F MRI-CT multimodal imaging agent developed by CBNS scientists.

Responsive imaging agents Stimuli-responsive imaging agents have excellent potential for the early detection and understanding of the biology of cancerous tissue. In particular, imaging agents that respond to changes in the ionic makeup of cells can potentially allow monitoring of both the development of cancer and the efficacy of new therapies. The group within the AIBN developed a series of copolymers of oligo(ethylene glycol) methyl ether methacrylate (OEGMA) and 2,2,2-trifluoroethyl acrylate (TFEA) (poly(OEGMA-co-TFEA)) which change dimensions in the presence of salt. This dimensional change can be monitored through changes in 19F NMR relaxation

parameters. The group used highresolution NMR and molecular dynamics to develop a deep understanding of the changes in conformation experienced by these ion-responsive agents. The polymers were readily taken up by normal breast cells and cancerous (MCF-7) cells and pronounced differences in their relaxation behaviour in these two cells types were observed. Experiments in animal models of the disease are underway.1 In a joint research effort between CBNS researchers and collaborators at the University of Nottingham (CBNS PI Alexander), novel probes to recognise

specific nucleic acids have been developed. The diagnosis component of these materials has been based on 19F MRI, where a significant shift in signal intensity has been observed depending on whether a specific nucleobase is present in solution; this is driven by structural changes in the molecules depending on variability in hybridisation potential. These highly specific and sensitive probes are now being further developed for in vivo recognition and sensing.2 1 2

ACS Sensors, 2016, 1, 757; Polym. Chem., 2016, 7, 2180.

Figure: In vitro 19F NMR measurements. (a) 19F NMR spectra of the poly(OEGMA-co-TFEA) copolymer in water, MCF-12A normal cells and MCF-7 cancer cells. The multiple peaks in the 19F NMR spectrum arise from different sequences of TFEA in the copolymer. (b) 19F NMR T2 relaxation curves and fits to exponential decays for the copolymer in water, normal breast (MCF-12A) and cancer cells (MCF-7).

Theranostic devices A key area of focus for the CBNS is understanding how to control nanobio interactions. Such control importantly allows the directing of materials to specific tissue. Using animal models in which multiple different tumourtypes are grown simultaneously, CBNS researchers have shown that nanomedicines can be developed that selectively show high affinity for one or the other tumour type, depending on expression levels of specific proteins. In particular, prostate cancer was used as a model system and clearly demonstrated that the propensity for a nanomedicine to accumulate within a xenograft tumour was very much driven by target-receptor density, with minimal accumulation due to the so-called enhanced permeability and retention (EPR) effect.1

Figure: Fluorescence images showing distribution of nanomedicine targeted to prostate specific membrane antigen (PSMA) overexpressed on LNCaP cells (blue) and nanomedicine targeted to EphA2 overexpressed on PC3 cells (fire scale). Both nanomedicines were co-injected into a single mouse bearing both tumours; clear selective accumulation is observed for the nanomedicines in tumours that express their selective receptors. 1

Parm. Res., 2016, 33, 2388.

CBNS Annual Report 2016 29

Imaging of the cell New methods to dissect endosomal structure and function We recently developed a new method for cytoplasmic protein localisation utilising a genetic tag, Apex, that is compatible with electron microscopy (EM) fused to a GFP-binding protein.1 In 2016 we have applied these methods to study the effect of specific mutations in endocytic proteins associated with Parkinsonâ&#x20AC;&#x2122;s disease2 and we have further developed these methods in a number of directions. Firstly, we have optimised conditions to increase sensitivity of the method. This has

allowed us to detect Apex-tagged proteins at the level of expression of endogenous proteins in genomeedited cells. Secondly, we have further developed systems to allow EM detection of proteins in a model organism, the zebrafish Danio rerio.3 Thirdly, we have developed complementary systems based on an Apex-mCherry nanobody. Fourthly, we have developed a destabilised Apex-nanobody construct that causes degradation of the unbound nanobody and so increases the signal to noise ratio.

New insights into endocytic trafficking Effective drug delivery depends on delivering drugs to the sites in the cell where they are therapeutically active. The goal of this project is to gain a fundamental understanding of how nanoparticles are trafficked in cells. In particular, we focus on understanding how nanoparticles and their cargo are internalised, trafficked in the endosome and trafficked from the endosome into the cytoplasm (i.e. endosomal escape). We have focused on fundamental aspects of trafficking to the endosome and the role of endosomal structure in endosomal function. We have previously identified the crucial regulator of endosomal trafficking, Rab5, and its effector EEA1. We have now shown using state of the art electron microscopy that EEA1 forms long filaments that extend out from the surface of the endosome. These filaments bind Rab5 on incoming vesicles causing a conformational change in the EEA1 that allows vesicle fusion.1 1

Nature, 2016, 537, 107.

Figure: Endosomal trafficking via Rab5 and EEA1. Incoming vesicles carrying cargo from the cell surface are captured by the endosomal EEA1 filaments (green) through interaction with Rab5 (blue). The EEA1 filaments change conformation to bring the vesicles in contact with the endosome surface to allow efficient membrane fusion and delivery of cargo into the endosome. Illustration courtesy of Mario Avellaneda and Marino Zerial, MPI, Dresden. See reference 1 for further details.

30 CBNS Annual Report 2016

These applications are restricted to cytoplasmic proteins. We have therefore extended this approach to lumenal/ extracellular proteins by generating monovalent peroxidase-labelled fluorescent proteins. Uptake of the extracellular marker protein allowed correlation with novel fluorescent methods to determine mobility of the marker in cells and allowed detailed analysis of their properties in specific compartments.4 Dev. Cell, 2015, 35, 513; J. Biol. Chem., 2016, 291, 18283; Zebrafish, 2016, 13, 232; 4 J. Cell Biol., 2016, a215, 277. 1 2 3

Key goals for 2017 Imaging technologies are enabling sciences, and activities within the theme are highly complementary with both the Delivery Systems and the Sensors and Diagnostics Themes. The challenges ahead in imaging lie in two directions: development of smarter (responsive) and more sensitive agents that can be applied across multiple imaging modalities; and maximising the synergistic combination of imaging and delivery functions into a single nanoparticle system. Of course Imaging Technologies is a fundamental tool in addressing important biological challenges, such as understanding biological distribution, cellular uptake and trafficking, tumour penetration, etc. In 2017 our main goals are to:

1. Design and test in vivo novel

responsive USPIO contrast agents.

2. Prepare theranostic agents which respond to elevated levels of reactive oxygen species.

3. Demonstrate MRI agents that enable high sensitivity tracking of stem cells.

4. Demonstrate bimodal PET/MRI probes employing a range of clinically applied radioisotopes.

5. Develop an MRI probe that enables in vivo monitoring of nanoparticle drug release.

6. Develop a theranostic probe that combines radio-sensitising and imaging moieties within a single nanoparticle.

7. Optimisation of methods to allow

8. Segmentation and VR visualisation

of metastasising cancer cells in vitro (with Professor Maria Kavallaris (UNSW)) and in vivo.

9. Quantitative mapping of the entire endocytic system â&#x20AC;&#x201C; clathrindependent and independent â&#x20AC;&#x201C; by 3D electron microscopy.

single molecule detection, mapping and quantitation of specific proteins within whole cells.

Raheleh Pardekhorram, PhD Candidate (UNSW)

CBNS Annual Report 2016 31

Signature project: A material scientist’s guide to the cell Leaders: Professor Rob Parton (UQ) and Dr Angus Johnston (Monash) CBNS Chief Investigators involved in this project: Professor Chris Porter (Monash), Dr Nicholas Veldhuis (Monash), Associate Professor Kris Thurecht (UQ), Professor Justin Gooding (UNSW), Associate Professor John McGhee (UNSW)

The big question Can we control the trafficking of nanoparticles inside cells to optimise the therapeutic response of drugs?

Research outline Effective drug delivery depends on delivering drugs to the sites in the cell where they are therapeutically active. The goal of this project is to gain a fundamental understanding of how nanoparticles are trafficked in cells. In particular, we will focus on understanding how nanoparticles and their cargo are internalised, trafficked in the endosomes and trafficked from the endosome into the cytoplasm (ie endosomal escape). These fundamental interactions are poorly understood and by understanding these interactions we aim to engineer the next generation of nanoparticles that can respond intelligently to the cellular environment.

2016 progress The focus of our work in 2016 has been developing better tools to understand nanoparticle interactions with cells, and to understand the fundamental mechanisms governing intra-cellular transport. Research highlights have included: Understanding trafficking pathways Trafficking of endocytic vesicles is an important process that governs the fate of nanoparticles and their therapeutic cargo. In a significant advance, CBNS researchers have reported in Nature in 2016 the mechanism by which these endocytic vesicles fuse with early endosomes. Hair like filaments (Early Endosome Antigen 1 (EEA1)) on the surface of the early endosomes bind to a protein (Rab5) on the surface of the endocytic vesicles. Binding of Rab5 to EEA1 causes the EEA1 to collapse, drawing the vesicle towards the early endosome, enabling fusion of the two compartments. Insight into the mechanism by which subcellular compartments interact and fuse, is likely to help engineer delivery systems that deliver the therapeutic cargo to the optimal location in the cell.1 1 Nature, 2016, 537, 107–111.

32 CBNS Annual Report 2016

3D illustration of cell environment by Associate Professor John McGhee

The effect of particle shape on intracellular transport The size and shape of nanoparticles affects how they interact with cells. Using an innovative pair correlation technique, CBNS researchers probed the rate of transport of nanoparticles in live cells. High aspect ratio nanoparticles (rod and wormlike structures) were found to access the nucleus via passive diffusion, whereas spherical particles (micellar and vesicle structures) showed significantly less accumulation in the nucleus. The addition of peptides that target the nanoparticles to the nucleus (nuclear localisation sequences (NLS)) improved the localisation of the high aspect ratio particles in the nucleus, but did not significantly increase the localisation of the spherical particles. These results suggest that the physical barrier of the nuclear membrane overrides the signalling function of the NLS. These results offer significant insight in the delivery of therapeutics to intracellular compartments, and are especially important for anti-cancer drug delivery and gene therapy.1 1

Improving the quantification of nanoparticle-cell interactions Understanding nanoparticle-cell interactions is critical for engineering effective therapeutic delivery. CBNS researchers have developed a new technique to improve the analysis of nanoparticle association with cells using flow cytometry. A common limitation when analysing flow cytometry data generated with nanoparticles is the low fluorescent signal emitted from the particles. The low signal means that a large number of nanoparticles must associate with the cell before the interactions are detected. Using a new deconvolution algorithm, we have been able to improve the sensitivity of flow cytometry assays by an order of magnitude, compared to traditional analysis techniques. The algorithm also enables hidden populations of cells to be revealed from the autofluorescent cell background.1 1

Adv. Healthc. Mater., 2016, 5, 2333–2338.

Nature Nano., 2017, 12, 81–89.

Key goals for 2017 1. Engineer nanoparticles to target subcellular locations 2. Develop techniques to quantify cellular localisation in live cells 3. Translate the fundamental understanding of cellular processing to the Visualisation Theme to develop VR models of the cell

Signature project: Predictive models of bio-nano interactions Leader: Professor Stephen Kent (Melbourne) CBNS Chief Investigators involved in this project: Professor Tom Davis (Monash), Dr Angus Johnston (Monash), Associate Professor Kris Thurecht (UQ), Dr Simon Corrie (Monash), Professor Nico Voelcker (UniSA)

The big question How can we better understand and predict how nanomaterials interact with cellular environments?

Research outline One of the key challenges associated with translating nanomaterials into vaccines and other therapeutics is understanding how nanomaterial characteristics interact with cellular environments. The development of predictive relationships between structure, function and subsequent physiological response will drive the rational design of novel nanomedicines. These relationships are often determined by the intrinsic characteristics of nanoparticles, such as chemical composition, size, surface charge, architecture, roughness and surface chemistry. Throughout 2016, multiple CBNS collaborations investigated how material properties can affect immune cell-nanoparticle interactions.

Hyperbranched polymers and other nanoparticles to probe immune cell interactions As a model to investigate these interactions CBNS researchers are using well-defined nanomaterials known as hyperbranched polymers (HBPs; Rolfe et al. J. Am. Chem. Soc.). Surface charge was an initial focus of this investigation since they are the dominant physical parameters that dictate the route (absorption, distribution, metabolism and excretion) of polymeric nanocarriers in the human body and whether they can by-pass the numerous biological barriers or obstacles and take effect at the desire locations. The HBPs were evaluated for activation of human immune cells and were found to have a charge- dependent activation of dendritic cells, which are responsible for the immune response to vaccines and pathogens. Positively charged HBPs activated a major dendritic cell subset within human blood, while neutral and negatively charged HBPs had no immunostimulatory effect. Moreover, charge dictated their association with different immune cell subsets. At physiological temperatures, all cell types associated with positively charged HBPs, while negatively charged HBPs selectively associated with cells specialised for pathogen clearance and processing.

Reducing non-specific uptake of nanoparticles is essential for the development of effective drug delivery systems. In one study, we investigated how the surface chemistry of nanoparticles (linear or branched PEG molecules) can be modified to reduce non-specific clearance in human blood (Mann et al. Polym. Chem). In other work, we modified the surface of star polymers (small nanoparticles with drug delivery and imaging potential) to interact with reactive groups (thiols) found on the outer surface of certain cancer and some immune cells. We demonstrated that thiol-reactive star polymers showed increased association with cancer cells and some key cell types of human blood (dendritic cells, B cells and platelets). This represents a non-conventional (i.e. non-antibody) method of targeting small nanoparticles to cells and may lead to improved drug delivery and imaging capabilities. These studies provide us with strategies to predict and evaluate the fate of polymers at whole body and cellular levels, making the application of polymeric materials in vaccine delivery more time and cost effective. J. Am. Chem. Soc., 2014, 136, 2413; Polym. Chem., 2016, 7, 6015-6024.

Understanding the rules of immune cell-nanoparticle interactions A key gap in the field is (a) a consensus on a framework of how to study nanoparticle – cell interactions and (b) a comprehensive matrix to carefully dissect the physico-chemical properties of nanoparticles and how that influences their interaction with immune cells. Chief Investigator Caruso and CBNS researchers Faria and Dr Björnmalm published a thoughtful article on this fundamental gap in the field during 2016. The CBNS is perhaps the only group worldwide with the collective range of materials, immunology and computational biology expertise to address these issues. A range of CBNS researchers across all nodes are now preparing matrices of particles where particular characteristics of the particle are minimally changed, including but not limited to size, charge, surface chemistry, shape, and elasticity. We are now comparing particles headto-head for their ability to be taken up by immune cells and activate immune cells as potential future candidate vaccines. To date we have glimpsed the exciting potential of this work through examination of individual properties, including size, charge and surface chemistry. Figure: Study of the internalisation pathway of nanoparticles into cells. The images show pHlexi particles are internalised into lysosomes. For details see reference: J. Am. Chem. Soc., 2014, 136, 2413; Polym. Chem., 2016, 7, 6015-6024.

Key goals for 2017 1. Develop a deeper understanding of the rules by which immune cells interact with a wide range of nano-engineered particle systems and physical properties (Signature Project).

2. Understand the balance between efficient targeting with surface antibodies and the potential for increased non-specific uptake by immune cells.

3. Study matrices of particles for their capacity to interact with immune cells. CBNS Annual Report 2016 33

Signature project: Measuring the â&#x20AC;&#x153;magic bulletâ&#x20AC;?: Quantifying active targeting vs the EPR effect Leader: Associate Professor Kris Thurecht (UQ) CBNS Chief Investigators involved in this project: Professor Maria Kavallaris (UNSW), Professor Frank Caruso (Melbourne), Professor Stephen Kent (Melbourne), Professor Ben Boyd (Monash), Professor Nico Voelcker (UniSA)

The big questions Does targeting nanomedicines to cellular proteins enhance accumulation and therapeutic efficacy compared to nanomedicines that rely on the enhanced permeability and retention (EPR) effect alone? Can we quantify the direct contribution that a targeting ligand plays on tumour accumulation and biodistribution?

Research outline With only one exception, FDA-approved nanomedicines rely on the EPR effect to enhance accumulation within diseased tissue. This is despite the fact that there is significant and extensive evidence showing that targeted nanomedicines show enhanced binding and uptake into cells that overexpress the target protein. This is most likely due to the inability to clearly define the benefits associated with spending additional resources to develop complex targeted

Nanoparticle alone

nanomaterials, when the untargeted analogue may fulfil the required criteria. The ability to directly assess the impact that a targeting ligand can have on ultimate tumour accumulation will clearly be of benefit throughout the whole development process of new nanomedicines, and will undoubtedly rely on numerous factors, including size of nanomedicine, density of ligand, immunogenicity of the carrier etc. Utilisation of the vast expertise within the CBNS, along with ability to study many different classes of nanomaterials that are developed by CBNS groups, provides an excellent opportunity to investigate this phenomenon through a systematic and rational approach. Through the development of new animal models, the accumulation and interaction of nanomedicines with the tumour environment can be interrogated using advanced molecular imaging techniques, informing on design criteria for next generation targeted nanomedicines. Importantly, this will be of significance to both clinical and commercial partners.

Spleen

Tumour

EphA2-targeted construct Low-expressed protein

2016 progress During 2016 CBNS researchers explored various methods for assessing the effect of targeting ligand on tumour accumulation, and whether this actually led to improved outcomes. The overarching theme was very much focused on whether the added benefit of increased binding to tumour cells (often demonstrated using in vitro assays) could overcome the increased immune recognition of the nanomaterials under study (owing to the often proteinaceous corona of targeted nanomaterials which decreases their stealth like properties). An important example of such a system is large PEGylated nanomaterials that have been synthesised via layer-by-layer technology. These materials have a welldefined size with structured presentation of functional groups to the biological surface. In a multi-group collaboration across the CBNS, researchers used bispecific antibodies1 to investigate how three different nanomaterials

EGFR-targeted construct Over-expressed protein

Figure 1: Distribution of different nanomedicines within tumour bearing mice. (Materials provided by Frank Caruso (Melbourne); Antibodies and imaging provided by Kris Thurecht (UQ); antibody binding by Stephen Kent (Melbourne))

34 CBNS Annual Report 2016

Figure 2: PET-CT image showing Cu-64 labelled nanoparticles targeted to breast cancer. Orthotopic tumour is grown in the mammary fat pad of female mice. Image shows accumulation of nanoparticle within the tumour 24 hours post i.v. injection. (Frank Caruso (Melbourne); Kris Thurecht (UQ)

accumulated in a xenograft model of breast cancer in mice. The tumours are known to show high expression of epidermal growth factor receptor (EGFR), and hence it was chosen as a suitable target to investigate targeting vs EPR effect. As shown in Figure 1, the PEGylated nanomaterials alone showed minimal accumulation in the tumour over 24 hrs (this is a measure of the pure EPR effect of long circulating, stealthy materials). When the nanomaterial was decorated with bispecific antibodies against a protein marker that is only minimally expressed on the breast cancer cell line (the ephrin subfamily – EphA2), only minimal accumulation was observed.

However, when the EGFR-targeting bispecific antibody was utilised, increased accumulation was observed. Of interest in this study however, was the change in accumulation in organs related to phagocytic clearance. In particular, the stealthy PEGylated nanomaterial that was not targeted showed minimal spleen signal (marked in Figure 1), while those that were decorated with the antibody proteins for targeting showed significant spleen signal. This highlights one of the key directions that this Signature Project will address in the coming year; maximising tumour accumulation, while minimising immune recognition. In order to further validate the distribution of nanomaterials within the tumour microenvironment, CBNS researchers also investigated new approaches to visualise the nanomaterials at higher resolution in vivo. Using recently acquired technology, multispectral optoacoustic tomography was used to investigate where nanomedicines distribute within a tumour as a function of oxygenated and deoxygenated regions. This gives insight into the propensity and potential for large nanomedicines to diffuse and propagate throughout a complex tumour environment following accumulation within tumour tissue. An example is shown in Figure 3. See also: Adv. Healthc. Mater., 2016, 5(16), 2055-2068.

Key goals for 2017 1. The initial concept of this Signature Project was to investigate mechanisms

Figure 3: Real-time multispectral optoacoustic tomography of a hyperbranched polymer targeted with an EphA2 bispecific antibody (green) in a subcutaneous prostate tumour. Oxygenated (red) and deoxygenated (blue) blood, also imaged simultaneously in real-time, show highly vascularised and hypoxic regions.

of quantifying active targeting vs the EPR effect through judicious choice of model and nanomaterial systems. This will be further explored by expanding the panel of nanomaterials to include those that might be expected to enhance the EPR effect to see if that can be effectively predicted using the 2-compartment model that has been used thus far.

2. One of the key factors that drive the improved accumulation of

nanomaterials in tumours is optimising the trade-off between direct cellular binding (targeting) and minimising immune response (stealthiness). In 2017, one of the key directions will be to develop new systems that can address this issue through informed design.

3. Future data will be correlated with the complementary Signature Project investigating targeted nanomedicines to tumours within the CBNS.

CBNS Annual Report 2016 35

Signature project: Isolating viable single diseased cells Leaders: Professor Justin Gooding (UNSW), Dr Stephen Parker (UNSW) CBNS Chief Investigator involved in this project: Professor Maria Kavallaris (UNSW)

The big questions How does cellular heterogeneity affect the progression of a disease and prognosis/treatment of a patient?

Research outline Cellular heterogeneity within diseased tissue plays a key role in the progression of diseases which has implications for their therapeutic treatments. Information collected from ensemble measurements can potentially mask these rare but important events, such as the spread of the disease and response to a therapy. The ability to select single diseased cells out of a complex population of cells will clearly be of benefit to better understand the variation of association and internalisation at the single cell level of new nanomedicines that are developed by CBNS groups. Furthermore, by analysing the single diseased cells that show to be vital to the progression of the disease and a low level of nanomedicine internalisation, through methods such as single-cell mass spectrometry and single-cell gene sequencing, a better understanding of these cells can be gained that will shape the development of the next generation of targeted nanomedicines.

2016 was a pivotal year for this project as it progressed from cell line mixtures to whole blood samples. MCF-7 breast cancer cells were spiked into whole human blood before being selectively captured on the modified silicon surface. Single MCF-7 cells were selected and then electrochemically-released from the silicon surface, based on immunostaining. Furthermore, collaborations were established to combine this technique with novel methods to perform single MCF-7 cell mass spectrometry. The lipidome of single MCF-7 cells were determined. Deciphering the lipidome of single cells allows us to construct the lipid membrane of single cells to better

understand nanomedicine internalisation within that cell of interest. The next generation of mass spectrometry will involve transitioning from small molecules to proteins of interest within a predetermined single diseased cell. This information will be complementary to work done previously to determine the gene expression of a predetermined single diseased cell. This work, along with other viability assays such as alamarBlueÂŽ and trypan blue-staining, showed that the process of isolating single diseased cells from a complex sample did not affect their behaviour or genetic make-up.

2016 progress Isolating single diseased cells is possible due to a technique known as light activated electrochemistry, developed in the Gooding lab at UNSW. In this technique, light promotes electrons from the valence band to the conduction band in poorly-doped (10-20 ÎŠ.cm) p-type (boron-doped) silicon. The illuminated region becomes electrochemically active whilst the nonilluminated neighbouring regions remain electrochemically inactive. These silicon surfaces are modified with antibodies via an electrochemically-cleavable linker unit. These antibodies bind to antigens upregulated within the rare target cells. Once the cells are captured on the surface, an individual cell of interest can be viewed under a microscope, and in doing so, activating the region of silicon directly below that cell only. The electrochemical event (the cleavage of the monolayer below the cell) will thus be limited to the illuminated cell only.

36 CBNS Annual Report 2016

Figure: Capturing MCF-7 cells on a modified silicon surface, followed by their subsequent electrochemical release. Microscopy images confirm 87% of cells are released after electrochemically cleaving the underlying monolayer.

Key goals for 2017â&#x20AC;&#x192; 1. The overall plan for this project is to explore heterogeneity within diseased real samples. For this reason, the next step is to test the technique with tumour cells spiked into whole blood and show that single tumour cells can be isolated out of the complex sample. Single cell gene expression can be performed on these tumour cells to explore their heterogeneity.

2. Developing a new immunomagnetic pre-enrichment step that can be

incorporated into this technique will allow a transition to whole blood containing rare and diseased cells. This will be part of a PhD project that will focus on optimising this technique.

3. Growing colonies from these rare diseased cells so that their behaviour, such as the formation of tumours from single circulating tumour cells (CTCs), can be observed to better predict the prognosis of a patient.

4. Treating these tumour-forming CTCs with a range of nanomedicines

developed by the CBNS will be attempted to improve the prognosis of the patient.

Signature project: Nanoparticles in cancer delivery Leader: Professor Maria Kavallaris (UNSW) CBNS Chief Investigators involved in this project: Professor Tom Davis (Monash), Professor Nico Voelcker (UniSA), Professor Justin Gooding (UNSW), Professor Chris Porter (Monash), Associate Professor Kris Thurecht (UQ), Professor Andrew Whittaker (UQ), Associate Professor John McGhee (UNSW), Associate Professor Matthew Kearnes (UNSW)

The big questions

Research outline

How can we best develop biocompatible and effective delivery vehicles for drug or RNAi therapeutics for aggressive cancers?

Cancer remains a significant clinical problem and is a major cause of morbidity and mortality in society. It is well established that the development of resistance to therapies (eg. chemotherapy, radiotherapy) is a major clinical challenge. The propensity of solid tumours to metastasise to distant organs poses another major barrier to cure, since metastatic cancer cells are often refractory to therapy. For both childhood and adult cancers, it is imperative that we develop ways of more effectively treating malignancies that are refractory to standard therapies. Current chemotherapies are generally given systemically and this causes toxicity to healthy normal tissues and rapid clearance of the chemotherapy.

How do the biophysical characteristics such as size, shape or charge influence how effective a drug delivery vehicle will be inside a tumour? Can we improve our understanding of the impact of changes to tumour stroma on nanoparticle penetration and drug delivery? Can we develop delivery vehicles to target micrometastatic disease where blood vessels within the tumour are not well formed?

As chemotherapy is given at maximum tolerated doses, even small levels of chemotherapy resistance within a tumour means doses for patients cannot be increased due to unacceptable toxicity. Nanomedicine (medical application of nanotechnology) has enormous potential to revolutionise cancer therapy through the development of biocompatible and biodegradable drug and gene delivery systems. Through development of effective drug delivery vehicles, nanomedicine has the potential to lead to increased drug delivery to tumours and improve treatment outcomes. The extensive expertise within the CBNS from nanomaterial design, biodistribution, biological and animal models places us in an ideal environment to advance our knowledge of nanomaterial design for medical applications.

Figure: A schematic diagram showing the structure and synthetic steps required to produce different star-POEGMA polymers.

CBNS Annual Report 2016 37

Figure: Biodistribution and gene-silencing activity of star 3-βIII-tubulin siRNA in orthotopic pancreatic tumors in mice. (A) Ex vivo fluorescent images of heart, lungs, liver, spleen, kidney and orthotopic pancreatic tumors from mice injected (via the tail vein) with PBS, fluorescent siRNA (AlexaFluor-647), or star 3-fluorescent siRNA (AlexaFluor-647). Organs were collected and imaged at 1, 4, and 24 h postinjection. (B,C) Confocal images of frozen sections of orthotopic pancreatic tumors showing the presence of fluorescent siRNA (red) in tumor tissue in mice administered (via the tail vein) with star 3-fluorescent siRNA (AlexaFluor-647), 24 h postinjection. Fluorescent siRNA was extravasated from the tumor vasculature into the surrounding tumor cells. Mice injected with fluorescent siRNA (AlexaFluor-647) alone served as controls. Fluorescent siRNA (red) and nuclear DNA (blue), tumor vessels (green) (white arrows indicate the location of siRNA). (D) Graph showing knockdown of βIII-tubulin mRNA expression in orthotopic pancreatic tumors in mice 24 h after the final injection with star 3-βIII-tubulin siRNA (4 mg/kg). Mice injected with star 3-control siRNA served as controls (n = 3–4 mice/ group, *p < 0.01). (E,F) Western blot and immunohistochemistry staining from 2 individual mice showing reduced βIII-tubulin protein expression in orthotopic pancreatic tumors in mice injected with star 3-βIII-tubulin siRNA (4 mg/kg) 24 h after the final injection. Mice injected with star 3-control siRNA served as controls. GAPDH was used as a protein loading control.

2016 progress Delivery vehicles for siRNA Cancer is a genetic disease that is associated with mutations, changes in expression or loss of genes. Approximately 90% of cancerassociated genes cannot be targeted with small molecule inhibitors. However, an evolutionarily conserved mechanism of controlling (“turning off”) gene expression is called RNA interference (RNAi). Short interfering RNA (siRNA) can be chemically synthesised and can turn off specific target genes. A major challenge with using RNAi, however, is that it cannot enter cells without a delivery vehicle. To address this challenge CBNS researchers have developed a star-polymer-based siRNA delivery system to deliver siRNA and

38 CBNS Annual Report 2016

silence cancer genes that affect growth and chemosensitivity. Pancreatic cancer is one of the most lethal of cancers as it is often diagnosed at advanced stage disease, can rarely be surgically removed and is poorly responsive to chemotherapy or radiotherapy. Five-year overall survival rates are less than 5% and there is an urgent need to identify effective treatments for this cancer. Pancreatic cancer is a highly stromal tumour and chemotherapy and radiotherapy are poorly effective against these tumours. TUBB3/βIII-tubulin is part of the cytoskeleton of cells and is abnormally expressed in a number of epithelial cancers including pancreatic cancer. It is strongly linked with aggressive disease and chemoresistant disease. To date, there are no small molecule

inhibitors that can target TUBB3/ βIII-tubulin so we developed an RNA interference (siRNA) gene silencing approach. To address the RNAi delivery challenge, CBNS researchers have developed a star-polymer-based siRNA delivery system to deliver siRNA and silence TUBB3/βIII-tubulin which is overexpressed in cancer cells. A panel of Star-polymers with different charges and polymer content were developed and evaluated in cancer cells. The StarsiRNA delivery system could effectively silence gene expression, sensitise cells to chemotherapy and inhibit cell growth in pancreatic cancer cells in vitro. Star-polymer siRNA nanoparticles biodistribution studies in tumour-bearing mice showed that the siRNA-loaded nanoparticles could penetrate the complex stromal rich pancreatic tumours

Figure: siRNA binding efficiency and cell uptake of star-POEGMA-siRNA complexes in pancreatic cancer cells. (Aâ&#x20AC;&#x201C;C) Agarose gels showing a fixed concentration of free siRNA (siRNA, 60 ng) (lane 1) or when complexed to increasing amounts of star 1, star 2, star 3 or star polymer without POEGMA (star) (8:1â&#x20AC;&#x201C;30:1 w/w ratio with siRNA) (n = 3 individual experiments). (D) Confocal microscope images demonstrating cell uptake of fluorescently labeled-siRNA (green) complexed to star 1 (panel I), star 2 (panel II) or star 3 (panel III), (Blue, nuclear DNA, DAPI stained). Cells were stained with lysotracker red to stain for lysosomes. Panels IV, V, and VI are high power (zoomed) confocal microscope images showing that star 1- and star 2-siRNA readily colocalize with endosomes (yellow-orange indicated by white arrows) compared to star 3-siRNA (white arrows indicate free siRNA, green) in MiaPaCa-2 cells.

in vivo. However, a key challenge in the design of star polymers is there efficacy in vivo. Using an orthotopic model of pancreatic cancer we demonstrated that the star polymers were biocompatible and were effectively taken up by the tumours resulting in potent gene silencing in vivo. The star polymer siRNA delivery system is an effective therapeutic strategy for the treatment of pancreatic as well as other cancers that aberrantly express this gene or non-targetable genes. Delivery vehicles for chemotherapy Neuroblastoma is the second-most common solid tumour in children. Neuroblastoma is classified into three risk groups, with the most aggressive high-risk subtype characterised by a significant propensity to metastasise. High-risk neuroblastoma patients represent half of all new neuroblastoma cases each year and have a poor prognosis of less than 50% survival. Children presenting with high-risk neuroblastoma tumours undergo invasive and toxic medical procedures during treatment, which can severely impact their quality of life. Even if treatment is successful, they often suffer from life-long consequences of the aggressive therapy. There is, therefore,

an urgent unmet need for new therapies, which circumvent the biological barriers to deliver therapeutics, enhance conventional treatments specifically at the tumour site, and reduce the nonspecific toxicity to healthy tissue. Our CBNS team has recently developed a unique platform of antibody-coated and drug-loaded porous silicon nanoparticles, which actively target neuroblastoma cells through binding to cell-surface receptors specific to these cancer cells. Building on these results, we have

been performing preclinical studies to investigate the targeting and efficacy of drug-loaded and antibody-coated porous silicon nanoparticles in a panel of neuroblastoma cells. Once these are completed we plan to move our studies to our preclinical models of orthotopic and metastatic human neuroblastoma. These preclinical studies are essential to provide proof-of-concept and advance the clinical development of our antibody-coated and drug-loaded porous silicon nanoparticles.

Key goals for 2017â&#x20AC;&#x192; 1. Advance the development and design of the star polymer siRNA delivery

system by attaching targeting moieties and determining efficacy in vitro and in vivo.

2. Determine the biodistribution and fate of the different star polymer siRNA delivery systems in othotopic and metastatic models of cancer in vivo.

3. Evaluation of the dose-effect relationship and biodistribution of the

drug-loaded porous silicon nanoparticles in vivo in a human neuroblastoma xenograft model.

4. Determination of the therapeutic efficacy of antibody-coated and

drug-loaded porous silicon nanoparticles in vivo in orthotopic and metastatic human neuroblastoma models.

CBNS Annual Report 2016 39

Signature project: Visualisation â&#x20AC;&#x201C; journey to the centre of the cell (JTCC) Leaders: Associate Professor John McGhee (UNSW), Professor Tom Davis (Monash), Professor Maria Kavallaris (UNSW) CBNS Chief Investigators involved in this project: Dr Angus Johnston (Monash), Professor Rob Parton (UQ), Associate Professor Kris Thurecht (UQ)

The big questions Can the use of 3D computer visualisation provide greater insight in to the mechanisms of internalisation of a drug delivery system? Can Virtual Reality (VR) through the use of Head Mounted Displays (HMD) provide improved modes of communication and education of the scientific data?

Research outline Project rationale The therapeutic effect of most drugs occur in specific locations within the cell, so the intracellular fate of the drug is vital. Therefore, it is important to understand the mechanisms involved in internalisation of the delivery systems, as they play a significant role in the intracellular trafficking and chemical environment that the therapeutic cargo is exposed to. Research in this area is a critical part of the Delivery Systems and Vaccines application areas within the CBNS.

Internalisation of particles and intracellular trafficking are extremely complex processes. Describing such processes, even to scientifically literate audiences, presents a significant challenge to researchers in this field. Visualisation tools available to assist in describing the processes are quite limited. Intracellular processes are often presented as complicated 2D diagrams of whole cells, with schematic representations of proteins, organelles and other intracellular components. Images produced by fluorescence microscopy, whilst rich in data and information, require expert interpretation and would not be readily understood by a student audience. The latest developments in Virtual Reality (VR) and consumer Head Mounted Displays (HMD) such as HTC Vive and Oculus Rift have made it possible for users to be completely immersed in 3D datasets. Pilot research work carried out within UNSW 3D Visualisation Aesthetics Lab (strategically funded through the CBNS) has demonstrated that raw scan data can be postprocessed and displayed in 3D VR.

3D illustration of cell environment by Associate Professor John McGhee

40 CBNS Annual Report 2016

2016 progress JTCC Phase 1 3D visualisation and VR â&#x20AC;&#x201C; Led by Associate Professor John McGhee. In collaboration with Dr Angus Johnston (Monash), Professor Robert Parton (UQ), Mr John Bailey (UNSW), Dr Andrew Lilja (UNSW) JTCC is a multi-disciplinary initiative exploring the visualisation of nanoscience and technology. The work completed in Phase 1 has demonstrated how VR head mounted HMD can be used as a platform to interact with cell image data in a compelling immersive way. Using data from scientific cellular imaging modalities in CBNS nodes, in this case Fluorescence Microscopy and Serial Block Face Scanning Electron Microscopy, the team has been able to capture detailed cross-sectional image slices of molecular structures. The subsequent post-processed 3D data visualisation can potentially provide additional insight for both the scientific and student communities in bionanotechnology.

In 2016, a world first interactive VR cell environment generated from electron microscope (EM) cellular data was prototyped on the HTC Vive HMD. The prototype VR work created in 2016 allows users to see nanoparticle cellular interactions on the surface of the cell as they enter the internal structure. The immersive visual work is a hybrid of surface data and 3D arts-led representation. The prototype generated in Phase 1 illustrates three cellular processes for nanoparticle internalisation: caveolar, macropinocytic and clathrin-mediated. Scientific Imaging – Led by Professor Robert Parton and Dr Nicholas Ariotti (UQ). Raw serial block face scanning electron micrographs are filtered and aligned using the xfalign program in IMOD software. The three-dimensional ISO surface is generated using semi-automated segmentation tools in 3Dmod. The membrane-bound organelles including the plasma membrane, mitochondria, the nucleus, early endosomes and late endosomes are treated as separate objects.

All surfaces of each separate object are manually traced every 10 slices and linear interpolation is utilised to fill the contours between these slices. This process is repeated until an accurate three-dimensional representation of all surfaces of each organelle in the cancer cell is generated.

User Testing and Evaluation – Led by Dr Angus Johnson (Monash). In collaboration Associate Professor John McGhee (UNSW) and Professor Rob Parton (UQ).

Key goals for 2017 1. Phase 2 of the JTCC project will be to explore 3D VR visualisation

of new datasets related to the dynamic within the cell, working with CBNS’ Kavallaris, Thurecht, Parton and Johnston lab groups. We intend to continue the user testing of the VR content with both students and scientific communities within the CBNS. The goal of this research is to establish whether VR immersive data interaction provides benefits as an education tool. We also intend to investigate whether it can also actually contribute to the scientific discovery process with the CBNS.

2. As a continuation of this evaluation of the VR HMD 3D Visualisation

content and interface, we will also be to develop a VR platform to ‘share’ content. The plan is to connect VR 3D cellular data between multiple users and sites simultaneously (VR Cell Arena System) across CBNS nodes. We will install multiple linked VR Arenas at each CBNS node with the intention of creating a multiuser VR visualisation tool.

CBNS Annual Report 2016 41

Signature project: Social dimensions: into the panoply of precision and personalisation Leader: Associate Professor Matthew Kearnes (UNSW) CBNS Chief Investigators involved in this project: Professor Stephen Kent (Melbourne), Associate Professor Kris Thurecht (UQ), Professor Pall Thordarson (UNSW), Professor Justin Gooding (UNSW), Professor Maria Kavallaris (UNSW)

The big questions How can we understand the social dimensions of personalised and precision medicine, at the interface between bio- and nano-technology? What is the significance and implications of notions of targeting, personalisation and precision in bio-nano research for publics, researchers and policymakers? What does precision mean for standardising nano-experimentation? How are current and future patients imagined in health planning and how does this shape nano-medicine?

Associate Professor Matthew Kearnes (UNSW) with Associate Professor Diana Bowman at a UNSW public lecture.

Research outline Our research is examining the connections between policies, technologies and concepts of precision and targeting. As the development of bio-nano technologies, together with advances in precision and personalised medicine, are likely to precipitate profound changes in health care practice, our social science engagement with CBNS research is designed to document the ‘imagined social worlds’ that underpin research in precision and personalised medicine, particularly in areas such as bio-nano sensor technologies, targeted cancer therapies and vaccines. This approach is devised will provide insights into the societal dimensions of predictive and precision technologies and their implications for bio-nano technology

research through collaboration with key CBNS research initiatives. These insights are gleaned from social media monitoring, ethnographic observation of CBNS research, analysis of Australian and US policies, and interdisciplinary workshops bringing CBNS researchers into dialogue with clinicians and health policy makers. While the targeting of therapies, and the tailoring of medical practice to individual patients, has long been a goal of biomedical research, the concept of precision has taken a central place in recent science policy since President Obama announced the Precision Medicine Initiative (PMI) in January 2015. This policy initiative builds on the mapping of the human genome

using advances in computing and big data to process genomic information and progress a molecular-level understanding of disease. The PMI has spurred the creation of several large biobanks, standards for genomic screening and new cancer trials (NCI MATCH). Patient groups, public health hospital administration, information technology companies, and advocates of rare disease have begun using the language of ‘precision medicine’ to variously promote agendas seeking efficient diagnoses, efficient care systems, and therapies targeted at individuals’ genomic and exoposomic profiles. Developments in drug delivery, diagnostics and medical devices, alongside new modes of delivering patient care and augmenting clinical practice and decision-making are the first signs of profound changes in healthcare practices (how and by whom we are diagnosed, treated and cared by), biomedical research, and associated health and innovation policies. Our research will provide insights into how these connections shape the societal reception of bio-nano research as a foundation for targeted and precision biomedical technologies.

2016 progress

Dr Declan Kuch (right) during a lab visit to CBNS researchers. Dr Nick Fletcher and Dr Zach Houston at the UQ node.

42 CBNS Annual Report 2016

Our research has found significant new clusters of discussion around precision that are shaping public and policy agendas around targeting and personalisation. We see an emerging societal debate around notions of equity

in research funding and outcomes, that is visible as clusters on social media commentary and in policy discussions around race. These findings have emerged from the five main streams of our work: Firstly, social media monitoring – focusing on twitter hashtags such as #precisionmedicine this work is examining how online public discourse can be mapped to show clusters of conversation around issues such as patient involvement, race and ethnicity. At the International Nanomedicine conference, we presented a poster with social network analysis of tweets about key issues raised by the initiative’s progress, particularly around how and whom targeted populations are chosen to benefit. Secondly, ethnographic observation – working alongside laboratory researchers to see how metaphors of precision, targeting and personalisation operate in both policy and scientific landscapes. Declan has also commenced lab-based collaborative research with other nodes. This has involved engaging in observational research at Monash, UNSW and UQ laboratories where Signature Project research is being conducted to understand how experiments are conducted and scope existing outreach and collaborations that can be built upon in the future. Thirdly, in our policy analysis we have been examining how Australian and United States health, research and innovation policies compare in their treatment of intersecting discourses of precision, targeting and personalisation. Declan and Matthew conducted a round of key informant interviews with such agencies as the National Institute of Health, California Precision Medicine Initiative and other significant precision medicine proponents in the United States. They found the work of building biobanks in the United States required considerable sociological thinking about participants’ relationships to technology and government by the project developers. For example, whilst military veterans were overwhelmingly happy to provide tissue and blood samples for a dedicated biobank to researchers, the design of the voluntary cohort initiative required active enrolment of different populations based on their concerns about the ownership, control and use of the data. Such concerns are embedded in the chequered history of state-sponsored biomedical research where, as late as the 1970s, minority populations were harmed in unethically conducted studies. Building and maintaining the public value and benefit of research requires careful

Public engagement at the Science in the Cinema event.

and sustained dialogue, considering this history. Care is required especially as new models of patienthood emerge with interactive technologies, social media platforms and patient group-led research funding. Fourthly, we commenced a series of interdisciplinary exchange workshops in December. The Biomedical Futures workshop brought together primary care networks, clinicians, care professionals, CBNS researchers, healthcare administrators, to co-design major public events in NSW, Victoria and Queensland on precision medicine. Fifthly, Targeted Public Engagement Initiatives Associate

Professor Matthew Kearnes and Dr Declan Kuch also presented papers at the combined conference of the Society for Social Studies of Science (4S) and the European Association for the Study of Science and Technology (EASST) in Barcelona in September 2016. Both 4S and EASST are the preeminent scholarly societies in the sociological studies of science and technology. in addition to our presentation at these academic conferences, our work was showcased at the CBNS ‘Science in the Cinema’ held during National Science Week, and at a UNSW Science and Society forum.

Key goals for 2017 1. Build Biomedical Futures workshops into major events. These

events will be multi-disciplinary dialogues to critically assess promises of precision and targeted therapies that bring together CBNS, social science, policy, public health, clinicians, rural and indigenous health. The events will include speculative design, outreach, and potentially pilot ‘targeted health’ research with rural and remote communities.

2. National Academies of Science partnership and events on public

value of innovation. We have initiated a partnership with the Australian Academy of Science to jointly develop major events to inform innovation policy. These events will be developed together with Engineered Quantum Systems Centre of Excellence, The Brain Dialogue and Science and Technology Australia. Series of major public events at Shine Dome, Canberra, to bring scientists, social science and policy makers into to discuss innovation pathways and questions of public and social value. The events will culminate in a White Paper building upon the Social Compact report (from the Chief Scientist) that a ‘deep understanding of societal context’ is vital to the effectiveness of STEM.

3. Outreach Committee. Matthew, Declan and Jason will lead the

formation of an Outreach Committee. The committee will produce events for National Science Week and consult with CBNS scientists on developing workshops in writing and communication.

4. Book project on Precision Medicine that will seek to document the

changing notions of healthcare that are emerging at the interface between advances in medical technologies and biomedical data infrastructures.

CBNS Annual Report 2016 43

Cross-Centre activity: Computational and systems biology Systems biology and modelling in bio-nano science Leader: Professor Edmund Crampin (Melbourne) CBNS Chief Investigators involved: Professor Frank Caruso (Melbourne), Professor Stephen Kent (Melbourne), Professor Tom Davis (Monash), Dr Angus Johnston (Monash), Associate Professor Kris Thurecht (UQ) A major aim of the CBNS is to develop understanding of, and thereby ability to control, the interface between nano-scale materials and biological systems. Rational design of nanomaterials with specific, known bio-interactions would enable applications of bio-nano technology in the clinic, through the ability to predict how the body will respond when exposed to a particular nanomaterial. This remains a major unmet challenge for the field. Understanding which characteristics and properties of nanomaterials give rise to which biological responses would enable a framework for engineering design of nanomaterials with desired and predictable biological interactions. While this ambition remains a long way off, an important initial challenge is development of standards and approaches which will allow us to compare data from different empirical investigations. We are pursuing a number of different projects across the Centre to address this major challenge for bio-nano science. Three key projects that are underway in 2016 in this direction are development of standards for consistent data collection and annotation of nanoparticle properties; methodology for comparison of nano-bio properties for nanoparticles, currently a major gap in the field; and application of these ideas to nanoparticle-whole blood assays to develop predictive models of nanoparticle interaction with fresh blood cells. As part of this ‘convergent science’ approach, we are developing strategies for consistent data collection and annotation, and computational approaches for modelling of data generated in the Centre to better understand, and hence predict, how specific properties of nanoscale materials lead to specific biological responses.

Figure: Accelerating scientific discovery and translational research at the intersection of chemistry, materials science, engineering, and biomedicine through convergent science. Reproduced from: Mattias Björnmalm; Matthew Faria; Frank Caruso; J. Am. Chem. Soc., 2016, 138, 13449-13456. DOI: 10.1021/jacs.6b08673. Copyright © 2016 American Chemical Society

Developing standards and methodology for comparison of nanoparticles Currently it is difficult to reliably compare data generated across different experimental platforms. Combining data across different experiments would allow us to analyse merged datasets in order to identify underlying patterns, which would reveal the properties of nano-materials that dictate their biological interactions. We are developing standards for recording and reporting such experiments, as well as mathematical modelling approaches for merging data from different experimental assays, in order to further this approach.

44 CBNS Annual Report 2016

A mathematical modelling framework to control for sedimentation and diffusion in particle−cell interaction assays

Figure: Controlling for variable association of advanced particle systems due to the effect of sedimentation and diffusion. (a) Scheme of the preparation of core–shell hybrid particles (SC/ MS@PMA) and hollow hydrogel (PMA) capsules. (b) Experimental design of upright, inverted, and vertical orientations to investigate cell association of particles. (c) Scheme of computational modelling to analyse particle sedimentation and diffusion, as well as orientation-dependent cell association of these particles.

In vitro assays are currently the basis for understanding the interactions between particles and biological systems. Commonly, these assays consider nanoparticles held in suspension in fluid above a surface containing cells. A confounding variable for interpreting the results of such assays is the difference between the concentration of particles initially administered, and the amount of the nanomaterial which actually reaches the cells. We have shown that a modelling approach to account for variation due to sedimentation and diffusion of nanoparticles can remove inconsistencies in data arising from such assays, so that the cell association properties of different nanoparticle-cell combinations can more easily be compared.

Reproduced from Jiwei Cui; Matthew Faria; Mattias Björnmalm; Yi Ju; Tomoya Suma; Sylvia T. Gunawan; Joseph J. Richardson; Hamed Heidari; Sara Bals; Edmund J. Crampin; Frank Caruso; Langmuir, 2016, 32, 12394-12402. DOI: 10.1021/ acs.langmuir.6b01634 Copyright © 2016 American Chemical Society

Human blood-nanoparticle interaction assay The human blood-nanoparticle interaction assay provides a very useful testing ground for these ideas of standardisation and model-based data analysis for the Centre, as well as being an important application area for the use of nanoparticles for vaccine delivery. The challenge is to understand what determines the distribution of uptake of nanoparticles between different blood cell types in whole blood. Preliminary work has focused on making sure that results are reproducible, and assessing and controlling sources of variability which may otherwise mask important factors. The range of nanoparticle technologies available in the CBNS provides the opportunity to perform high throughput assays across a wide range of particle sizes, charge, surface chemistry and so forth, in order to generate a data set that may help to reveal which properties influence the observed cellular distributions when incubated in whole blood.

Figure: Human blood-nanoparticle interaction assay: Stephen Kent lab.

Key goals for 2017 1. Extend mathematical modelling framework to evaluate nanoparticle – cell association performance of different nanomaterials

2. Formalise ‘minimum information’ style approach to reporting and annotating nanomaterials and assays across the Centre.

3. Expand measurement and model-based analysis of the interaction of

nanomaterials with blood, and with immune cells in whole blood, across a range of nanoparticles with varying size, charge and surface chemistry available through the Centre.

CBNS Annual Report 2016 45

Strategic Projects – overview In addition to the core research undertaken in the four primary Research Themes and the Centre-wide research, detailed in the previous pages, the CBNS provides funding for activities that meet the strategic objective of the CBNS to increase collaboration whilst extending the research capabilities. Strategic Projects are assessed by all Chief Investigators and are supported through a dedicated fund. The strategic funding is managed centrally and all collaborating organisations contribute part of their ARC funding each year.

• Involve collaboration between at least two nodes;

• Not exceed an annual cost of $100,000.

• Introduce skills, expertise or activities not presently available within the Centre;

In addition to small amounts of funding supporting student attendance at workshop, one major project was funded in 2016. It is detailed in the following section.

When assessing proposals for strategic funding the CBNS Management Committee consider whether the projects:

• Have a duration no longer than two years (although after two years successful projects can apply for additional funding to continue the project);

• Involve collaboration between at least two Chief Investigators, or members of their research groups;

• Address at least one non-research KPI (such as media, public or industry engagement, visitors, training etc); and

46 CBNS Annual Report 2016

Strategic Project: Open Data Fit The Open Data Fit project1 is creating a portfolio of websites that bring together tools and information of relevance to the CBNS as well as the wider international research community. Leader: Professor Pall Thordarson (UNSW) CBNS Chief Investigators involved: Professor Tom Davis (Monash), Professor Ben Boyd (Monash), Professor Edmund Crampin (Melbourne), Dr Simon Corrie (Monash), Professor Maria Kavallaris (UNSW) The project focuses on what we call small scale data, i.e. the small data sets that are the bread-and-butter of research in bio-nano science research, ranging from kinetic measurements (kinetics) and small-angle scattering curves (nanoparticle characterisation) to cell viability measurements (IC50 for drug treatments). Currently, there are no universal tools that encourage scientists to share small scale data effectively, even the results are published. Small scale data from well-designed and well-executed experiments that is part of unsuccessful or unfinished research programs is in most cases never shared with the wider community at all, becoming what is called dark data2, languishing forever in the (digital) archives of individual laboratories around the world. The goal of the Open Data Fit is therefore to shine light on small scale dark data and transform the way scientists share small scale data sets. To this end we designed the Open Data Fit project to assist researchers with their everyday work while at the same time capturing the raw data for effective sharing. The Open Data Fit (http:// opendatafit.org) web portal (tools) we are building will achieve this by allowing the end-user scientist to upload their data and then perform data fit (analysis) on these data sets, while at the same time capturing the raw data, the analysis method and the data analysis results simultaneously in an open access database. The end-user experience is explained further in this YouTube video: https://www.youtube.com/ watch?v=Gc3f85Hhclw) With CBNS support, we built and successfully launched our pilot website supramolecular.org in 2015. This website provides tools for end-users to determine binding constants from NMR, UV-Vis or fluorescence titration data. In the 18 months since this website was launched it had over 12,000 visit with the average session lasting 3 minutes, showing a

high level of engagement from endusers. Moreover, the website has already been cited 11 times in the literature (Scopus).

2016 progress In 2016 our focus was on reconfiguring the backend software to create a robust but expandable framework. Once implemented, the open source framework we developed will allow others to freely contribute their “apps”

or module and connect those at relative east to our framework. At the same time, we are also built modules for spectra deconvolution and IC50 determination that are scheduled for launch in early 2017. With support from the School of Chemistry at UNSW we are also building a basic data analysis (statistics) module to use in teaching of undergraduate courses in Chemistry and related subject. 1 2

Chem. Commun., 2016, 52, 12792-12805; J. Am. Chem. Soc., 2016, 138, 13449-13456.

Key goals for 2017 1. The emphasis of our work in 2017 will be on completing and launching the first modules that utilise our newly built framework. We will also increase our publicity effort to raise the awareness of the project. And building on discussions that we started in 2016, we will continue to negotiate various types of partnerships with potentially interested organisations in order to secure the future and expansion of the Open Data Fit project.

CBNS Annual Report 2016 47

48 CBNS Annual Report 2016

engagement CBNS Annual Report 2016 49

collaborations and partnerships CBNS researchers have a long history of collaboration with other universities, research centres, industry and medical organisations. These collaborations take a wide variety of forms – from formal relationships such as Linkage Projects or contract research, to informal and ad hoc collaborations.

Intellectual Property and Commercialisation Policy The CBNS Intellectual Property and Commercialisation Committee (IPCC) provides advice for IP management to CBNS Chief Investigators. The IPCC comprises the Centre Executive (Director, Deputy Director and Manager), plus the Business Development Manager from the Administering Organisation (Monash). In discussing IP from collaborating organisations the IPCC co-opts the Business Development Manager (or equivalent) from that organisation. Intellectual Property The CBNS does not own project intellectual property (PIP) resulting from CBNS activities. Project intellectual property is owned by the organisation (administering, collaborating or partner) making the major inventive contribution to the IP. Whilst a single organisation assumes control of PIP, in the cases of cross institutional participation in PIP generation, beneficial interest in PIP is determined by relative contributions to IP generation based on cash and in kind contributions to that project (cash is weighted by a factor of 2). The CBNS maintains an Intellectual Property Register, which includes

up to date details of CBNS IP and each organisation’s background IP. It includes: • the owners of each item of background and CBNS IP and the proportion of ownership; • any and all third party interests in background and CBNS IP; and • any patents or patent applications relating to CBNS IP. Commercialisation The organisation owning the PIP supports protection and commercialisation through its IP commercialisation group and meets the cost of protection.

CBNS commercial partners provide real world advice to Centre Chief Investigators but also provide a potential path-to-market and a defined route to impact. As such, industry partners have the right of first refusal to a license to exploit project IP on terms to be agreed. In relation to the commercialisation of PIP, all parties negotiate in good faith to agree on a Commercialisation Lead and the terms of any Commercialisation. The Commercialisation Lead has the right to sublicense PIP in the interests of all parties and the CBNS, without restricting the use of the PIP for research, teaching and scholastic endeavours.

Patent applications, invention disclosures and selected Commerical activities Monash University node Type

Date

Inventors / researchers involved

Summary

Provisional application

23 Feb 2016

Nigel Bunnett

Inhibitors of β-arrestin-neurokinin 1 receptor interactions for treatment of pain

Invention disclosure

26 Apr 2016

Ben Boyd, Wye-Khay Fong, Stefan Salentinig

A means of identification of humanised infant formula, or other milk substitutes

Invention disclosure

26 Apr 2016

Ben Boyd, Jessica Lyndon, Nick Birbilis*

Magnesium orthopaedic implants with controlled drug delivery

Provisional application

20 May 2016

Nigel Bunnett

Inhibition of pain using endocytic inhibitors and endosomally targeted antagonists of protease-activated receptor-2. The invention relates to compounds that inhibit endosomal par2 signalling and endocytosis of the receptor and their use for treating protease-evoked pain.

PCT application

8 Sep 2016

Chris Porter, Jamie Simpson, Natalie Trevaskis, Tim Quach, Sifei Han, Luojuan Hu

Enhanced lymph-directing prodrugs. The current invention relates to the design and application of novel lipid mimetic prodrugs to both promote drug transport to the lymphatic system and to enhance reversion to the parent drug, either within the lymphatic system or systemically.

Invention disclosure

20 Sep 2016

Nigel Bunnett, Bernie Flynn, Luigi Aurelio*

Novel PAR2 antagonists for treatment of GI diseases

Invention disclosure

11 Oct 2016

Nigel Bunnett, Tom Davis, Michael Nanoparticle encapsulation to target G protein-coupled receptors in Whittaker, Nicholas Veldhuis endosomes

Provisional application

21 Dec 2016

Nigel Bunnett, Chris Porter

Targeting endosomal GPCRs for the treatment of chronic disease

International patent application

8 Sep 2016

Chris Porter, J Simpson, NL Trevaskis, Tim Quach, S Han, L Hu

Lymph directing prodrugs

*Inventors / researchers from other institutions or faculties may also have contributed but are not listed

Other commercial activity: Research services were performed for Noxopharm Pty Ltd (Trevaskis), Gordagen Pharmaceuticals Pty Ltd (Porter), Clarity Pharmaceuticals Pty Ltd (Bunnett) and WRS Therapeutics Pty Ltd (Trevaskis).

50 CBNS Annual Report 2016

The University of New South Wales node Type

Date

Inventors / researchers involved

Summary

Invention disclosure

1 Nov 2016

Pall Thordarson, Kristel Tjandra

Doxorubicin peptide conjugate. This invention concerns a novel highly active doxorubicin peptide conjugate that is more active against certain cancer cells than doxorubicin itself.

Published Patent

23 Jun 2016

Maria Kavallaris, Pei Pei Gan, Joshua Adam McCarroll

Methods for detecting and modulating the sensitivity of tumor cells to anti-mitotic agents and for modulating tumorigenicity

Invention disclosure

1 Mar 2016

Justin Gooding

Nanoparticle-based nanopore sensor for biomolecular sensing

Invention disclosure

19 Sep 2016

Justin Gooding

Ultrasensitive electrochemical sensors

Provisional application

1 Mar 2016

Justin Gooding

Photosensitive printing composition

Provisional application

30 May 2016

Maria Kavallaris

Copper-dependent chemotherapeutics

Other commercial activity: Research services were performed for RR Medsciences Pty Ltd (Thordarson), Clockwerk Pty Ltd (Thordarson) and Ettason Pty Ltd (Thordarson).

The University of Queensland node Type

Date

Inventors / researchers involved*

Summary

PCT filing

5 Feb 2016

Kris Thurecht, Christopher Howard, Stephen Mahler

Targeting Constructs for Delivery of Payloads”. This invention describes a new approach for linking proteins to synthetic polymers for targeted imaging and therapy.

Published Patent

7 Jan 2016

Idriss Blakey; Ya-Mi Chuang; Andrew Whittaker; Kevin Stanley Jack

A method for modifying line edge roughness on a lithog.- produced feature in a material, the method comprising applying a block copolymer to an area on the feature having line edge roughness, the block copolymer comprising a charged hydrophilic polymer block and a non- charged hydrophilic polymer block.

Published Patent

12 July 2016

Simon Corrie, Mark Kendall

Analyte detection using a needle projection patch. Apparatus for use in detecting analytes in a subject, wherein the apparatus includes a number of projections provided on a patch, such that applying the patch to the subject causes at least some of the projections to be inserted into the subject and target one or more analytes and a reagent for detecting the presence or absence of analytes.

*Inventors / researchers from other institutions or faculties may also have contributed but are not listed

Other commercial activity: UQ has been actively involved in research contract work with InterK Peptide Therapeutics, Minomic LTD, Clarity Pharmaceuticals and Samyang Biopharmaceuticals Corp. We also were awarded a Linkage Grant with InterK Peptide Therapeutics.

The University of Melbourne node

Type

Date

Published Patent

8 Dec 2016

Inventors / researchers involved* Frank Caruso, Junling GUO, Hirotaka EJIMA

Summary Glucose sensitive phenylborate acid capsules for insulin delivery. Capsules and methods for making the same are of particular interest in the development of stimuli-responsive capsules for applications including cell encapsulation, advanced drug delivery, biomedical diagnostics, micro-reactions, and the formation of biomimetic protocells. “Smart” capsules have previously been prepared using layer-by-layer techniques involving multistep assembly. The present invention relates to capsules and the method for making capsules having a boronate linked organic network layer which are responsive to externally applied stimuli.

Other commercial activity: CBNS researchers from the Melbourne node are engaged in a strategic alliance with Sanofi Pasteur, the vaccines division of Sanofi. The node also received an Australia-India Strategic Research Fund award from DIISTE, in formal partnership with CSL. Members are also actively partnered with CSL on development of their influenza vaccines and immunoglobulins products.

CBNS Annual Report 2016 51

Industry and commercial engagement CBNS researchers have a range of collaborations with commercial organisations. These relationships are typically led by one of our Chief Investigators and link with Australian and international biotech experts. The collaborations provide an opportunity for bio-nano research to be translated into product development and, ultimately, application and use. Examples include: • Development of a new dispersible electrode concept for detecting

low levels of microRNA in blood as a biomarker of disease. An ARC Linkage Project funded collaboration between Professors Maria Kavallaris and Justin Gooding (both UNSW), and AgaMatrix Inc. • Generation of novel anti-HIV antibodies. A collaboration between Professor Stephen Kent (Melbourne) and Affinity Bio. The work is funded from a Victorian Infection and Immunity Industry Alliance grant and an NHMRC Program Grant.

• Biodistribution and targeting of antibodies towards prostate cancer. A research contract collaboration between Associate Professor Kris Thurecht (UQ) and Minomic. Further details on the range of industry and commercial engagements of the CBNS can be found on our website: http://bionano.org.au/content/industryand-commercial-engagement

Health and medical sector engagement CBNS researchers have a range of links with organisations in the health and medical sector. These relationships are typically led by one of our Chief Investigators and link with hospitals and medical research institutes. The collaborations provide an opportunity for bio-nano research to be undertaken in collaboration with medical researchers and practitioners, informed by end user needs. • Vascular remodelling and drug delivery. A collaboration between Professor Andrew Whittaker (UQ) and Professor Guangjun Nie, National Centre

for Nanoscience and Technology, Chinese Academy of Science (CAS). The research is funded by a CAS President’s International Fellowship awarded to Andrew Whittaker. • 3D MED-i – An exploration of immersive arts-led 3D visualisation and VR HMD in stroke rehabilitation. A collaboration between Associate Professor John McGhee (UNSW) and Associate Professor Steven Faux, Director of Rehabilitation and Pain Medicine, St Vincent’s Hospital, Sydney. The research is supported by UNSW and St Vincent’s Hospital, Sydney.

• Scaffolds for regulatory T cell expansion. Professor Nico Voelcker (UniSA), in collaboration with Associate Professor Simon Barry, Gastroenterology Department, Women’s and Children’s Hospital, Adelaide. Funded by the CRC for Cell Therapy Manufacturing. Further details on the range of industry and commercial engagements of the CBNS can be found on our website: http://bionano.org.au/content/industryand-commercial-engagement

Collaboration with partner organisations The CBNS engagement with our partner organisations varies as research activities gain in focus. In 2016 there have been research visits to Australia from Partner Investigators Professor Dave Haddleton, Warwick University, and Professor Cameron Alexander, University of Nottingham. Australian CBNS researchers have travelled to our local and overseas partners to undertake collaborative activities.

on combining polymers and radioactive isotopes to transport PET tracers with greater accuracy to cancer cells – in order to provide more detailed, higher contrast images than are currently available to oncologists. Ultimately, the advancement that Jeroen and his team at the CBNS are working on will allow more precision targeting for the treatment of tumour cells, potentially leading to improved clinical imaging and faster eradication of tumour cells.

Dr Jeroen Goos (Monash), whose position is partially funded by ANSTO, travelled to Memorial Sloan Kettering Cancer Center in New York, US, along with Dr Simon Puttick (UQ), to undertake research in the PET labs of Partner Investigator Professor Jason Lewis.

For CBNS researchers, being able to visit and access the expertise and facilities in the lab of Professor Jason Lewis provides an incredible research opportunity. Not only is Jason Lewis a world leader in the field of PET imaging, but the lab itself allows faster and more integrated research.

During his PhD, Jeroen developed a new type of PET tracer that aids in gaining a more accurate understanding of the location and inner biology of cancer cells. His research now focuses

This can occur because of the Memorial Sloan Kettering Cancer Center’s rare combination of access to materials labs, radiochemistry facilities, a pre-clinical department and an operational hospital,

52 CBNS Annual Report 2016

allowing clinical trials. This perfect infrastructure for the development of new PET imaging technology is a significant benefit that researchers at the CBNS have the potential to access. The long standing collaboration of CBNS Director Tom Davis and Partner Investigator Dave Haddleton at Warwick University has led to two major joint international events in the UK in 2016. The Warwick Polymer Conference, held every four years, brings together world experts in polymer science. In 2016 this included 14 CBNS researchers and with over 400 delegates the conference is significant. The polymer conference was followed by a Molecular Imaging Meeting at University Hospital Coventry and Warwickshire. It brought together researchers with clinical/medical associations and clinicians, presenting their latest work in the design and application of imaging probes and the visual arts for medicine.

events Events provide an excellent opportunity to share important research, form new collaborations and strengthen existing ones. The CBNS delivered another series of successful events during 2016. Here are some of the highlights.

Annual CBNS Workshop Almost 100 members of the CBNS came together at the Barossa Valley during December for our annual workshop. The workshop was an excellent opportunity for members to learn about the latest research taking place, and to create an environment that stimulated collaboration. Researchers of all levels from across our five nodes were present, along with research administration staff. The sublime surroundings at the Barossa Valley provided an ideal, peaceful backdrop for lively discussion around showcasing our research and emerging opportunities for collaboration across the centre. As well as highlighting important research, there were valuable contributions from experienced members of the centre on working with industry and applying for

Chief Investigator, Professor Chris Porter (Monash)

a range of grants and funding options. The workshop also included recognition of members for the most significant publication of 2016, Science by Design competition, best presentation at the workshop and best poster. The workshop provided an opportunity for the CBNS education committee to receive feedback for events and training

that will take place during 2017. The committee’s programme during 2016 was positively received by members at the workshop. This has resulted in a range of beneficial activities that not only build the capacity of members of the CBNS, but also provide a platform to demonstrate the centre’s important work to the public.

Research Fellow, Dr Anna Cifuentes-Rius (UniSA) Senior Research Fellow, Dr Pu-Chun Ke (Monash)

23rd IUPAC Conference on Physical Organic Chemistry During the 23rd IUPAC Conference on Physical Organic Chemistry the CBNS sponsored the Forum on the Future of Chemistry, along with the Royal Australian Chemical Institute (RACI) and Angewandte Chemie International Edition. Over 80 people attended to listen to a panel discussion of significant national and international chemists – Professor George Whitesides (Harvard University), Professor Andrew Holmes (President, Australian Academy of Science), Dr Peter Gölitz (Editor in Chief, Angewandte Chemie), Professor Peter Junk (President, RACI), Professor Veena Sahajwalla (Associate Dean Strategic

Industry Relations Science UNSW) and CBNS Chief Investigator Professor Justin Gooding (UNSW). The forum was moderated by CBNS Chief Investigator Professor Pall Thordarson (UNSW) and a lively discussion ensued. Topics ranged from the need for the community to move towards identifying interesting problems to solve to breaking away from the traditional metrics that reward both research students and academics based on publications but don’t reward those focusing on innovation and solving problems with industry or society. It was agreed that there are some very important scientific challenges that

need to be solved – the management of the carbon cycle; from capturing CO2 to renewable energy generation and new more energy efficient methods to make materials were frequently mentioned; precision medicine, noting that the chemistry community should not lose focus on the economics of health care and should perhaps work on improvements in public health, both in the developed and developing world. Finally, there was discussion about the need to be much more inclusive in defining chemistry research and that researchers should be talking to and including people in other fields, specifically the social sciences.

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International Nanomedicine Conference The CBNS was once again the co-host with UNSW of the Australian Centre for Nanomedicine’s International Nanomedicine Conference. The conference has been held annually at Coogee in New South Wales for seven years. The conference brings together Australian nanomedicine researchers from medicine, chemistry, engineering and sociology, with international experts. The CBNS Visiting Professor is a feature at the conference annually, as a plenary speaker. In 2016 Professor Vince Rotello was joined by the other plenary speakers, Professor George Whitesides, Harvard University, USA; Professor Fiona Wood, University of Western Australia; Professor Patrick Stayton, University of Washington, and;

CBNS Chief Investigator, Professor Frank Caruso, from The University of Melbourne. In addition to the talks and poster sessions, the conference is a confluence of national and international expertise and most CBNS researchers attend. There is such a critical mass at the conference that the CBNS Scientific Advisory Board meets during it, with expert input and advice from the plenary speakers each year.

2016 Visiting Professor: Vince Rotello Our annual Visiting Professor program brings outstanding international scientists to Australia to advance bio-nano science. In 2016, Professor Vince Rotello, an expert in the biomedical and materials applications of nanosystems, spoke about his research all around Australia during his visit in the middle of the year. Professor Rotello, University of Massachusetts Amherst, was in Australia from 26 June until 16 July before travelling back to the United States via the University of Auckland in New Zealand. During his time in Australia and New Zealand he visited all of the CBNS nodes, giving research presentations, he attended the Nanomedicine Conference and gave the opening plenary talk as well as participating in the CBNS Scientific Advisory Board. Professor Rotello’s visit to Melbourne coincided with the Royal Australian Chemical Institute Victorian Polymer Symposium and he was the plenary speaker there. The whole visit was well received and Vince has said that it was scientifically fruitful.

2016 Visiting Professor: Vince Rotello

The Visiting Professor in 2017 will be Wolfgang Parak, Professor of biophotonics at the University of Marburg. Attendees at the conference

Science in the cinema As part of National Science Week, the CBNS and Doherty Institute presented science in the cinema, an event held in August. The event was emceed by CBNS Director, Professor Tom Davis (Monash). The screening of the 2011 medical thriller Contagion was followed by a panel discussion. The panellists discussed the film and how research underway at the CBNS and Doherty Institute could aid in the response to a similar event in the future. There was a lively discussion from the panellists and this included audience responses.

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The panellists were: • Dr Julian Druce – Royal Melbourne Hospital at the Doherty Institute • Associate Professor Katherine Kedzierska – Doherty Institute • Dr Angus Johnston – CBNS Chief Investigator (Monash) • Associate Professor Matthew Kearnes – CBNS Chief Investigator (UNSW)

The event was very well received, with a follow up interview with Dr Angus Johnston (Monash) on 774 ABC Melbourne’s radio show Breakfast with Red Symons on 10 August leading to further exposure of the event and related Centre research.

Education committee The CBNS education committee met monthly during 2016 to assess the training and outreach needs of the Centre. The committee is formed of members from across all nodes and is comprised of a PhD student member and postdoctoral member from each. The committee surveys the training needs of each node and responds with capacity building activities and workshops. This section includes a review of a selection of activities.

Imaging Workshop On 30 June 2016, the day following the International Nanomedicine Conference, 24 CBNS postdocs and students gathered in the Lowy Cancer Research Centre at UNSW for an illuminating workshop on advanced cell imaging techniques for nanomedicine, jointly hosted by the CBNS Education Committee and the Biomedical Imaging Facility (BMIF) at UNSW. In the morning Dr Renee Whan, Head of the BMIF, presented an overview of the basics of imaging and essential considerations when planning imaging experiments. After a lunch break with lively discussions, participants were separated into small groups and taken into the BMIF for introduction to and demonstration of lightsheet imaging, fluorescence lifetime imaging and super-resolution imaging led by friendly and knowledgeable BMIF staff scientists. Feedback following the workshop was overwhelmingly positive and the CBNS education committee is currently working on organising another cell imaging workshop with a different focus in the middle of 2017.

Australian Synchrotron Workshop The Introduction to the Australian Synchrotron day-long workshop was run by the CBNS in April. It was held onsite at the Australian Synchrotron, Melbourne, and included a welcome from Professor Michael James, the Head of Science, plus talks from various beamline staff. Various local and interstate CBNS researchers with synchrotron experience also attended and presented. Each beamline was introduced, its capabilities explored and some examples of the cutting edge research being conducted were highlighted. Professor Ben Boyd (Monash) and Dr Adam Martin (from UNSW), gave interesting presentations on their research that had benefited from synchrotron-based techniques. The day was rounded out with Dr Stephen Mudie from the Small Angle X-ray Scattering (SAXS) beamline providing the attendees with advice on how to strengthen proposals so as to improve their applications for securing beam equipment time.

Animal Imaging Workshop The Animal imaging workshop was a co-sponsored collaboration between the CBNS and the Centre for Advanced Imaging (CAI). The full-day imaging workshop was organised by Associate Professor Kris Thurecht (UQ) and Dr Zach Houston (UQ), and utilised the special expertise of Gary Cowin for PET-MRI, Karine Mardon for PET-CT, and Nicholas Westra van Holthe and Anna Gemmel for MSOT from the CAI. The event covered all aspects that are important to designing a small animal imaging experiment from theory to practical demonstrations. The workshop covered optical Imaging, Multi-Spectral Optoacoustic Tomography (MSOT), Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) and Computed Tomography (CT).

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CBNS Mentoring Program In August 2016 we launched our CBNS mentoring program. The program complements the informal mentoring that occurs every day in the CBNS through supervisory and collegial interactions. The CBNS mentoring program is part of our drive to provide a training environment for the next generation of bio-nano researchers. The Program sets out the benefits that a professional mentor can provide as well as the expectations on both the mentor and the mentee in the relationship. It also provides general information on how to select a mentor and establish a mentoring relationship. The CBNS mentoring program called for applications from postgraduate and postdoctoral researchers who were interested in being professionally mentored. Applicants were asked for an overview of their research, where they were planning on working in five to ten years’ time and what they were looking for from a mentoring relationship. Suggestions included: mentoring in applying for fellowships or grants, increasing independence in research, working in the Australian research system, balancing work and family commitments and working with colleagues or supervisors.

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The CBNS established a small mentoring team to review the applications and try and match each with a mentor – either from within the CBNS or externally. Applications and interest in the program have been strong so far. Initial meetings have taken place with most mentors and the preliminary feedback from the mentees has been very positive. The CBNS mentoring team is available to all mentors and mentees throughout the program, to provide advice. All pairings have been asked to review the relationships after 12 months to consider whether the relationship is still valuable. The CBNS aims to continue the program each year, creating new mentoring matches for our staff and students, to provide them with the best environment in which to work and study.

“Just letting you know that I met with my mentor today. The meeting was extremely helpful and matches perfectly with the plans and thoughts of my current professional situation. Thanks a lot for arranging this mentor relationship!” – CBNS postdoctoral researcher with a mentor who is a researcher leader in industry. [Nadja BertleffZieschang, matched with David Owen at Starpharma] “I’ve met with my mentor last Friday and he was very nice. We got to know each other a bit more now and have scheduled a second meet up next month.” – CBNS postgraduate student with a mentor who is a research leader in a CRC. [Danzi Song, matched with Warwick Tong at the Cancer CRC]

CBNS Awards During 2016, members of all levels were recognised for their contribution to the Centre, as well as their hard work and dedication to science and pushing the boundaries of understanding in the area of bio-nano science. This section includes some of the highlights. See page 71-72 for a comprehensive list.

CBNS Internal Awards During the CBNS annual workshop, we recognised members for the most significant publication of 2016, Science by Design competition, best presentation at the workshop and best poster. Congratulations once again to the following awardees:

Most significant publication of 2016 Christopher Howard – University of Queensland. Overcoming instability of antibody-nanomaterial conjugates: Next Generation Targeted nanomedicines using Bispecific Antibodies (Adv. Healthc. Mater., 2016, 5, 2055-2068.

Science by Design

Best oral presentation

• Judge’s choice: Laura Selby – Monash University • Honourable mention: Manchen Zhau – University of New South Wales • People’s choice: Johan Gustafsson – University of South Australia

• Nicholas Fletcher – University of Queensland • Honourable mention: Mattias Björnmalm and Matt Faria – University of Melbourne

Best poster • Gayathri Ediriweera – University of Queensland • Honourable mention: Daniel Brunde – Monash University and Nadja Bertleff-Zieschang – University of Melbourne Winning ‘Science by Design’ entry by Laura Selby

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Dr John Dixon Hughes Medal for Medical Research Innovation Professor Mark Kendall (UQ) was awarded the Dr John Dixon Hughes Medal for Medical Research Innovation in December.

Fellowship of the Australian Academy of Health and Medical Sciences Professor Maria Kavallaris (UNSW) was inducted as a Fellow of the Australian Academy of Health and Medical Sciences (AAHMS) on 6 October. The induction took place at the AAHMS second Annual Scientific Meeting at the Translational Research Institute in Brisbane. Professor Kavallaris was among 50 new Fellows nationally, selected through ordinary election, bringing the total Fellowship to 272. New Fellows are drawn from all states and territories of Australia, and from all aspects of health and medical science across clinical practice and allied health care, with representation from basic translational and clinical research, health economics, general practice and public health. Professor Ian Frazer, President of the Academy, said, “I am delighted on behalf of the Academy council to welcome the new Fellows to the Australian Academy of Health and Medical Sciences this evening. Their election as Fellows of the Academy will help to ensure that the Academy can promote use of the best in research-informed health care for all Australians.”

Fellowship of the Australian Academy of Science In May, the Australian Academy of Science announced the election of 21 new Fellows for their outstanding contributions to science and scientific research. CBNS Chief Investigator Professor Justin Gooding from our UNSW node is one of the new Fellows. The fellowship citation noted Professor Gooding’s work using chemistry to modify surfaces at the molecular level to enable them to specifically recognise biochemical molecules and to transfer electrons with them in biological fluids. For a comprehensive list of awards, memberships and grant successes, see pages 71-72.

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International Biosensors and Bioelectronic Award Professor Justin Gooding (UNSW) also won the Biosensors and Bioelectronic Award for the most original contribution to the 26th Anniversary World Congress on Biosensors in Gothengburg, Sweden. The congress was organised by leading scientific publisher, Elsevier. The award was as a result of Professor Gooding’s keynote lecture at the congress entitled, “Towards single molecule biosensors using super-resolution fluorescence microscopy”. The congress was the largest ever gathering of biosensor scientists in the world and demonstrates the impact and international recognition of the work being undertaken by CBNS researchers.

The Medal, developed in honour of Dr John Dixon Hughes OAM (NFMRI’s longest standing Trustee) to showcase and celebrate the achievements of Australia’s recent biomedical research innovators, entails a $50,000 prize in the form of a research grant for the recipient. Dr John Dixon Hughes OAM said “that the nominations were simply of exceptionally high calibre, demonstrating the sector’s progress and improvement of innovation commercialisation.” He noted that the Foundation’s research advisory committee felt it was impossible to compare and decide between the final two finalists and hence the Board made the decision to award two medals: one to Professor Mark Kendall, for his successes with his Nanopatch™ vaccine delivery system.

This major award was one of many for Professor Gooding in 2016, who received an Archibald Liversidge Medal for Chemistry and the Walter Burfitt Prize for Science from the Royal Society of New South Wales, as well as the Faraday Medal of the Royal Society of Chemistry Electrochemistry Division. Professor Gooding was also Elected Fellow of the International Society of Electrochemistry. Unity award nomination In December, UNSW’s Associate Professor John McGhee’s 3D visualisation of a breast cancer cell was nominated for an international Unity Award, joining the likes of the visual effects company behind Disney’s Jungle Book. The Unity Awards are presented by Unity Technologies, the award-winning development platform for games and interactive 3D used by 5.5 million developers globally. Journey to the Centre of the Cell was nominated for the Best VizSim Project which acknowledges visualisations that have real world applications for simulation and training. The project was also up for an overall Golden Cube award.

Batteard-Jordan Australian Polymer Medal CBNS Director, Professor Tom Davis (Monash) was awarded the BatteardJordan Australian Polymer Medal in November. The award took place at the 36th Australasian Polymer Symposium, which took place at the picturesque coastal town of Lorne, Victoria. Tom also delivered the opening plenary at the symposium. The Batteard-Jordan Australian Polymer Medal, the highest award of the Polymer Division, is awarded for outstanding achievement in Polymer Science in Australia. It has only been awarded ten times since 1974. It was awarded to Tom for his significant contribution to the Australian polymer science community.

media Media coverage of the CBNS provides the public with important insights into the type of research being undertaken at the Centre and its contribution to tackling vitally important advances in the understanding and treatment of human disease. This coverage also gives Centre members a key opportunity to contribute to public debates on science and to facilitate increased understanding of the importance of scientific advance. We continued our strong media presence during 2016, with 81 newspaper or magazine articles, 97 radio interviews and 23 television appearances. A particularly strong story that was picked up by multiple outlets was the work being led by Associate Professor McGhee (UNSW) on using VR technology to journey inside the cell (see Signature Project Journey to the centre of the cell on page 40–41). This work was highlighted in the New Scientist in July, and was subsequently picked up by multiple international and national news outlets. (See: https://www.newscientist.com/ article/2095746-virtual-reality-letsyou-stroll-around-a-breast-cancer-cell)

TV production taking place at CBNS facility

The story culminated in television features on ABC’s Catalyst program and on Channel 10’s Scope program for younger audiences. The VR system has since been demonstrated at numerous events, including during visits to high schools, and has had an extremely enthusiastic reception by the public.

Associate Professor John McGhee being broadcast on ABC TV.

media

3D illustration of cell environment by Associate Professor John McGhee

newspaper or magazine articles

radio appearances

television appearances

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governance CBNS Annual Report 2016 61

Governance and management The CBNS Governance Board has an independent advisory role to the Centre Director, Executive and Management Committee. The Board provides guidance on governance, strategy and stakeholder engagement. The Scientific Advisory Board provides strategic scientific insight and commercial direction to the Centre. The CBNS Executive meets regularly to discuss the research program and operational matters, referring items to the Management Committee for ultimate decision-making about the structure of the research program and Centre finances.

Governance Board

Scientific Advisory Board

Chaired by Professor Peter Doherty

Chaired by Professor Alan Rowan

CBNS Executive

Director

Director, Deputy Director, Manager

Professor Tom Davis

Deputy Director

IP & Commercialisation Committee

Professor Frank Caruso

(Executive, Business Development Managers)

Management Committee (Senior Chief Investigators, Manager)

National Education Committee Chaired by Professor Maria Kavallaris

Research Program

CBNS Governance Board Members of the CBNS Governance Board are all research leaders and governance experts in scientific, research-based organisations. The Board monitors progress towards delivery of Key Performance Indicators and approves research, operational and financial plans. The Governance Board met twice in 2016: Tuesday 3 May 2016 and Monday 15 August 2016.

Professor Peter C Doherty AC FAA FRS Chair

Professor Doherty shared the 1996 Nobel Medicine Prize for discovering the nature of the cellular immune defence. Based at the University of Melbourne and also spending part of his year at St Jude

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Children’s Research Hospital, Memphis, he continues to be involved in research directed at understanding and preventing the severe consequences of influenza virus infection. In addition, he goes in to bat for evidence-

based reality, relating to areas as diverse as childhood vaccination, global hunger and anthropogenic climate change. In an effort to communicate more broadly, he has published four ‘lay’ books, and has another in progress.

Professor Calum J Drummond PhD FTSE FAICD FRACI FRSC CChem

Professor Drummond is currently Deputy Vice-Chancellor Research and Innovation and a Vice President at RMIT University, playing a leadership role in the development of discovery and practice-based research and in building and

Professor Michelle Haber AM BSc (Psych) (Hons) PhD Hon DSc (UNSW)

Professor Haber joined the Children’s Cancer Institute as a staff scientist in 1984. She was appointed Director of the Institute in June 2000 and Executive Director in June 2003. Professor Haber is known for her world-class research into the treatment of neuroblastoma and acute lymphoblastic leukaemia in children. Professor Haber holds Ms Maureen O’Keefe BSc (Hons) DipEd MBA GAICD WCLP

Ms O’Keefe was appointed as Chief Executive Officer of the Australian College of Optometry in March 2013, an organisation providing public health eye care, tertiary clinical teaching and education, and research to preserve sight and prevent blindness. She spent the previous seven years as Chief Operating Officer at the Walter and Eliza Hall Institute of Medical

Dr Warwick Tong BSc MB ChB MPP GAICD

Dr Tong is currently the CEO of the Cancer Therapeutics Cooperative Research Centre headquartered in Melbourne. In 2013 he led the CRC through a successful extension application receiving another six years of funding until 2020. Formerly a director of Primecare Medical Ltd

Professor Gordon Wallace FAA FTSE FIOP FRACI

Professor Wallace is currently the Executive Research Director at the ARC Centre of Excellence for Electromaterials Science and Director of the Intelligent Polymer Research Institute. He is Director of the ANFF Materials node. He previously held an ARC Federation Fellowship and currently holds an ARC Laureate Fellowship.

enhancing capability in research and innovation across the University. He is also an active research professor and has published over 200 papers and patents in the area of advanced materials, including biomedical and energy storage applications. Professor Drummond joined RMIT University in 2014 from CSIRO where he was Group Executive

a conjoint appointment as Professor in the Faculty of Medicine at the University of New South Wales. She has served as President (2010-2012) and currently serves on the Steering Committee of the International Advances in Neuroblastoma Research Association. In 2007 Professor Haber was appointed a Member of the Order of Australia for services

Research and prior to that held several senior executive roles at the University of Melbourne. Ms O’Keefe is a graduate of the Australian Institute of Company Directors, the Williamson Community Leadership Program and an Executive Education Program at Massachusetts Institute of Technology, Cambridge. Ms O’Keefe has spent her career in higher education, research and health organisations and has more than fifteen years’

(NZ) and MedInnovate Ltd (UK) he is currently a member of the Advisory Board for Cortex Health. He has spent more than 20 years in executive management in drug development and commercial roles in both the major pharmaceutical and biotech industry.

for Manufacturing, Materials and Minerals comprising 1300 researchers and research support staff. Earlier he was seconded from CSIRO to be the inaugural Vice President Research at CAP-XX, an Intel portfolio company that developed supercapacitors for consumer electronic products.

to science in the field of research into childhood cancer, to scientific education and to the community. In 2008, she was awarded an Honorary Doctorate from the University of New South Wales for her eminent service to the cancer research community. More recently, in 2014, Professor Haber was awarded the Cancer Institute NSW’s Premier’s Award for Outstanding Cancer Researcher of the Year.

experience in senior executive roles. She is a Board member of Vision2020 Australia, the Victorian Department of Health’s Clinical Trial Research Ministerial Consultative Council and the BioMelbourne Network. Previously, Ms O’Keefe was a member of the Council of the Victorian Cancer Agency for six years, a Ministerial appointment, including two years as a member of the VCA Clinical Trials Working Group.

After graduating as Senior Scholar in Medicine from Auckland

University and working in General Practice Dr Tong joined Glaxo in NZ as Medical Director and subsequently worked in Singapore and London, in regional and global business development and commercial roles for Glaxo. Prior to coming to Melbourne Warwick spent five years in Boston as SVP, Development, for Surface Logix Inc.

Professor Wallace is an elected Fellow at the Australian Academy of Science, the Australian Academy of Technological Sciences and Engineering, the Institute of Physics (UK) and the Royal Australian Chemical Institute. In addition to being named NSW Scientist of the Year in the chemistry category in 2008, he was also appointed to the Korean World Class University System, and received the Royal

Australian Chemical Institute HG Smith Prize. In 2004, Professor Wallace received the Royal Australian Chemical Institute Stokes Medal for research in Electrochemistry, after being awarded an ETS Walton Fellowship by Science Foundation Ireland in 2003. The Royal Australian Chemical Institute awarded him the Inaugural Polymer Science and Technology Award in 1992.

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CBNS Scientific Advisory Board The Scientific Advisory Board (SAB) has an independent mentoring and advisory role to the Scientific Management Group, providing strategic insight and commercial direction to the Centre. The SAB plays a key role in advising the Centre on the development of the strategic and commercialisation plans. The Board advises on patent versus publication strategy, and commercialisation and spin-out strategy, as required. They assist in identifying intellectual property partnering and licensing opportunities and organisations with which the CBNS can ally. In addition to the core members of the SAB, there are temporary international members, including the CBNS Visiting Professor, who provide variation to the scientific mix of the SAB.

Professor Alan Rowan BSc PhD FRSC Chair

Professor Alan Rowan has performed his research at the interface of chemistry and biology with seminal and pioneering work on processive catalysis and functional self-assembly. His latest scientific achievement has been the development of the first truly biomimetic hydrogel which mimics the mechanic and functional properties of the extracellular membrane. This scientific breakthrough is already now being developed commercial for wound dressing, drug therapeutic and cell growth, and has further established Professor Rowan as a truly innovative scientist, working

toward understanding at the molecular level the functional of hierarchical materials and catalysis. Professor Rowan’s considerable scientific curiosity has resulted in him working in many areas, ranging from magnetic materials, single enzyme catalysis, supramolecular catalysis through to nanometersised solar cells and photonic materials. In the last ten years he developed the concept of processive catalysis, mimicking the natural exo- and endonucleases and demonstrated that a macrocyclic catalyst can thread onto and move along a polymer

substrate in a highly efficient process. In January 2016 Professor Rowan Professor joined the University of Queensland as the Director of the Australian Institute of Bioengineering and Nanotechnology. He previously led a research group at Radboud University’s Institute of Molecules and Materials, one of Europe’s leading research centres for the nanosciences. He was awarded an ARC Australian Laureate Fellowship to continue his work on novel biomimetic and dynamic materials.

Peter French BSc MSc MBA PhD FRSM

Dr French is currently an Executive Director of BCAL Diagnostics, an Australian company developing a novel blood-based screening test for breast cancer. He is a Past President of the Australia and New Zealand Society for Cell and Developmental Biology and served as a member of the Board of the International Society of Differentiation from 1998-2014. He served as CEO and Managing Director of ASX- and NASDAQ-

listed gene therapy company Benitec Biopharma Limited from June 2010 to December 2015. He is an Adjunct Senior Lecturer at UNSW and an Honorary Fellow at Macquarie University. Dr French is a cell and molecular biologist who has extensive experience in both basic and clinical medical research and biotechnology. His research areas of expertise include cell biology, immunology, infectious disease, neurobiology,

oncology and gene therapy. He was awarded a PhD for elucidating the molecular composition of keratin proteins in the developing hair follicle. Following a postdoctoral position studying neuronal development he was appointed Principal Scientific Officer in the Centre for Immunology, St Vincent’s Hospital Sydney. Whilst at St Vincent’s, he completed a MBA in Technology Management.

Dr Sridhar Iyengar PhD

Dr Iyengar is a founder and director of Misfit Wearables, makers of highly wearable computing products, including the award-winning Shine, an elegant activity monitor. Dr Iyengar also founded and served as CTO of AgaMatrix,

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a blood glucose monitoring company that made the world’s first hardware medical device to connect directly to the iPhone, winning both the Red Dot and the GOOD Design Awards. He built AgaMatrix from a two-person start-up to shipping 15+ FDA-cleared medical device

products, 3B+ biosensors, 3M+ glucose meters for diabetics, with partnerships with Apple, Sanofi, and Walgreens. Dr Iyengar holds over 20 US and international patents and received his PhD from Cambridge University as a Marshall Scholar.

Dr David Owen BSc (Hons) PhD

Dr Owen is the Vice President of Research at Starpharma and has extensive experience in medicinal chemistry and biochemistry, and in managing teams focused on commercially directed drug discovery. He has held several positions in the biotech industry including Mimotopes, Cerylid and

Glykoz and gathered extensive international experience in biotechnology and pharmaceutical research and development. Since joining Starpharma Dr Owen has driven the drug delivery programs by developing and executing a number of successful proof-ofconcept studies. The results from

these studies have led to a number of commercial partnerships such as Stiefel a GSK company, Lilly and AstraZeneca, as well as driving Starpharma’s own internal drug delivery program focused on an improved dendrimer-docetaxel formulation.

Cooperative Research Centre for Cell Therapy Manufacturing and is a member of the SA Economic Development Board and the Council for the University of South Australia. Prior roles included CEO of the Cooperative Research Centre for Tissue Growth and Repair and the founding managing director of Adelaide biotechnology

company, TGR BioSciences Pty Ltd. She has received a number of awards, including an Honorary Doctorate from the University of South Australia, the 2006 South Australian of the Year (Science and Technology) and the 2011 Central Region winner of the Ernst & Young Entrepreneur of the Year in the Technology Category.

involves several collaborative research projects focused on the multidisciplinary clinical and scientific team approach to the treatment of burn injury. The ultimate aim is scarless healing to ensure the quality of the outcome is worth the pain of survival.

to Medicine” Award, in 2003 and also received the Order of Australia Medal for work with Bali bombing victims. She was named West Australian of the Year for 2004, and was nominated as a National Living Treasure and Australian Citizen of the Year in 2004. In 2005 she received the honour of being named Australian of the year.

Dr Leanna Read FTSE FAICD

Dr Leanna Read is the Chief Scientist for South Australia and chairs the South Australian Science Council. She is a renowned biotechnology expert and brings a wealth of executive, board and investment experience in technology-based businesses. In addition to her role as Chief Scientist, Leanna chairs the

2016 temporary members Professor Fiona Wood

Professor Fiona Wood is a plastic surgeon and currently Director of Burn Service of Western Australia working at Royal Perth Hospital and Princess Margaret Hospital for Children. She is the Chair of the McComb Research Foundation which she established in 1999 along with scientist Marie Stoner. Fiona’s research through the McComb Research Foundation

Fiona was awarded the Australian Medical Association “Contribution

Professor Vincent Rotello

Professor Vince Rotello is the Charles A. Goessmann Professor of Chemistry Professor of Chemistry at University of Massachusetts Amherst. His research program focuses on using synthetic organic chemistry to engineer the interface

between hard and soft materials, and spans the areas of devices, polymers, and nanotechnology/ bionanotechnology, with over 460 peer-reviewed papers published to date. He is actively involved in the development of new

nanomanufacturing methods, and in the area of bionanotechnology his research includes programs in delivery, imaging, diagnostics and nanotoxicology.

on TRD and collaborative projects involving polymeric nanoparticles and engineered proteins. Professor Stayton has extensive experience in the areas of synthesis of polymeric nanoparticles for drug delivery as well as site-directed mutagenesis of proteins and the preparation of oriented proteins.

University of Illinois-Champaign in 1989 and was a Postdoctoral Research Associate at the Beckman Institute for Advanced Science and Technology. His research group works at the interface of fundamental molecular science and applied molecular bioengineering, with application of nanomaterials to the drug delivery, medical diagnostics, and regenerative medicine fields.

Professor Patrick S Stayton

Professor Pat Stayton is Washington Research Foundation Professor of Bioengineering and Director of the Molecular Engineering & Sciences Institute at the University of Washington. Professor Stayton will have a primary role in the TRD and collaborative projects involving the synthesis of polymeric nanoparticles for drug delivery, as well as the synthesis of peptides and ordered proteins. He will act as a consultant

Professor Stayton received his PhD in Biochemistry from the

CBNS Annual Report 2016 65

66 CBNS Annual Report 2016

Performance CBNS Annual Report 2016 67

Performance and KPIs CBNS achievements are evaluated by the Australian Research Council on an annual basis with a formal review in the third year (2017). CBNS performance is assessed against key performance indicators that were set at the commencement of the Centre. These cover the traditional research metrics of outputs like journal publications, and conference presentations. There are also metrics that cover the interdisciplinarity of CBNS research, new research partnerships, measures of esteem, public awareness and student and mentoring. The CBNS is progressing well and has exceeded almost all of the targets for 2016. The KPIs for 2016 are summarised in this infographic. It shows the targets for each of the KPI areas, as well as our actual achievements.

Research findings: Number of research outputs: Book chapters target: 1 actual:

Patents (filed) target: 1

Journal publications, target: 45

actual: 251

Refereed conference proceedings target: 15 actual: 8

actual: 9

Quality of research outputs: Publications impact factor >10 target: 6 actual: 24 % journals articles impact factor >2

New research fellowships

target: 50% actual:

target: no target actual:

93%

Number and nature of commentaries about the Centreâ&#x20AC;&#x2122;s achievements Media releases target: 7

Membership on editorial boards, target: no target

actual: 53

Number of invited talks/ papers/keynote lectures given at major international meetings target: 25

actual: 96

actual: 27 Articles, target: 3

actual: 81

Collaboration and interdisciplinarity:

Research outputs featuring co-authorship between nodes target: 8

actual: 18

68 CBNS Annual Report 2016

Postgraduates or postdocs working on cross node or interdisciplinary projects target: 4

actual: 23

Organisational support: Number of new organisations collaborating with, or involved in, the Centre target: 1

actual: 56

Research training and professional education: Number of professional training courses for staff and postgraduate students attended target: 8

actual: 23 Number of students mentored target: 30 actual: 119

Number of Centre attendees at all training/ development courses offered by the Centre target: 20 actual: 199

Number of new postgrads working on core CBNS research target: 8

actual: 25

Number of mentoring programs offered by the Centre, target: 6 actual: 3

Number of postgrad completions, by students working on core CBNS research target: 5

Number of new postdocs recruited to the CBNS working on core CBNS research target: 6

actual: 19

actual: 13

Number of ECRs (within five years of completing PhD) working on core CBNS research target: 14

actual: 37

Number of new Honours students working on core CBNS research target: 11

actual: 7

International, national and regional links and networks: Examples of relevant interdisciplinary research supported by the Centre:

Number of international visitors and visiting fellows target: 15

Number of national and international workshops held/ organised by the Centre, target: 2

Number of visits to overseas laboratories and facilities target: 30

actual: 72

actual: 10

actual: 32

Publications that result from CoE interdisciplinary research target: 3 actual: 11 Operational interdisciplinary projects in the research program target: 2 actual: 12

End-user links:

Number of government, industry and business community briefings target: 5

actual: 16

Number and nature of public awareness/ outreach programs target: 10 Number of website hits (page views) target: 20,000

actual: 47,262

actual: 10 Number of talks given by Centre staff open to the public, target: 10

actual: 101

Video material produced and publicised each year on the website target: >10 mins

actual: 3hrs10min

CBNS Annual Report 2016 69

Financial report 2016 Income and Expenditure Income

2016 ($)

ARC grant income

$3,961,283

Collaborating organisation contribution

$1,243,514

Total income

$5,204,797

Expenditure

2016 ($)

Salaries $2,759,308 Equipment $48,362 Consumables and maintenance

$763,475

Travel* $310,895 Scholarships and student support

$218,393

Administration $51,839 Other # $125,376 Total expenditure

Carry forward

$4,277,648

$2,538,531

Balance $3,465,680 * includes accommodation and conference expenses #

includes media consultant, website development, training courses

In Kind contributions

2016 ($)

Monash University

$1,156,060

University of Melbourne

$1,007,835

University of New South Wales

$751,604

University of Queensland

$689,174

University of South Australia

$724,429

Australian Synchrotron

$556,800

Australian Nuclear Science and Technology Organisation

$69,500

Sungkyunkwan University

$20,000

University of Wisconsin-Madison

$10,000

University of Warwick

$60,000

University of Nottingham

$22,962

Imperial College London

$5,000

Memorial Sloan Kettering Cancer Center

$65,000

University College Dublin

$15,000

University of California, Santa Barbara

$26,000

Total $5,179,364

70 CBNS Annual Report 2016

Awards, Memberships and Grant Success Awards Professor Ben Boyd Invited speaker “ACS Award in Colloid and Surface Chemistry: Symposium in Honour of Nick Abbott” at the 251st ACS Meeting; Faculty Research Award Professor Tom Davis Eureka Prize for Outstanding Mentor of Young Researchers (Finalist); BatteardJordan Australian Polymer Medal Professor Justin Gooding Faraday Medal by the RSC; Elsevier Biosensors and Bioelectronics Award – this is for the most innovative contribution to the 2016 World Biosensor Congress; Archibald Liversidge Medal for Chemistry from the Royal Society of New South Wales; Walter Burfitt Prize for Science from the Royal Society of New South Wales Professor Peter Doherty, Professor Maria Kavalaris, Professor Mark Kendal, Dr Tina MarieLieu, Dr Elva Zhao Five Scientist Pledge (Identified national scientists by Chief Scientist Dr Alan Finkel) Professor Mark Kendall CSL Young Florey Medal; John Dixon Hughes Award Professor Stephen Kent Eureka Award for Interdisciplinary Research (Finalist)

Professor John McGhee UNSW ‘20 Rising Stars’

Professor Tom Davis Polymer Chemistry

Professor Chris Porter The Clarivate Analytics Highly Cited Researchers List

Professor Frank Caruso Chemistry of Materials

Professor Nico Voelcker National Institute of Forensic Science Award for best published paper, 2016

Elected Fellows Professor Justin Gooding Fellow of the Australian Academy of Science; Elected Fellow of the International Society of Electrochemistry Professor Maria Kavalaris Fellow of the Australian Academy of Health and Medical Sciences Professor Mark Kendall Fellow of the Queensland Academy of Arts and Science

Editors of journals Professor Ben Boyd Journal of Colloid and Interface science; Drug delivery and translational research (Associate Editor); Journal of Pharmaceutical Sciences; Current Drug Delivery; Journal of Liposome Research; Journal of Pharmacy and Pharmacology Professor Nigel Bunnett American Journal of Physiology, Gastrointestinal and Liver Physiology (Editor in Chief); Molecular Pharmacology

Professor Justin Gooding ACS Sensors (Editor in Chief) Associate Professor Matthew Kearnes Environmental Humanities Professor Rob Parton Traffic Professor Chris Porter Molecular Pharmaceutics; Journal of Pharmaceutical Sciences; Pharmaceutical Research; Journal of Pharmacy and Pharmacology Professor Pall Thordarson Australian Journal of Chemistry Professor Nico Voelcker Australian Journal of Chemistry

Committee and other memberships Professor Ben Boyd International Synchrotron Access Program Assessment Committee for the Australian Synchrotron; Secretary of the Controlled Release Society Professor Justin Gooding Co-Director, The Australian Centre for NanoMedicine, The University of New South Wales; Co-Director, New South Wales Smart Sensing Network

CBNS Annual Report 2016 71

Professor Stephen Kent NHMRC Development grant panel member; Crucell (A pharmaceutical company of Johnson & Johnson) Consultant; ARC Centre of Excellence Mentorship panel; NIH (Study Section Member on HIV vaccines); NHMRC Program Grant Mentorship panel; “Council of 100” for vaccinology (Member); Faculty of 1000 (Member); University of Melbourne Human Research Ethics Committee (Member); American Foundation for AIDS Research (Grant review panel member); AIDS Vaccine for Asia Network (Executive Committee); University of Melbourne (Academic Board); Australian Society for Medical Research; Australian Health and Medical Research Congress; Australasian Society for Infectious Diseases; ASID representative to ASMR Dr Cheng Zhang AIBN Centre for Theoretical and Computational Molecular Science

Grant success During 2016, over $26M in additional funding was secured to further support research being undertaken at the Centre. This funding reinforces the collaborative nature and expertise of CBNS researchers. Details of grant successes are as follows.

Australian Research Council (ARC) grants The following CBNS researchers secured over $4M in combined grant funding with eight ARC grants: Linkage Project, Discovery Project and Linkage Infrastructure, Equipment and Facilities. Professor Ben Boyd (Monash) Professor Tom Davis (Monash) Dr Angus Johnston (Monash) Professor Thomas Nann (MacDiarmid Institute) Associate Professor Kris Thurecht (UQ) Professor Nico Voelcker (UniSA) Professor Andrew Whittaker (UQ)

Australian Competitive Grants Register (ACGR) grants The following CBNS researchers secured over $14M in combined grant funding with eleven National Health and Medical Research Council (NHMRC) grants: Program Grant, Project Grant and Development Grant. Professor Ben Boyd (Monash) Professor Tom Davis (Monash) Dr Amy Chung (Melbourne) Professor Justin Gooding (UNSW) Dr Angus Johnston (Monash) Professor Maria Kavallaris (UNSW) Dr Matthew Parsons (Melbourne)

72 CBNS Annual Report 2016

Professor Chris Porter (Monash) Associate Professor Kris Thurecht (UQ) Dr Adam Wheatley (Melbourne) Professor Andrew Whittaker (UQ)

Dr Josh McCarroll Cancer Institute NSW Career Fellowship Dr Ting Yi Wang JDRF–Sanofi Fellowship

Public sector grants Over $375,000 through five separate public sector grants was secured by the following CBNS researchers: Professor Justin Gooding (UNSW) Professor Chris Porter (Monash) Professor Andrew Whittaker (UQ) Professor Stephen Kent (Melbourne)

Industry grants The following CBNS researchers secured over $2.5M in combined grant funding with nine industry grants: Professor Ben Boyd (Monash) Professor Frank Caruso (Melbourne) Professor Justin Gooding (UNSW) Dr Angus Johnston (Monash) Professor Pall Thordarson (UNSW) Associate Professor Kris Thurecht (UQ)

Other grants The following CBNS researchers secured over $5M in combined grant funding with nine additional grants: Dr Meri Canals (Monash) Professor Frank Caruso (Melbourne) Professor Justin Gooding (UNSW) Dr Angus Johnston (Monash) Professor Maria Kavallaris (UNSW) Professor Pall Thordarson (UNSW) Professor Nico Voelcker (UniSA) Dr Adam Wheatley (Melbourne) Professor Andrew Whittaker (UQ) Dr Cheng Zhang (UQ)

Fellowships Dr Maria Alba NHMRC Early Career Fellowship Professor Ben Boyd ARC Future Fellowship Dr Jacob Coffey American Australian Association Fellow Professor Tom Davis Australian Laureate Fellowship Dr Roey Elnathan DECRA Fellowship Professor Maria Kavallaris NHMRC Early Career Research Fellowship; NHMRC Principal Research Fellowship (2017-2021); NHMRC Established Career Fellowship Award Dr Kristian Kempe The Dementia Research Development Fellowship

Vince Rotello presents an award to Josh Glass

Student awards Josh Glass Royal Society of Chemistry prize for best presentation abstract, International Conference on Nanomedicine and Nano-biotechnology, Paris, France 2016; Best oral presentation by a PhD student, 7th International Nanomedicine Conference, Sydney 2016; International travel award for best oral presentation, NHMRC HIV Meeting, Hamilton Island Tang Li Best oral presentation at the Emerging Therapeutics Summit, Melbourne Emily Pilkington Australian Bicentennial Scholarship Kings College London Parisa Sowti Khiabani 2nd place in 1 minute thesis competition, Science Faculty, UNSW Manish Sriram ACS Sensors Poster Presentation Prize, 7th International Nanomedicine Conference, Sydney

CBNS personnel Chief Investigators Professor Tom Davis ARC Australian Laureate Fellow, CBNS Director, Delivery Systems, Imaging Technologies Monash University

Professor Edmund Crampin Systems Biology and Computational Modelling Leader Delivery Systems University of Melbourne

Professor Maria Kavallaris Delivery Systems, Sensors and Diagnostics University of New South Wales

Professor Frank Caruso ARC Australian Laureate Fellow, CBNS Deputy Director, University of Melbourne CBNS Node Leader Delivery Systems, Imaging Technologies, Vaccines University of Melbourne

Associate Professor Matthew Kearnes ARC Future Fellow Social Dimensions of Bio-Nano Science and Technology Leader University of New South Wales

Professor Rob Parton Delivery Systems, Vaccines University of Queensland

Professor Justin Gooding Sensors and Diagnostics Theme Leader, University of New South Wales CBNS Node Leader University of New South Wales

Professor Stephen Kent Vaccines Theme Leader Delivery Systems University of Melbourne

Professor Christopher Porter Delivery Systems Theme Leader Monash University Vaccines Monash University Professor Andrew Whittaker ARC Australian Professorial Fellow Imaging Technologies Theme Leader University of Queensland

Professor Mark Kendall University of Queensland CBNS Node Leader Vaccines University of Queensland

Professor Nicolas Voelcker University of South Australia CBNS Node Leader Delivery Systems, Sensors and Diagnostics University of South Australia

Dr Angus Johnston ARC Future Fellow Monash University Node Leader Delivery Systems, Vaccines Monash University

Professor Benjamin Boyd ARC Future Fellow Delivery Systems, Sensors and Diagnostics, Vaccines Monash University

Associate Professor Pall Thordarson ARC Future Fellow Delivery Systems, Imaging Technologies University of New South Wales

Associate Professor Kristofer Thurecht ARC Future Fellow Delivery Systems, Imaging Technologies, Vaccines University of Queensland

Dr Simon Corrie ARC DECRA Fellow Sensors and Diagnostics University of Queensland

Associate Professor John McGhee Visualisation University of New South Wales

Dr Beatriz Prieto-Simรณn Sensors and Diagnostics University of South Australia

CBNS Annual Report 2016 73

Partner Investigators Professor Nicholas Abbott John T. and Magdalen L. Sobota Professor, Hilldale Professor, and Director, Materials Research and Engineering Center, Chemical and Biological Engineering University of Wisconsin, Madison, USA

Professor Cameron Alexander Head of Division of Drug Delivery and Tissue Engineering, Faculty of Science University of Nottingham, UK

Professor Nigel Bunnett Delivery Systems Columbia University, USA

Professor Kenneth Dawson Director of the Centre for BioNano Interactions, Chair of Physical Chemistry University College Dublin, Ireland

74 CBNS Annual Report 2016

Dr Ivan Greguric Head of Radiochemistry Australian Nuclear Science and Technology Organisation, Australia

Professor David Haddleton Head of Inorganic and Materials Section, Department of Chemistry University of Warwick, UK

Professor Craig Hawker Director of the California Nanosystems Institute, Dow Materials Institute, Co-Director of the Materials Research Lab University of California, Santa Barbara, USA

Professor Doo Sung Lee Director Theranostic Macromolecules Research Center, Dean of College of Engineering Sungkyunkwan University, South Korea

Professor Jason Lewis Vice Chair for Research, Chief of the Radiochemistry and Imaging Sciences Service Memorial Sloan Kettering Cancer Center, USA

Professor Thomas Nann ARC Future Fellow Imaging Technologies Director of the MacDiarmid Institute, New Zealand

Professor Molly Stevens Research Director for Biomedical Material Sciences, Institute of Biomedical Engineering Imperial College London, UK

Research staff Postdoctoral and other research staff Dr Maria Alba-Martin Research Associate University of South Australia Dr Nicholas Ariotti Research Officer University of Queensland Dr Lakmali Atapattu Postdoctoral Researcher University of New South Wales Dr Michele Bastiani Postdoctoral Researcher University of Queensland Dr Craig Bell Postdoctoral Research Fellow University of Queensland Dr Nadja Bertleff-Zieschang Postdoctoral Researcher University of Melbourne Dr Quinn Besford Postdoctoral Researcher University of Melbourne Dr Mattias BjĂśrnmalm Postdoctoral Researcher University of Melbourne Dr Thomas Blin Research Fellow Monash University Dr Miriam Brandl Postdoctoral Researcher University of New South Wales Dr Julia Braunger Postdoctoral Researcher University of Melbourne Dr Meritxell Canals Research Fellow Monash University Dr Fu Changkui Postdoctoral Researcher University of Queensland Dr Pavel Cherepanov Postdoctoral Fellow University of Melbourne Dr Anna Cifuentes Research Associate University of South Australia Dr Jacob Coffey Postdoctoral Researcher University of Queensland Dr Christina Cortez-Jugo Postdoctoral Researcher University of Melbourne Dr Michael Crichton Postdoctoral Researcher University of Queensland

Dr Matthew Crum Postdoctoral Researcher Monash University

Dr Luojuan Hu Postdoctoral Researcher Monash University

Dr Stephen Parker Postdoctoral Researcher University of New South Wales

Dr Jiwei Cui Postdoctoral Researcher University of Melbourne

Dr Pie Huda Postdoctoral Research Fellow University of Queensland

Dr Hui Peng Postdoctoral Researcher University of Queensland

Dr Joseph Cursons Postdoctoral Researcher University of Melbourne

Dr AleksanDr Kakinen Research Fellow Monash University

Dr Joshua Peterson Laboratory manager University of New South Wales

Dr Yunlu Dai Postdoctoral Researcher University of Melbourne

Dr Pu Chun Ke Senior Research Fellow Monash University

Dr Sela Poâ&#x20AC;&#x2122;uha Postdoctoral Researcher University of New South Wales

Dr Alexandra Depelsenaire Postdoctoral Researcher University of Queensland

Dr Kristian Kempe Joint Research Fellow with Warwick University Monash University

Dr Daniel Poole Research Fellow Monash University

Dr Laura Edgington-Mitchell Research Fellow Monash University Dr Roey Elnathan Research Fellow University of South Australia Dr Francesca Ercole Research Fellow Monash University Dr Germain Fernando Senior Research Officer University of Queensland Dr Christopher Fife Postdoctoral Researcher University of New South Wales Dr Nicholas Fletcher Postdoctoral Fellow University of Queensland Dr Adrian Fuchs Postdoctoral Researcher University of Queensland Dr Jeroen Goos Research Fellow Monash University Dr Bin Guan Research Associate University of South Australia Dr Yi Guo Postdoctoral Researcher University of Queensland Dr Johan Gustafsson Research Associate University of South Australia Dr Thomas Hall Postdoctoral Researcher University of Queensland Dr Celine Heu Postdoctoral Researcher University of New South Wales Dr Zachary Houston Research Fellow University of Queensland Dr Christopher Howard Postdoctoral Fellow University of Queensland

Dr Biao Kong Postdoctoral Researcher University of Melbourne Dr Declan Kuch Postdoctoral Researcher University of New South Wales Dr Marion Le Grand Postdoctoral Researcher University of New South Wales

Dr Andrew Lilja Postdoctoral Researcher University of New South Wales Dr Shea Fern Lim Research Assistant (Professional) Monash University Dr Qingtao (Jason) Liu Research Fellow Monash University Dr Guillaume Longatte Postdoctoral Researcher University of New South Wales Dr Friederike Mansfeld Postdoctoral Researcher University of New South Wales Dr Adam Martin Postdoctoral Researcher University of New South Wales Dr Joshua McCarroll Postdoctoral Researcher University of New South Wales Dr Dharmini Mehta Research Fellow Monash University Dr Ekaterina Nam Research Associate University of New South Wales Dr Emilie Nehlig Research Associate University of South Australia Dr Susan Nixon Lab Manager University of Queensland

Dr Simon Puttick Postdoctoral Researcher University of Queensland Dr Tim Quach Research Fellow Monash University Dr John Quinn Senior Research Fellow Monash University Dr Md Arifur Rahim Postdoctoral Researcher University of Melbourne Dr Gishan Ratnayake PhD Student University of Queensland Dr Sougata Sinha Research Associate University of South Australia Dr Alexander Soeriyadi Postdoctoral Researcher University of New South Wales Dr Adrian Sulistio Research Fellow Monash University Dr Hang Ta Postdoctoral Researcher University of Queensland Dr Roya Tavallaie Postdoctoral Researcher University of New South Wales Dr Wee Teo Postdoctoral Researcher University of New South Wales Dr Nghia Truong Research Fellow Monash University Dr Robert Utama Postdoctoral Researcher University of New South Wales Dr Nicholas Andrew Veldhuis Research Fellow Monash University

CBNS Annual Report 2016 75

Dr Orazio Vittorio Postdoctoral Researcher University of New South Wales

Mr Charles Ferguson Research Assistant University of Queensland

Ms Efremova Varvara Research Assistant University of New South Wales

Dr Ting Yi Wang Postdoctoral Researcher University of Melbourne

Ms Helen Forgham Research Assistant University of New South Wales

Mr James Wilmot Research Assistant University of New South Wales

Dr James Webb Postdoctoral Researcher University of New South Wales

Ms Katelyn Gause Research Assistant University of Melbourne

Mr Jin Zhang Research Assistant University of Queensland

Dr Adam Wheatley Postdoctoral Researcher University of Melbourne

Mr Robert Healey Research Assistant University of New South Wales

Students

Dr Michael Whittaker Senior Research Fellow Monash University

Ms Hannah Kelly Research Assistant University of Melbourne

Mr Hazem Abdelmaksoud University of South Australia

Dr Paul Wilson Joint Research Fellow with Warwick University Monash University

Ms Kathleen Kimpton Research Assistant University of New South Wales

Dr Daniel Ming Tak Yuen Postdoctoral Fellow Monash University

Mr Alistair Laos Research Assistant University of New South Wales

Dr Gyeongwon Yun Postdoctoral Fellow University of Melbourne

Dr Shea Fern Lim Research Assistant (Professional) Monash University

Dr Cheng Zhang Postdoctoral Researcher University of Queensland

Ms Sarah Mann Research Assistant Monash University

Dr Elva Zhao Postdoctoral Researcher Monash University

Mr Nick Martel Research Assistant University of Queensland

Dr Wei (Joyce) Zhao Postdoctoral Researcher University of Queensland

Mr Alex Mason Research Assistant University of New South Wales

Dr Yuanhui Zheng Postdoctoral Researcher University of New South Wales

Dr Susan Nixon Lab Manager University of Queensland

Research support staff Ms Christiana (Christie) Agyei-Yeboah Research Assistant University of Queensland Ms Sheilajen (Vinca) Alcantara Research Assistant University of Melbourne Ms Moore Chen Research Assistant Monash University Mr Harry Copeland Research Assistant University of Queensland Miss Ewa Czuba Research Assistant Monash University Ms Tanya Dwarte Research Assistant/ Program Officer University of New South Wales

76 CBNS Annual Report 2016

Ms Rose-Marie Olsson Research Assistant University of New South Wales Dr Joshua Peterson Laboratory manager University of New South Wales Mr James Rae Research Assistant University of Queensland Ms Thippayawan (Pim) Ratanakomol Research Assistant (Masters student) University of Queensland Ms Sona Samuel Research Assistant University of New South Wales Ms Danielle Senyschyn Research Assistant Monash University Ms Jenny Tran Research Assistant University of Melbourne

PhD students

Ms Nabila Akhtar Monash University Ms Dewan Akhter University of Queensland Mr Mahbub Alam University of Queensland Mr Nicholas Alcaraz Monash University Ms Fidaâ&#x20AC;&#x2122;a Alshawawreh University of New South Wales Ms Tara Alvarez Monash University Mr Adit Ardana University of Queensland Mr Gregory Bass University of Melbourne Mr Brandon Binnie University of Queensland Mr Mattias BjĂśrnmalm University of Melbourne Mr Nathan Boase University of Queensland Mr Daniel Brundel Monash University Ms Enyuan Cao Monash University Mr Lachlan Carter University of New South Wales Mr Ian Cartmill University of Queensland Mr David Chang University of New South Wales Ms Xi (Cathy) Chen University of Melbourne Mr Ao Chen University of Queensland Mr Liyu Chen University of Queensland Ms Sun Cheng Monash University

Ms Rinku Chhasatia University of South Australia Dr Matthew Crum Monash University Mr Kristofer Cupic University of Melbourne Ms Ewa Czuba University of Melbourne Ms Qiong (Ada) Dai University of Melbourne Mr Bobo Daniel University of Queensland Ms Nayeleh Deircam University of Melbourne Mr Jesse Di Cello Monash University Mr Eric Du University of New South Wales Ms Genevieve Duche University of New South Wales Ms Gayathri Ediriweera University of Queensland Mr Lars Esser Monash University Mr Sanjun Fan University of New South Wales Mr Abbas Farahani University of New South Wales Mr Matthew Faria University of Melbourne Ms Orlagh Feeney Monash University Ms Helen Forgham University of New South Wales Ms Anna Gemmell University of Queensland Mr Joshua Glass University of Melbourne Mr James Grace Monash University Ms Gracia Gracia Monash University Mr Junling Guo University of Melbourne Mr Keying Guo University of South Australia Mr Fei Han University of New South Wales Mr Shadabul Haque Monash University Mr Md Musfizur Hassan University of New South Wales Mr Robert Healey University of New South Wales

Ms Linda Hong Monash University

Mrs Shebbrin Moonshi University of Queensland

Mr Manish Sriram University of New South Wales

Mr Jiang Zhen University of Queensland

Ms Susan Ireland University of New South Wales

Mr Saimon Moraes Silva University of New South Wales

Mr Ian Styles Monash University

Ms Kelly Zong University of New South Wales

Mr Jiaul Islam Monash University

Mr Walter Muskovic University of New South Wales

Mr Tomoya Suma University of Melbourne

Masters students

Mr Ibrahim Javed Monash University

Mr Hweeing Ng University of Queensland

Ms Estelle Suys Monash University

Mr Rebecca Hodgetts University of Melbourne

Ms Imanda Jayawardene University of Queensland

Ms Duyen Nguyen University of New South Wales

Mr Vincent Tan University of New South Wales

Mr Cheng (Johnson) Jiang University of New South Wales

Mr Ka Fung (Leo) Noi University of Melbourne

Ms Safura Taufik University of New South Wales

Mr Nachnicha Kongkatigumjorn University of Melbourne

Mr Yi (David) Ju University of Melbourne

Mr Pietro Pacchin Tomanin University of Melbourne

Ms Lih En Tiah Monash University

Mr WooRam Jung University of Queensland

Mr Shuaijun Pan University of Melbourne

Ms Kristel Tjandra University of New South Wales

Ms Mohadesseh Kahram University of New South Wales

Ms Raheleh Pardekhorram University of New South Wales

Ms Nicole Van der Berg University of Queensland

Ms Felicity Kao University of New South Wales

Ms Maryam Parviz University of New South Wales

Ms Kesarwani Vidhishri Monash University

Mr Song Yang Khor Monash University

Ms Amanda Pearce University of Queensland

Ms Julie Walker Monash University

Ms Ruby Kochappan Monash University

Ms Emily Pilkington Monash University

Mr Miaoyi (Marvin) Wang Monash University

Mr Alistair Laos University of New South Wales

Ms Ranjana Piya University of New South Wales

Mr Hareth Wassit Monash University

Ms Given Lee Monash University

Mr Bijan Po University of New South Wales

Mr Jonathan Wei University of Queensland

Mr Hong Seng (Nick) Lee University of Queensland

Mr Md Arifur Rahim University of Melbourne

Ms Alessia Weiss University of Melbourne

Ms Tang Li Monash University

Mr Pradeep Rajasekhar Monash University

Mr Gan Lin University of Melbourne

Dr Gishan Ratnayake University of Queensland

Mr Nicholas Westra van Holthe University of Queensland

Ms Haiyin Liu University of Melbourne

Mr Samuel Richardson University of Queensland

Mr Yi Liu University of Melbourne

Mr Kye Robinson Monash University

Mr Xun Lu University of New South Wales

Mr Andrew Robinson University of New South Wales

Mr Yong (Jerry) Lu University of New South Wales

Mr Abu Sadat Md. Sayem Rahman University of New South Wales

Ms Joanne Ly Monash University Mr Yutian Ma University of Melbourne Ms Quynh Mai Monash University Mr Alex Mason University of New South Wales Mr Mark Mathew University of Queensland Ms Georgia Miller University of New South Wales Ms Mahdie Mollazade University of New South Wales

Mr Jonathan Wojciechowski University of New South Wales Mr Marcin Wojinilowicz University of Melbourne Ms Adelene Wong Monash University Mr Chin (Ken) Wong University of New South Wales Mr Yanfang Wu University of New South Wales

Mrs Laura Selby Monash University

Mr Ken Yong Monash University

Mr Saimon Silva University of New South Wales

Ms Sul Hwa (Elly) Yu Monash University

Mr Amal Sivaram University of Queensland

Ms Leila Zarei University of New South Wales

Ms Danzi Song University of Melbourne

Mr Wenjie Zhang University of Melbourne

Ms Jiaying Song University of Melbourne

Mr Dexiang Zhang University of South Australia

Ms Parisa Sowti University of New South Wales

Ms Manchen Zhao University of New South Wales Ms Yongmei Zhao University of Queensland

Ms Ngoc Mai Vu Monash University

Honours students Ms Farah Azme University of Queensland Mr Lin Ian University of New South Wales Mr Lawler Michael University of New South Wales Mr Peter Oâ&#x20AC;&#x2122;Mara University of New South Wales Ms Sophie Trieu Monash University Mr Dimuthu Wickramasinghe Monash University

Administrative staff Ms Gabrielle Bright Monash University Centre Manager (Until December 2016) Ms Barbara Chamberlain University of South Australia Administrator Ms Carla Gerbo University of Queensland Executive Assistant to Professor Mark Kendall Dr Natalie Jones Monash University Centre Manager (From December 2016) Ms Tara McGilligan University of New South Wales Executive Assistant to Professor Maria Kavallaris Mr Jason Murphy Monash University Senior Events and Communications Coordinator Mr Marc Riemer University of Melbourne Administrator Mrs Katrina Sewell Monash University Centre Administrator â&#x20AC;&#x192;

CBNS Annual Report 2016 77

Visitors to the CBNS The CBNS has hosted a diverse range of visitors from academia and industry during 2016. CBNS visitors have presented seminars and met with research staff and students to establish collaborations and to investigate potential commercialisation opportunities.

Visitors from national organisations Professor Damien Arrigan Curtin University, Australia Dr Toby Bell Monash University, Australia Dr Alfonso Garcia-Bennett Macquarie University, Australia Professor James Camakaris The University of Melbourne, Australia Professor Michelle Coote Australian National University, Australia Associate Professor Ross Dickins Monash University, Australia Professor Heike Ebendorff-Heidepriem The University of Adelaide, Australia Professor Amanda Ellis Flinders University, Australia Dr Charles Farnsworth Cell Signalling Technology, Australia Professor Bart Follink Head of Chemistry Monash University, Australia

78 CBNS Annual Report 2016

Associate Professor John Forsythe Monash University, Australia

Dr Belinda Parker La Trobe University, Australia

Dr Johan Gustafsson University of South Australia, Australia

Professor Clive Prestidge University of South Australia, Australia

Professor Christoph Hagemeyer Monash University, Australia

Professor Gail Risbridger Peter MacCallum Cancer Centre, Australia

Professor David Huang Walter and Eliza Hall Institute of Medical Research, Australia

Professor Phillip Robinson The University of Sydney, Australia

Professor Mark Hutchinson The University of Adelaide, Australia Professor Killugudi Swaminatha Iyer The University of Western Australia, Australia

Professor Alan Rowan University of Queensland, Australia Dr Samir Taoudi Walter and Eliza Hall Institute of Medical Research, Australia

Dr Anna Johnston CSIRO, Australia

Dr Paul Timpson Garvan Institute of Medical Research, Australia

Dr Declan Kuch UNSW, Australia

Professor Brandon Wainwright The University of Queensland, Australia

Associate Professor Lyria B Moses University of New South Wales, Australia

Professor Tiff Walsh Deakin University, Australia

Dr Richard Di Natale Australian Greens Party, Australia

Professor Dave Winkler CSIRO, Australia

Visitors from international organisations Professor Cameron Alexander University of Nottingham, UK Mr Ananda Anandapadmanabhan Indian Institute of Science Education and Research, India Ms Nuria Pena Auladell Universitat Ramon Llull, Spain

Professor David Haddleton University of Warwick, UK Dr Curtis Harris National Cancer Institute, USA Dr Brandy Houser Celdara Medical, USA Dr Shinichiro Iwamoto National Institute of Advanced Industrial Science and Technology, Japan

Professor Eric Bakker University of Geneva, Switzerland

Professor Xingyu Jiang National Center for Nanoscience and Technology, China

Dr Alessandro Bertucchi University of Rome Tor Vergata, Italy

Dr Silke Krol Istituto tumori “Giovanni Paolo II”, Italy

Associate Professor Diana M Bowman Arizona State University, USA

Dr Annette Kuenkele Charité Universitätsmedizin Berlin, Germany

Professor Volga Bulmis Izmir Institute of Technology, Turkey

Associate Professor James Lai University of Washington, USA

Dr Jane Calvert University of Edinburgh, UK

Professor Jason Lewis Memorial Sloan-Kettering Cancer Centre, USA

Professor Felix Castellano North Carolina State University, USA Mr Edgar Eduardo Antunez Ceron Autonomous University of the State of Morelos, Mexico

Dr Sijie Lin Tongji University, China Professor Sijie Lin Tongji University, China

Dr Pavel Cherepanov University of Bayreuth. Germany

Dr Xian Jun Loh National University of Singapore, Singapore

Dr Giuseppe Cirillo The University of Calabria, Italy

Dr Jack London Thomas Jefferson University, USA

Professor Heather Clark Northeastern University, USA

Professor Ian Manners University of Bristol, UK

Professor Andy Cooper University of Liverpool, UK

Professor Keji Maruoka Kyoto University, Japan

Professor Pengyang Deng Changchun Institute of Aplied Chemistry, China

Professor Raffaele Mezzenga Eth Zurich, Switzerland

Professor Feng Ding Clemson University, USA Professor Angelika Eggert Berlin School of Integrative Oncology, Germany

Professor Daisuke Nagao Tohoku University, Japan Professor Guagjun Nie National Centre for Nanoscience and Technology, China

Dr Annette Kuenkele

Professor Andrew Spakowitz Stanford University, USA Professor Jerry Sobelman University of Minnesota, USA Professor Patrick Stayton University of Washington, USA Professor Atsushi Takahara Kyushu University, Japan Professor Eri Tanaka Tohoku University, Japan Professor Xiaolin Tang Fudan University, China Professor Joseph Wang University of California, San Diego, USA Professor Yajun Wang Fudan University, China Professor Arieh Warshel University of Southern California, USA Dr Kanako Watanabe Tohoku University, Japan Professor Paul Weiss University of California, Los Angeles, USA Professor George Whitesides Harvard University, USA

Professor Jae Hyung Park Sungkyunkwan University, South Korea

Professor James Wilsdon Sheffield University, UK

Professor Bronwyn Parry King’s College London, UK

Professor Gi-Ra Yi Sungkyunkwan University, South Korea

Professor Addy Pross Ben-Gurion University of the Negev, Israel

Professor Pil J. Yoo Sungkyunkwan University, South Korea

Professor Kun Qian Shanghai Tongji University, China

Professor Afang Zhang Shanghai University, China

Dr Peter Goelitz Wiley-VCH, Germany

Professor Vincent Rotello University of Massachusetts at Amherst, USA

Professor Haijiao Zhang Shanghai University, China

Dr Peter Gölitz Wiley-VCH, Germany

Professor Mitsuo Sawamoto Kyoto University, Japan

Professor Véronique Gouverneur Oxford University, UK

Professor Baojian Shen China University of Petroleum, China

Professor David Grainger The University of Utah, USA

Professor Jun Shen Shanghai Tongji University, China

Dr Markus Elsner Nature Biotechnology, Germany Professor Jan H van Esch Delft University of Technology, Netherlands Dr Tito Fojo Columbia University Medical Centre, USA Professor Stephan Förster University of Bayreuth, Germany

Mr Yunti Zhang Wuhan University, China Professor Dongyuan Zhao Fudan University, China Professor Ruhong Zhou IBM/Columbia University, USA

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Publications Books and book chapters Boyd, B., 2016, Applications of Small Angle X-ray Scattering in Pharmaceutical Science, in Analytical Techniques in the Pharmaceutical Sciences, Springer-Verlag, New York, pp. 339-360. Byrne, F.L., McCarroll, J.A. and Kavallaris, M. 2016, Analyses of Tumor Burden In Vivo And Metastasis Ex Vivo Using Luciferase-Expressing Cancer Cells in an Orthotopic Mouse Model of Neuroblastoma, in Methods in Molecular Biology, pp. 61-77. 2016, Remaking Participation: Science, Environment and Emergent Publics, Chilvers J., Kearnes M., eds. Routledge, Abingdon. Chilvers J., Kearnes M., 2016, Preface, in Remaking Participation: Science, Environment and Emergent Publics, Routledge, Abingdon, Oxon, pp. XIII. Chilvers J., Kearnes M., 2016, Science, Democracy and Emergent Publics’, in Remaking Participation: Science, Environment and Emergent Publics, Routledge, Abingdon, Oxon, pp. 1-27. Chilvers J., Kearnes M., 2016, ‘Participation in the Making: Rethinking Public Engagement in Co-Productionist terms’, in Remaking Participation: Science, Environment and Emergent Publics, Routledge, Abingdon, Oxon, pp. 31-63. Chilvers J., Kearnes M., 2016, ‘Remaking Participation Towards Reflexive Engagement’, in Remaking Participation: Science, Environment and Emergent Publics, Routledge, Abingdon, Oxon, pp. 261-288. Corrie S., Kendall MAF, 2017, Trandsdermal Drug Delivery, in Drug Delivery: Fundamentals and Applications, 2 ed, pp. 215-228, CRC Press/ Taylor & Francis Group, Florida. (Published 2016).

Crichton M.L., Kendall M.A.F., 2017, Nanopatches for Vaccine Delivery, in Micro and Nanotechnologies for Vaccine Development, 1 ed, Skwarczynski & Toth, et al., Elsevier. Oxford; Cambridge, pp. 343-354. (Published October 2016). Depelsenaire A.C.I., Kendall, M.A.F, Young P.R., Muller D.A., 2017, Introduction to Vaccines and Vaccination, in Micro and Nanotechnology in Vaccine Development, 1 ed, Skwarczynski & Toth, et al., Elsevier, Oxford; Cambridge, pp. 47-59. (Published October 2016). Fletcher, N. and Thurecht, K., 2016, Molecular imaging utilizing Aptamer-targeted probes, in Aptamers. Tools for Nanotherapy and Molecular Imaging, CRC Press, Taylor & Francis Group, Florida. Johnston, A., 2016, Analysis of Intracellular Trafficking of Dendritic Cell Receptors for Antigen Targeting, in Dendritic Cell Protocols, Springer, New York, pp. 199-209. Sharbeen G., McAlpine S., Phillips P., 2016, ‘HSP47: The New Heat Shock Protein Therapeutic Target’, in Topics in Medicinal Chemistry, pp. 197-220. Silva S.M., Gooding, J., 2016, Dispersible Electrodes: An Approach to Developing Sensing Devices That Can Quickly Detect Ultralow Concentrations Of Analyte’, in RSC Detection Science, 6 ed, pp. 279-295. Mansfeld F.M., Davis T.P., Kavallaris M., 2017, “Nanotechnology in Medical Research”, in Micro and Nanotechnologies for Vaccine Development, 1 ed, Skwarczynski & Toth, et al., Elsevier, Oxford; Cambridge, pp. 21-39. (Published October 2016).

Journal articles Akhlaghi, S. P.; Ribeiro, I. R.; Boyd, B. J.; Loh, W., Impact of preparation method and variables on the internal structure, morphology, and presence of liposomes in Phytantriol-pluronic® F127 cubosomes, Colloids and Surfaces B: Biointerfaces, 2016, 845-853. Alskär, L. C.; Porter, C. J. H.; Bergström, C. A. S., Tools for early prediction of drug loading in Lipid-based ormulations, Molecular Pharmaceutics, 2016, 1, 251-261. Ana-Sosa-Batiz, F.; Vanderven, H.; Jegaskanda, S.; Johnston, A.; Rockman, S.; Laurie, K.; Barr, I.; Reading, P.; Lichtfuss, M.; Kent, S.J., Influenza-specific antibodydependent phagocytosis, PLoS ONE, 2016, 4, e0154461. Anastasaki, A.; Nikolaou, V.; Haddleton, D.M., Cu(0)mediated living radical polymerization: Recent highlights and applications; A perspective, Polymer Chemistry, 2016, 5, 1002-1026. Anastasaki, A.; Nikolaou, V.; Nurumbetov, G.; Wilson, P.; Kempe, K.; Quinn, J. F.; Davis, T. P.; Whittaker, M. R.; Haddleton, D. M., Cu(0)-Mediated Living Radical Polymerization: A Versatile Tool for Materials Synthesis, Chemical Reviews, 2016, 3, 835-877. Andres-Arroyo, A.; Gupta, B.; Wang, F.; Gooding, J.J.; Reece, P.J., Optical Manipulation and Spectroscopy of Silicon Nanoparticles Exhibiting Dielectric Resonances, Nano Letters, 2016, 3, 1903-1910. Andrews, M.C.; Cursons, J.; Hurley, D.G.; Anaka, M.; Cebon, J.S.; Behren, A.; Crampin, E.J., Systems analysis identifies miR-29b regulation of invasiveness in melanoma, Molecular Cancer, 2016, 1, 72. Anouschka, A.; Claire, V.; George, S.; Sean, C.W.; Paul, T,; Phoebe, A.P., Novel therapeutics and preclinical imaging for pancreatic cancer – View from the lab, Cancer Forum, 2016, 1, 16-22. Azhari, H.; Strauss, M.; Hook, S.; Boyd, B. J.; Rizwan, S. B.,

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Stabilising cubosomes with Tween 80 as a step towards targeting lipid nanocarriers to the bloodbrain barrier, European Journal of Pharmaceutics and Biopharmaceutics, 2016, 148-155. Balmer, A.S.; Calvert, J.; Marris, C.; Molyneux-Hodgson, S.; Frow, E.; Kearnes, M.; Bulpin, K.; Schyfter, P.; Mackenzie, A.; Martin, P., Five Rules of Thumb for Post-ELSI Interdisciplinary Collaborations, Journal of Responsible Innovation, 2016, 1, 73-80. Barner-Kowollik, C.; D’Agosto, F.; Perrier, S.; Whittaker, A. K.; Schönherr H., Australian European self-assembly through macromolecular interactions, Macromolecular Chemistry and Physics, 2016, 20, 2207-2208. Beck, S. E.; Queen, S. E.; Viscidi, R.; Johnson, D.; Kent, S. J.; Adams, R. J.; Tarwater, P.M.; Mankowski, J. L., Central nervous systemspecific consequences of simian immunodeficiency virus Gag escape from major histocompatibility complex class I-mediated control, Journal of Neurovirology, 2016, 4, 498-507. Bennett, T. M.; Jack, K. S.; Thurecht, K. J.; Blakey, I., Perturbation of the Experimental Phase Diagram of a Diblock Copolymer by Blending with an Ionic Liquid, Macromolecules, 2016, 1, 205-214. Bergström, C.; Porter, C., Understanding the Challenge of Beyond-Rule-of-5 Compounds, Advanced Drug Delivery Reviews, 2016, 1-5. Bergströma, C. A.; Charman, W. N.; Porter, C. J. H., Computational prediction of formulation strategies for beyond-rule-of-5 compounds, Advanced Drug Delivery Reviews, 2016, 6-21. Björnmalm, M.; Faria, M.; Caruso, F., Increasing the Impact of Materials in and beyond Bio-Nano Science, Journal of the American Chemical Society, 2016, 41, 13449-13456.

Björnmalm, M.; Faria, M.; Chen, X.; Cui, J.; Caruso, F., Dynamic Flow Impacts Cell-Particle Interactions: Sedimentation and Particle Shape Effects, Langmuir, 2016, 42, 1099511001. Blin, T.; Kakinen, A.; Pilkington, E.H.; Ivask, A.; Ding, F.; Quinn, J.F.; Whittaker, M.R.; Ke, P.C.; Davis, T.P. , Synthesis and in vitro properties of iron oxide nanoparticles grafted with brushed phosphorylcholine and polyethylene glycol, Polymer Chemistry, 2016, 10, 1931-1944. Bobo, D.; Robinson, K. J.; Islam, J.; Thurecht, K. J.; Corrie, S. R., Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date, Pharmaceutical Research, 2016, 10, 2373-2387. Boetker, J. P.; Rantanen, J.; Arnfast, L.; Doreth, M.; Raijada, D.; Loebmann, K.; Madsen, C.; Khan, J.; Rades, T.; Müllertz, A.; Hawley, A.; Thomas, D.; Boyd, B. J., Anhydrate to hydrate solid-state transformations of carbamazepine and nitrofurantoin in biorelevant media studied in situ using time-resolved synchrotron X-ray diffraction, European Journal of Pharmaceutics and Biopharmaceutics, 2016, 119-127. Boyd, B.; Alcaraz, N., Cubosomes as carriers for MRI contrast agents, Current medicinal chemistry, 2016, 42. Budden, D.M.; Crampin, E.J., Distributed gene expression modelling for exploring variability in epigenetic function, BMC Bioinformatics, 2016, 1, 446. Budden, D.M.; Crampin, E.J., Information theoretic approaches for inference of biological networks from continuous-valued data, BMC Systems Biology, 2016, 1, 89. Byrne, F. L.; McCarroll, J. A.; Kavallaris, M., Analyses of Tumor Burden In Vivo and Metastasis Ex Vivo Using LuciferaseExpressing Cancer Cells in an Orthotopic Mouse Model of Neuroblastoma, Methods in Molecular Biology, 2016, 61-77. Carrington, B.; Al-Ejeh, F.; Lim, Y.C.; Ensbey, K.; Bruce, Z.; Jamieson, P.; Fuchs, A.; Thurecht, K.; Stringer, B.;

Boyd, A., PDTB-19. EphA receptor tyrosine kinases as targets for theapy in paediatric medulloblastoma, NeuroOncology, 2016, 6, vi153-vi154. Cecil, J.D.; O’Brien-Simpson, N.M.; Lenzo, J.C.; Holden, J.A.; Chen, Y.-Y.; Singleton, W.; Gause, K.T.; Yan, Y.; Caruso, F.; Reynolds, E.C., Differential Responses of Pattern Recognition Receptors to Outer Membrane Vesicles of Three Periodontal Pathogens, PLoS ONE, 2016, 4, e0151967. Cetó, X.; Voelcker, N. H.; Prieto-Simón, B., Bioelectronic tongues: New trends and applications in water and food analysis, Biosensors and Bioelectronics, 2016, 608-626. Chai, Y.J.; Sierecki, E.; Tomatis, V.M.; Gormal, R.S.; Giles, N.; Morrow, I.C.; Xia, D.; Götz, J.; Parton, R.G.; Collins, B.M.; Gambin, Y.; Meunier, F.A., Munc18-1 is a molecular chaperone for α-synuclein, controlling its self-replicating aggregation, Journal of Cell Biology, 2016, 6, 705-718. Chan, L. J.; Ascher, D. B.; Yadav, R.; Bulitta, J. B.; Williams, C. C.; Porter, C. J. H.; Landersdorfer, C. B.; Kaminskas, L. M., Conjugation of 10 kDa Linear PEG onto Trastuzumab Fab’ Is Sufficient to Significantly Enhance Lymphatic Exposure while Preserving in Vitro Biological Activity, Molecular Pharmaceutics, 2016, 4, 1229-1241. Chen, A.; Blakey, I.; Whittaker, A. K.; Peng, H., The influence of casting parameters on the surface morphology of PS-b-P4VP honeycomb films, Journal of Polymer Science Part A: Polymer Chemistry, 2016, 23, 3721-3732. Chen, X.; Cui, J.; Ping, Y.; Suma, T.; Cavalieri, F.; Besford, Q.A.; Chen, G.; Braunger, J.A.; Caruso, F. , Probing cell internalisation mechanics with polymer capsules, Nanoscale, 2016, 39, 17096-17101. Chen, X.; Cui, J.; Sun, H.; Müllner, M.; Yan, Y.; Noi, K.F.; Ping, Y.; Caruso, F., Analysing intracellular deformation of polymer capsules using structured illumination microscopy, Nanoscale, 2016, 23, 11924-11931.

Chen, X.; Liu, Z.; Parker, S.G.; Zhang, X.; Gooding, J.J.; Ru, Y.; Liu, Y.; Zhou, Y., Light-Induced Hydrogel Based on TumorTargeting Mesoporous Silica Nanoparticles as a Theranostic Platform for Sustained Cancer Treatment, ACS Applied Materials and Interfaces, 2016, 25, 15857-15863. Chen, X.; Yan, Y.; Müllner, M.; Ping, Y.; Cui, J.; Kempe, K.; Cortez-Jugo, C.; Caruso, F., Shape-Dependent Activation of Cytokine Secretion by Polymer Capsules in Human MonocyteDerived Macrophages, Biomacromolecules, 2016, 3, 1205-1212. Choi, G.H.; Rhee, D.K.; Park, A.R.; Oh, M.J.; Hong, S.; Richardson, J.J.; Guo, J.; Caruso, F.; Yoo, P.J., Ag nanoparticle/ polydopamine-coated inverse opals as highly efficient catalytic membranes, ACS Applied Materials and Interfaces, 2016, 5, 3250-3257. Cipolla, D.; Wu, H.; Salentinig, S.; Boyd, B.; Rades, T.; Vanhecke, D.; Petri-Fink, A.; RothinRutishauser, B.; Eastman, S.; Redelmeier, T.; Gonda, I.; Chan, H.K., Formation of drug nanocrystals under nanoconfinement afforded by liposomes, RSC Advances, 2016, 8, 6223-6233. Cirillo, G.; Curcio, M.; Vittorio, O.; Spizzirri, U. G.; Nicoletta, F. P.; Picci, N.; Hampel, S.; Iemma, F., Dual Stimuli Responsive Gelatin-CNT Hybrid Films as a Versatile Tool for the Delivery of Anionic Drugs, Macromolecular Materials and Engineering, 2016, 12, 1537–1547. Coffey, J. W.; Meliga, S. C.; Corrie, S. R.; Kendall, M. A. F., Dynamic application of microprojection arrays to skin induces circulating protein extravasation for enhanced biomarker capture and detection, Biomaterials, 2016, 13-143. Collins, J.; Kempe, K.; Wilson, P.; Blindauer, C. A.; McIntosh, M. P.; Davis, T. P.; Whittaker, M. R.; Haddleton, D. M., Stability Enhancing N-Terminal PEGylation of Oxytocin Exploiting Different Polymer Architectures and Conjugation Approaches, Biomacromolecules, 2016, 8, 2755-2766.

Cornely, R.; Pollock, A.H.; Rentero, C.; Norris, S.E.; AlvarezGuaita, A.; Grewal, T.; Mitchell, T.; Enrich, C.; Moss, S.E.; Parton, R.G.; Rossy, J.; Gaus. K., Annexin A6 regulates interleukin-2mediated T-cell proliferation, Immunology and Cell Biology, 2016, 6, 543-553. Corrie, S. R.; Thurecht, K. J., Nano-Bio Interactions: Guiding the Development of Nanoparticle Therapeutics, Diagnostics, and Imaging Agents, Pharmaceutical Research, 2016, 10, 23112313. Crichton, M.L.; Muller, D.A.; Depelsenaire, A.C.I.; Pearson, F.E.; Wei, J.; Coffey, J.; Zhang, J.; Fernando, G.J.; Kendall, M.A.F, The changing shape of vaccination: Improving immune responses through geometrical variations of a microdevice for immunization, Scientific Reports, 2016, , 27217. Crichton, M. L.; Archer-Jones, C.; Meliga, S.; Edwards, G.; Martin, D.; Huang, H.; Kendall, M. A. F., Characterising the material properties at the interface between skin and a skin vaccination microprojection device, Acta Biomaterialia, 2016, 186-194. Crum, M. F.; Trevaskis, N. L.; Williams, H. D.; Pouton, C. W.; Porter, C. J. H., A new in vitro lipid digestion – In vivo absorption model to evaluate the mechanisms of drug absorption from lipid-based formulations, Pharmaceutical Research, 2016, 4, 970-982. Cui, J.; Faria, M.; Björnmalm, M.; Ju, Y.; Suma, T.; Gunawan, S. T.; Richardson, J. J.; Heidari, H.; Bals, S.; Crampin, E. J.; Caruso, F., A Framework to Account for Sedimentation and Diffusion in Particle–Cell Interactions, Langmuir, 2016, 47, 1239412402. Cui, J.; Hibbs, B.; Gunawan, S. T.; Braunger, J. A.; Chen, X.; Richardson, J. J.; Hanssen, E.; Caruso, F., Immobilized Particle Imaging for Quantification of Nano- and Microparticles, Langmuir, 2016, 14, 35323540. Cui, J.; Richardson, J. J.; Björnmalm, M.; Faria, M.; Caruso, F., Nanoengineered Templated Polymer Particles: Navigating the Biological Realm, Accounts of Chemical Research, 2016, 6, 1139-1148.

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Cullen, J.K.; Murad, N.A.; Yeo, A.; McKenzie, M.; Ward, M.; Chong, K.L.; Schieber, N.L.; Parton, R.G.; Lim, Y.C.; Wolvetang, E.; Maghzal, G.J.; Stocker, R.; Lavin, M.F., AarF domain containing kinase 3 (ADCK3) mutant cells display signs of oxidative stress, defects in mitochondrial homeostasis and lysosomal accumulation, PLoS One, 2016, 4, e0148213. Dalilottojari, A.; Delalat, B.; Harding, F. J.; Cockshell, M. P.; Bonder, C. S.; Voelcker, N. H., Porous Silicon-Based Cell Microarrays: Optimizing Human Endothelial CellMaterial Surface Interactions and Bioactive Release, Biomacromolecules, 2016, 11, 3724-3731. de Jongh, P.A.; Bennett, M.R.; Sulley, G.S.; Wilson, P.; Davis, T.P.; Haddleton, D.M.; Kempe, K., Facile one-pot/one-step synthesis of heterotelechelic: N -acylated poly(aminoester) macromonomers for carboxylic acid decorated comb polymers, Polymer Chemistry, 2016, 44, 6703-6707. De Koker, S.; Cui, J.; Vanparijs, N.; Albertazzi, L.; Grooten, J.; Caruso, F.; De Geest, B. G., Engineering Polymer Hydrogel Nanoparticles for Lymph NodeTargeted Delivery, Angewandte Chemie – International Edition, 2016, 4, 1334-1339. Du, J. D.; Fong, W.K.; Caliph, S.; Boyd, B.J., Lipid-based drug delivery systems in the treatment of wet age-related macular degeneration, Drug Delivery and Translational Research, 2016, 6, 781-792. Edgington-Mitchell, L.E.; Wartmann, T.; Fleming, A.K.; Gocheva, V.; van der Linden, W.A.; Withana, N.P.; Verdoes, M.; Aurelio, L.; Edgington-Mitchell, D.; Lieu, T.; Parker, B.S.; Graham, B.; Reinheckel, T.; Furness, J.B.; Joyce, J.A.; Storz, P.; Halangk, W.; Bogyo, M.; Bunnet, N.W., Legumain is activated in macrophages during pancreatitis, American Journal of Physiology – Gastrointestinal and Liver Physiology, 2016, 3, G548-G560. Ercole, F.; Mansfeld, F. M.; Kavallaris, M.; Whittaker, M. R.; Quinn, J. F.; Halls, M. L.; Davis, T. P., Macromolecular Hydrogen Sulfide Donors Trigger Spatiotemporally Confined Changes in Cell Signaling,

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Biomacromolecules, 2016, 1, 371-383. Feeney, O. M.; Crum, M. F.; McEvoy, C. L.; Trevaskis, N. L.; Williams, H. D.; Pouton, C. W.; Charman, W. N.; Bergström, C. A. S.; Porter, C. J. H., 50 years of oral lipid-based formulations: Provenance, progress and future perspectives, Advanced Drug Delivery Reviews, 2016, 167-194. Fernando, G. J. P.; Zhang, J.; Ng, H. I.; Haigh, O. L.; Yukiko, S. R.; Kendall, M. A. F., Influenza nucleoprotein DNA vaccination by a skin targeted, dry coated, densely packed microprojection array (Nanopatch) induces potent antibody and CD8+ T cell responses, Journal of Controlled Release, 2016, 35-41. Fife, C.; Sagnella, S.; Teo, W.; Po’uha, S.; Byrne, F.; Yeap, Y.; Ng, D.; Davis, T.; McCarroll, J.; Kavallaris, M, Stathmin mediates neuroblastoma metastasis in a tubulin-independent manner via RhoA/ROCK signaling and enhanced transendothelial migration, Oncogene, 2016, 4, 501-511. Fletcher, N.; Ardana, A.; Thurecht, K.J., Preclinical Imaging of siRNA Delivery, Australian Journal of Chemistry, 2016, 10, 1073-1077. Follett, J.; Bugarcic, A.; Yang, Z.; Ariotti, N.; Norwood, S.J.; Collins, B.M.; Parton, R.G.; Teasdale, R.D. , Parkinson’s disease linked Vps35 R524W mutation impairs the endosomal association of retromer and induces a-synuclein aggregation, Journal of Biological Chemistry, 2016, 35, 18283-18298. Fong, W. K.; Hanley, T. L.; Thierry, B.; Hawley, A.; Boyd, B. J.; Landersdorfer, C. B., External manipulation of nanostructure in photoresponsive lipid depot matrix to control and predict drug release in vivo, Journal of Controlled Release, 2016, 67-73. Fong, W. K.; Negrini, R.; Vallooran, J. J.; Mezzenga, R.; Boyd, B. J., Responsive selfassembled nanostructured lipid systems for drug delivery and diagnostics, Journal of Colloid and Interface Science, 2016, , 320-339. Gan, W.J.; Zavortink, M.; Ludick, C.; Templin, R.; Webb, R.; Webb, R.; Ma, W.; Poronnik, P.; Parton,

R.G.; Gaisano, H.Y.; Shewan, A.M.; Thorn, P., Cell polarity defines three distinct domains in pancreatic beta cells, Journal of Cell Science, 2016, 1, 143-151. Gause, K. T.; Yan, Y.; O’BrienSimpson, N. M.; Cui, J.; Lenzo, J. C.; Reynolds, E. C.; Caruso, F., Codelivery of NOD2 and TLR9 Ligands via Nanoengineered Protein Antigen Particles for Improving and Tuning Immune Responses, Advanced Functional Materials, 2016, 41, 7526-7536. Gavin, P. D.; El-Tamimy, M.;, Keah, H, H.; Boyd, B. J., Tocopheryl phosphate mixture (TPM) as a novel lipid-based transdermal drug delivery carrier: formulation and evaluation, Drug Delivery and Translational Research, 2016, 53-65. Gawthrop, P.J.; Crampin, E.J. , Modular bond-graph modelling and analysis of biomolecular systems, IET Systems Biology, 2016, 5, 187-201. Gebala, M.; La Mantia, F.; Michaels, P. E.; Ciampi, S.; Gupta, B.; Parker, S. G.; Tavallaie, R.; Gooding, J. J. , Electric field modulation of silicon upon tethering of highly charged nucleic acids. Capacitive studies on DNA-modified silicon (111), Electroanalysis, 2016, 10, 2367-2372. Glass, J.J.; Kent, S.J.; De Rose, R., Enhancing dendritic cell activation and HIV vaccine effectiveness through nanoparticle vaccination, Expert Review of Vaccines, 2016, 6, 719-729. Glass, J.J.; Yuen, D.; Rae, J.; Johnston, A.P.; Parton, R.G.; Kent, S.J.; De Rose, R. , Human immune cell targeting of protein nanoparticles-caveospheres, Nanoscale, 2016, 15, 82558265 Gonçales, V. R.; Wu, Y.; Gupta, B.; Parker, S. G.; Yang, Y.; Ciampi, S.; Tilley, R.; Gooding, J. J., Stability of Chemically Passivated Silicon Electrodes in Aqueous Solutions: Interplay between Bias Voltage and Hydration of the Electrolyte, Journal of Physical Chemistry C, 2016, 29, 15941-15948 Gooding, J. J; Gaus, K., Single-Molecule Sensors: Challenges and Opportunities for Quantitative Analysis, Angewandte Chemie –

International Edition, 2016, 38, 11354-11366. Gooneratne, S.L.; Center, R.J.; Kent, S.J.; Parsons, M.S., Functional advantage of educated KIR2DL1+ natural killer cells for anti-HIV-1 antibody-dependent activation, Clinical and Experimental Immunology, 2016, 1, 101-109. Guinan, T. M.; Kobus,H.; Lu, Y.; Sweetman, M.; McInnes, S. J. P.; Kirkbride K. P.; Voelcker N. H., Nanostructured Silicon-Based Fingerprint Dusting Powders for Enhanced Visualization and Detection by Mass Spectrometry, ChemPlusChem, 2016, 3, 258-261. Guinan, T. M.; Neldner, D.; Stockham, P.; Kobus, H.; Della Vedova C. B.; Voelcker N. H. , Porous silicon mass spectrometry as an alternative confirmatory assay for compliance testing of methadone, Drug Testing and Analysis, 2016. Gunawan, C. A.; Nam, E. V.; Marquis, C. P.; Gooding, J. J.; Thordarson P.; Zhao, C., Scanning Electrochemical Microscopy of Cytochrome c Peroxidase through the Orientation-Controlled Immobilisation of Cytochrome c, ChemElectroChem, 2016, 7, 1150-1156. Guo, J.; Tardy, B.L.; Christofferson, A.J.; Dai, Y.; Richardson, J.J.; Zhu, W.; Hu, M.; Ju, Y.; Cui, J.; Dagastine, R.R; Yarovsky, I; Caruso, F, Modular assembly of superstructures from polyphenol-functionalized building blocks, Nature Nanotechnology, 2016, 12, 1105-1111. Gurzov,E. N.; Wang, B.; Pilkington, E. H.; Chen, P.; Kakinen, A.; Stanley, W. J.; Litwak, S. A.; Hanssen, E. G.; Davis, T. P.; Ding F.; Ke, P. C, Inhibition of hIAPP Amyloid Aggregation and Pancreatic β-Cell Toxicity by OHTerminated PAMAM Dendrimer, Small, 2016, 12, 1615-1626. Gurzov, E. N., Wang, B., Pilkington, E. H., Chen, P., Kakinen, A., Stanley, W. J., Litwak, S. A., Hanssen, E. G., Davis, T. P., Ding, F. and Ke, P. C. (2016), Inhibition of hIAPP Amyloid Aggregation and Pancreatic β-Cell Toxicity by OHTerminated PAMAM Dendrimer. Small, 12: 1615–1626.

Hall, T.E.; Ariotti, N.; Ferguson, C.; Xiong, Z.; Parton, R.G., New transgenic lines for localization of GFP-tagged proteins by electron microscopy, Zebrafish, 2016, 3, 232-233. Halls, M.L.; Yeatman, H.R.; Nowell, C.J.; Thompson, G.L.; Gondin, A.B.; Civciristov, S.; Bunnett, N.W.; Lambert, N.A.; Poole, D.P.; Canals, M., Plasma membrane localization of the μ-opioid receptor controls spatiotemporal signaling, Science Signaling, 2016, 414, ra16-ra16. Han, F.; Soeriyadi, A.H.; Vivekchand, S.; Gooding, J.J, Simple Method for Tuning the Optical Properties of Thermoresponsive Plasmonic Nanogels, ACS Macro Letters, 2016, 5, 626-630. Han, F.Y.; Thurecht, K.J.; Whittaker, A.K.; Smith, M.T., Bioerodable PLGA-based microparticles for producing sustained-release drug formulations and strategies for improving drug loading, Frontiers in Pharmacology, 2016, 185. Han, S.; Hu, L.; Gracia.; Quach, T.; Simpson, J. S.; Edwards, G. A.; Trevaskis, N. L.; Porter, C. J. H., Lymphatic Transport and Lymphocyte Targeting of a Triglyceride Mimetic Prodrug Is Enhanced in a Large Animal Model: Studies in Greyhound Dogs, Molecular Pharmaceutics, 2016, 10, 3351-3361. Han, S.; Hu, L.; Quach, T.; Simpson, J. S.; Trevaskis, N. L.; Porter, C.J., Constitutive Triglyceride Turnover into the Mesenteric Lymph Is Unable to Support Efficient Lymphatic Transport of a Biomimetic Triglyceride Prodrug, Journal of Pharmaceutical Sciences, 2016, 2, 786-796. Haque, S.; Whittaker, M. R.; McIntosh, M. P.; Pouton, C. W.; Kaminskas, L. M., Disposition and safety of inhaled biodegradable nanomedicines: Opportunities and challenges, Nanomedicine: Nanotechnology, Biology, and Medicine, 2016, 6, 1703-1724. Harding, F.J.; Surdo, S.; Delalat, B.; Cozzi, C.; Elnathan, R.; Gronthos, S.; Voelcker, N.H.; Barillaro, G, Ordered Silicon Pillar Arrays Prepared by Electrochemical Micromachining: Substrates for High-Efficiency Cell

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Krismastuti, F. S. H.; Cavallaro, A.; Prieto-Simon, B.; Voelcker, N. H., Toward Multiplexing Detection of Wound Healing Biomarkers on Porous Silicon Resonant Microcavities, Advanced Science, 2016, 6, 1500383. Kristensen, A.B.; Lay, W.N.; Ana-Sosa-Batiz, F.; Vanderven, H.A.; Madhavi, V.; Laurie, K.L.; Carolan, L.; Wines, B.D.; Hogarth, M.; Wheatley, A.K.; Kent, S.J., Antibody responses with Fc-mediated functions after vaccination of HIVinfected subjects with trivalent influenza vaccine, Journal of Virology, 2016, 12, 5724-5734. Kuehl, C.; Zhang, T.; Kaminskas, L. M.; Porter, C. J.; Davies, N. M.; Forrest, L.; Berkland, C., Hyaluronic Acid Molecular Weight Determines Lung Clearance and Biodistribution after Instillation., Molecular Pharmaceutics, 2016, 6, 1904-1914. Kunz-Schughart, L. A.; Dubrovska, A.; Peitzsch, C.; Ewe, A.; Aigner, A.; Schellenburg, S.; Muders, M. H.; Hampel, S.; Cirillo, G.; Iemma, F.; Tietze, R.; Alexiou, C.; Stephan, H.; Zarschler, K.; Vittorio, O.; Kavallaris, M.; Parak, W. J.; Mädler, L.; Pokhrel, S., Nanoparticles for Radiooncology: Mission, Vision Challenges, Biomaterials, 2016, 155-184. Law, I.K.M.; Jensen, D.; Bunnett, N.W.; Pothoulakis, C., Neurotensin-induced miR133α expression regulates neurotensin receptor 1 recycling through its downstream target aftiphilin, Scientific Reports, 2016, 22195. Lay, J.; Carbone, S.E.; DiCello, J.J.; Bunnett, N.W.; Canals, M.; Poole, D.P., Distribution and trafficking of the μ-opioid receptor in enteric neurons of the guinea pig, American Journal of Physiology – Gastrointestinal and Liver Physiology, 2016, 2, G252-G266. Lee, K. T.; Coffey, J. W.; Robinson, K. J.; Muller, D. A.; Grondahl, L.; Kendall, M. A. F.; Young, P. R.; Corrie, S. R., Investigating the effect of substrate materials on wearable immunoassay performance, Langmuir, 2016, 3, 773-782. Lee, W.S.; Richard, J.; Lichtfuss, M.; Smith, A.B.; Park, J.; Courter,

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Pageon, S.V.; Tabarin, T.; Yamamoto, Y.; Ma, Y.; Bridgeman, J.S.; Cohnen, A.; Benzing, C.; Gao, Y.; Crowther, M.D.; Tungatt, K.; Doltonc, G.; Sewellc, A.K.; Pricec, D.A.; Acutoe, O.; Partong, R.G.; Gooding, J.J.; Rossya, J.; Rossjohnc, J.; Gausa, K., Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination, Proceedings of the National Academy of Science, 2016, 37, E54545463. Pan, Y.; Short, J.L.; Choy, K.H.; Zeng, A.X.; Marriott, P.J.; Owada, Y.; Scanlon, M.J.; Porter, C.J.; Nicolazzo, J.A., Fatty acid-binding protein 5 at the blood–brain barrier regulates endogenous brain docosahexaenoic acid levels and cognitive function, Journal of Neuroscience, 2016, 46, 11755-11767. Parker, A.L.; Turner, N.; McCarroll, J.A.; Kavallaris, M., βIII- tubulin alters glucose metabolism and stress response signalling to promote cell survival and proliferation in glucose-starved non-small cell lung cancer, Carcinogenesis, 2016, 8, 787-98. Parsons, M.S.; Madhavi, V.; Ana-Sosa-Batiz, F.; Center, R.J.; Wilson, K.M.; Bunupuradah, T.; Ruxrungtham, K.; Kent, S.J., Seminal Plasma Anti-HIV Antibodies Trigger Antibodydependent Cellular Cytotoxicity: Implications for HIV Transmission, JAIDS-Journal of Acquired Immune Deficiency Syndromes, 2016, 1, 17-23. Parsons, M.S.; Richard, J.; Lee, W.S.; Vanderven, H.; Grant, M.D.; Finzi, A.; Kent, S.J., NKG2D Acts as a Co-Receptor for Natural Killer Cell-Mediated Anti-HIV-1 Antibody-Dependent Cellular Cytotoxicity, AIDS Research and Human Retroviruses, 2016, 10-11, 1089-1096. Parton, R.G.; Collins, B.M., Unraveling the architecture of caveolae, Proceedings of the National Academy of Science, 2016, 50, 14170-14172. Pasquier, E.; Andre, N.; Street, J.; Chougule, A.; Rekhi, B.; Gosh, J.; Philip, D. S. J.; Meurer, M.; MacKenzie, K. L.; Kavallaris, M.; Banavali, S. D. , Effective management of advanced angiosarcoma by the synergistic

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combination of propranolol and vinblastine-based metronomic chemotherapy: a bench to bedside study, EBioMedicine, 2016, 87-95. Pearce, A. K.; Fuchs, A. V.; Fletcher, N. L.; Thurecht, K. J., Targeting nanomedicines to prostate cancer: Evaluation of specificity of ligands to two different receptors In Vivo, Pharmaceutical Research, 2016, 10, 1-12. Peng, H.; Varanasi, S.; Wang, D. K.; Blakey, I.; Rasoul, F.; Symons, A.; Hill, D. J. T.; Whittaker, A. K., Synthesis, swelling, degradation and cytocompatibility of crosslinked PLLA-PEG-PLLA networks with short PLLA blocks, European Polymer Journal, 2016, 448-464. Pham, A. C.; Hong, L.; Montagnat, O.; Nowell, C. J.; Nguyen, T. H.; Boyd, B. J., In Vivo Formation of Cubic Phase in Situ after Oral Administration of Cubic Phase Precursor Formulation Provides Long Duration Gastric Retention and Absorption for Poorly Water-Soluble Drugs, Molecular Pharmaceutics, 2016, 1, 280-286. Pilkington, E.H.; Gurzov, E.N.; Kakinen, A.; Litwak, S.A.; Stanley, W.J.; Davis, T.P.; Ke, P.C, Pancreatic β-Cell Membrane Fluidity and Toxicity Induced by Human Islet Amyloid Polypeptide Species, Scientific Reports, 2016, 21274. Pinkevych, M.; Kent, S.J.; Tolstrup, M.; Lewin, S.R.; Cooper, D.A.; Søgaard, O.S.; Rasmussen, T.A.; Kelleher, A.D.; Cromer, D.; Davenport, M.P., Modeling of Experimental Data Supports HIV Reactivation from Latency after Treatment Interruption on Average Once Every 5-8 Days, PLoS Pathogens, 2016, 8, e1005740. Pollock, A.H.; Tedla, N.; Hancock, S.E.; Cornely, R.; Mitchell, T.W.; Yang, Z.; Kockx, M.; Parton, R.G.; Rossy, J.; Gaus, K., Prolonged intake of dietary lipids alters membrane structure and T Cell responses in LDLr-/-Mice, Journal of Immunology, 2016, 10, 3393-4002. Raftery, L.J.; Grewal, Y.S.; Howard, C.B.; Jones, M.L.; Shiddiky, M.J.; Carrascosa, L.G.; Thurecht, K.J.; Mahler, S.M.; Trau, M. , Biosensing made easy with PEG-targeted

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Waltemath, D.; Karr, J.R.; Bergmann, F.T.; Chelliah, V.; Hucka, M.; Krantz, M.; Liebermeister, W.; Mendes, P.; Myers, C.J.; Pir, P.; Alaybeyoglu, B.; Aranganathan, N.K.; Baghalian, K.; Bittig, A.T.; Burke, P.E.P.; Cantarelli, M.; Chew, Y.H.; Costa, R.S.; Cursons, J.; Czauderna, T.; Goldberg, A.P.; Gómez, H.F.; Hahn, J.; Hameri, T.; Gardiol, D.F.H.; Kazakiewicz, D.; Kiselev, I.; Knight-Schrijver, V.; Knüpfer, C.; König, M.; Lee, D.; Lloret-Villas, A.; Mandrik, N.; Medley, J.K.; Moreau, B.; NaderiMeshkin, H.; Palaniappan, S.K.; Priego-Espinosa, D.; Scharm, M.; Sharma, M.; Smallbone, K.; Stanford, N.J.; Song, J.H.; Theile, T.; Tokic, M.; Tomar, N.; Touré, V.; Uhlendorf, J.; Varusai, T.M.; Watanabe, L.H.; Wendland, F.; Wolfien, M.; Yurkovich, J.T.; Zhu, Y.; Zardilis, A.; Zhukova, A.; Schreiber, F., Toward Community Standards and Software for Whole-Cell Modeling, IEEE Transactions on Biomedical Engineering, 2016, 10, 20072014. Wang, B.; Blin, T.; Käkinen, A.; Ge, X.; Pilkington, E.H.; Quinn, J.F.; Whittaker, M.R.; Davis, T.P.; Ke, P.C.; Ding, F., Brushed polyethylene glycol and phosphorylcholine for grafting nanoparticles against protein binding, Polymer Chemistry, 2016, 45, 6875-6879. Wang, K.; Peng, H.; Thurecht, K. J.; Whittaker A. K., Fluorinated POSS-Star Polymers for 19F MRI, Macromolecular Chemistry and Physics, 2016, 20, 22622274. Wang, K.; Peng, H.; Thurecht, K.J.; Puttick, S.; Whittaker, A.K. , Multifunctional hyperbranched polymers for CT/19F MRI bimodal molecular imaging, Polymer Chemistry, 2016, 5, 1059-1069. Webb, J.E.; Chen, K.; Prasad, S.K.; Wojciechowski, J.P.; Falber, A.; Thordarson, P.; Hodgkiss, J.M., Quantifying highly efficient incoherent energy transfer in perylenebased multichromophore arrays, Physical Chemistry Chemical Physics, 2016, 3, 1712-1719. Webster, G. R.; Bisset, N. B.; Cahill, D. M.; Jones, P.; Killick, A.; Hawley, A.; Boyd, B. J., Kinetic Resolution of the Interactions between Agrochemical Products and Adjuvant Systems upon Mixing, Journal of

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