Overarching Projects

Social dimensions of bio-nano interactions

Leader: Associate Professor Matthew Kearnes Co-Leader: Dr Declan Kuch Collaborating organisations/groups: Professor Stephen Kent (UoM), Professor Justin Gooding, Associate Professor Orazio Vittorio and Professor Maria Kavallaris AM (UNSW), Professor Kris Thurecht and Professor Rob Parton (UQ), Dr Angus Johnston (Monash)

The project

Bio-nano technologies, together with advances in precision and personalised medicine, are likely to profoundly change health care practices. By exploring the social dimensions of research across this area of work, in collaboration with key CBNS research initiatives, this program will provide insights into the societal dimensions of predictive bio-nanotechnologies. This project seeks to address key questions related to the intersection between big data, healthcare, personalised and precision medicines, and regulation. The proposed program of work will entail the use of the following social science methodologies, and will be facilitated by a range of cross-node collaborations.

These methods include: • Social media monitoring and analysis tools (using tools such as NodeXL) will enable issue mapping of the institutional and discursive shaping of research agendas in precision, and personalised medicine; • Ethnographic observation: close analysis of science-inpractice will serve to document the imagined social worlds that underpin developments in bio-nanotechnology, focusing specially on CBNS research projects; • Interdisciplinary exchange workshops will bring CBNS researchers into conversations with researchers working in the social sciences, humanities and law to explore the broader social dimensions of their work; Targeted public engagement initiatives will also form part of the work plan of the program, enabling Centre researchers to address the societal dimensions of their research in appropriately designed and facilitated public forums.

Research

Research for the social dimensions signature project was enabled by a series of research collaborations across CBNS. These include ongoing research exploring the Enhanced Permeability and Retention (EPR) effect, the visualisation of nanoscale interactions, the use of nanoparticles in the development of vaccines, and the social and ethical dimensions of organoids and lab-on-a-chip systems.

Value

Characterising the sociological dimensions of research in bio-nano science and technology has broad importance for the general public and societal understanding and acceptance of bio-nano science applications in the real world.

Activities undertaken in 2019

Events • Coordinated the research symposium: Biomedical

Futures: Values, Responsibility, Critical Engagement in

Nanotechnology and Electromaterials, a collaboration between the CBNS & the ARC Centre of Excellence for Electromaterials Science (ACES).

This symposium included presentations from CBNS researchers CI Associate Professor John McGhee, Dr

Declan Kuch, and Associate Professor Matthew Kearnes (UNSW) alongside prominent HASS researchers exploring the social and ethical dimensions of nanotechnology and novel technologies Professor Susan Dodds (La Trobe

University) and Dr Eliza Goddard (La Trobe University). • Coordinated the Social Aspects & Regulation stream at the 10th International Nanomedicine Conference June, 2019, including keynote presentation from Professor

Rachel Ankeny (University of Adelaide) on Animal Models in Biomedicine: Past, Present, and Future Directions. Policy Engagement • Invited contribution on ‘Agricultural Nanotechnologies,

Public Engagement and Regulation’ for the Future of

Agricultural Technologies Project Horizon Scanning Project,

Australian Council of Learned Academies (ACOLA). Publications • Publications in Science, Technology & Human Values,

Journal of Environmental Policy & Planning, Policy Studies and a forthcoming research monograph manuscript on based on research conducted in collaboration with CBNS.

Activities planned for 2020

A series of research events will be coordinated throughout 2020, including a CBNS workshop on ‘responsible innovation’ and new methodologies for responding to questions pertaining to the social aspects of bio-nano research.

Predicting bio-nano interactions

Leaders: Professor Stephen Kent, Professor Edmund Crampin Co-Leaders: Dr Adam Wheatley, Dr Matt Faria Collaborating organisations/groups: Professor Molly Stevens (Imperial College London), Professor Robert Parton and Professor Kris Thurecht (UQ), Dr Angus Johnston and Dr Simon Corrie (Monash), Professor Frank Caruso (UoM)

The project

Understanding how materials and cells interact will be key to the future development of improved nanomedicines and vaccines. We aim to understand the rules by which immune cells interact with a range of nanoengineered particle systems with tailored physical properties. The combined effects of size, charge, surface chemistry and other physio-chemical characteristics will be studied for their effect on particle interactions with a wide range of immune cells.

Value

Understanding how materials and cells interact will be key to future development of improved nanomedicines and vaccines. • The experimental and theoretical techniques we develop will provide a roadmap for biological analysis of newly developed nanomaterials for the global research community. • Our fundamental understanding of the relative importance of nanoparticle physicochemical properties will be advanced, leading to a more rational design of these materials. • By increasing our ability to predict bio-nano interactions prior to clinical evaluation, we will vastly accelerate our ability to evaluate and design nanoparticles for diagnostic and therapeutic purposes.

Outcome/s

This work will increase our understanding of the rules by which immune cells interact with a range of nano-engineered particle systems with tailored physical properties. Our research examines the influence, and trends of different physicochemical characteristics of nanoparticles, on their interactions with immune cells in vitro and in vivo. This research will demonstrate the potential to standardise the way in which nanoparticle-cell interactions are studied, such that we can generate predictive algorithms for these interactions.

Activities undertaken in 2019

• Revisiting cell-particle association in vitro: A quantitative method to compare particle performance – this paper is a comprehensive approach to getting quantitative data on cell-particle interactions in vitro. Several potential kinetic models of cell-particle interaction are compared. The techniques developed within allows for boiling down

“cell-particle interaction” into a single number, which for the first time can quantitatively represent the targeting or stealth performance of a particle. • This paper has a companion webpage at http://bionano.xyz/ estimator, which allows researchers without an experimental background to apply the sophisticated kinetic modelling techniques to their data without a mathematical background • Link between low-fouling and stealth: a whole blood biomolecular corona and cellular association analysis on nanoengineered particles – this paper differentiates and goes into some detail about the difference between “stealth” (non-interaction with the immune system) “low-fouling” (interaction with proteins), and explores multiple potential definitions for the latter. It also represents one of the most

“complete” datasets on biological characterisation of a particle, including both cell-level response and proteomic response in whole human blood. • Progress in standardisation: positive response from the community that Nature Nanotechnology organised, multiple editorials, analysis, and responses from more than 20 international research groups and further promotion in the

Journal of Controlled Release of the Minimum information reporting in bio–nano experimental literature.

Activities planned for 2020

• Development and publication of kinetics-based particle approaches applied to complex in vitro systems under continuous flow.

Summary of cell-particle kinetic modeling. Characterisation information about cells and particles along with details of experimental protocol are used as parameters in a given mathematical model, which accounts for both dosimetry and the kinetics of cell-particle association. Ultimately, the fit kinetic parameters, which are the output of this modeling, can enable unbiased, quantitative comparison between in vitro experiments that vary in cell line, experimental protocol, and/or particle type.

Atomic force microscopy (AFM) and transmission electron microscopy (TEM) images of synthesised particles. (a–c) AFM images and corresponding cross-sectional AFM profiles of PMASH capsules with diameters of 1032 nm (a), 480 nm (b), and 214 nm (c). (d–j) TEM images of PMASH core–shells of 633 nm (d), 282 nm (e), 150 nm (f), 95 nm (g) and capsules with diameters of 1032 nm (h), 480 nm (i), and 214 nm (j). Scale bars are 500 nm in (d, h, i, j) and 100 nm in (e, f, g).

Development of complex cellular systems for the evaluation and characteristics of bio-nano interactions

Leaders: Professor Maria Kavallaris AM, Professor Benjamin Thierry Co-Leaders: Dr Frieda Mansfeld, Dr Michelle Maritz Collaborating organisations/groups: Professor Jason Lewis (Memorial Sloan Kettering Cancer Center), Professor Cameron Alexander (University of Nottingham), Professor Richard Lock (Children’s Cancer Institute)

The project

A major challenge in the development and implementation of effective nanomedicine, is the lack of preclinical models that recapitulate the complexity of the complex cellular systems and microenvironments. Towards accelerating the development of nanotechnology strategies that target specific organ and cellular systems, we are developing the next generation of in vitro models designed to replicate physiological and biological systems relevant to the characterisation and evaluation of bio-nano interactions. Ultimately, these advanced models will guide the development of nano-based diagnostic and therapeutic strategies better tailored to specific diseases.

Value

The development and characterisation of bioengineered microfluidic models will enable accurate prediction of healthy and tumour tissue responses to cancer therapeutics as well as an assessment of novel nano-based nanoparticle interactions for broader applications.

Outcome/s

Bioengineered microfluidic and 3D bio-printed models will enable the prediction of more physiologically relevant responses of healthy and disease tissue responses and serve as a more relevant pre-clinical model for nano-based therapies for cancer and other diseases.

Activities undertaken in 2019

• Professor Jason Lewis visited several nodes in January 2019 and in January 2020 to strengthen collaborations and provided mentorship to junior researchers • Developed and characterised bioengineered microfluidic vascularised tumour and organ-on-chip models for assessment of nano-based therapeutics • Advanced 3D bioprinting technology to produce and characterise tumouroids, complex in vitro models incorporating patient derived tumour cells • The effect of the fluidic condition on the phenotype and function of intestine-on-chip has been systematically investigated • Intestine-on-chip models have been used to investigate the binding and transcytosis of nanoparticles

Activities planned for 2020

• Further develop microfluidic and 3D tumour models to extend understanding of nanoparticle interactions with and transport across biological barriers and through tissues. • Complement biological models with mathematical modelling of bio-nano interactions. • Head and neck cancer patient derived organoids are being developed within a microfluidic air-liquid interface that main the tumour microenvironment. • Bioengineered tumour models are being used to developed radiogenemic models predictive of radioresistance • Intestine-on-chip models are being developed towards supporting the in vitro growth of cryptosporidium and norovirus. • Placenta-on-chip models are being developed to investigate the interaction between nanoparticles and placental tissues.

Bioprinted tumouroids

An intestine-on-chip to better study particles’ cellular uptake and interactions with mucus. Biomaterials Science 2019

Brightfield images of 96-well plate with bioprinted patient derived tumouroids. Right: Enlargements of two tumouroids shows consistency in size and morphology. (Image: Lakmali Attapattu)

Improved molecular imaging agents

Leaders: Professor Andrew Whittaker, Professor Tom Davis Co-Leaders: Dr Jeroen Goos, Dr Ruirui Qiao, Dr Cheng Zhang, Dr Changkui Fu, Dr Simon Puttick Collaborating organisations/groups: Dr Ivan Greguric (ANSTO), Professor Jason Lewis (Memorial Sloan Kettering Cancer Center), Professor Thomas Nann (MacDiarmid Institute), Professor Craig Hawker (University of California), Dr Sophie Laurent (Université de Mons), Professor Debra Bernhardt, Professor Maree Smith, Professor Trent Woodruff (UQ), Professor Stephen Rose (CSIRO), Professor Guangjun Nie (National Center for Nanoscience and Technology of China), Professor Afang Zhang (Shanghai University), Professor Zushun Xu and Professor Ling Li (Hubei University), Professor Fabienne Dumoulin (Gebze Technical University), Professor Petr Kral (University of Illinois at Chicago), Professor Simon Swift (University of Auckland), Professor Kishore Bhakoo (A*STAR)

The project

The project team aims to improve the resolution and accuracy of molecular imaging at different physiological sites and to exploit nanotechnology for specific diagnosis and theranostic applications.

Value

There is currently a re-evaluation of several aspects of nanomedicine, in particular delivery efficiency. Imaging agents will play a crucial role in advancing the field by enabling quantitation and higher-level information in the case of multi-modal or responsive agents.

Outcome/s

Imaging is a central technology in the field of nanomedicine. There are a plethora of current approaches; the primary outcome of this overarching project will be a clear direction on the design and choice of imaging agent.

Activities undertaken in 2019

• Study biological interactions: 1. Blood-NP interactions 2. Biological fate 3. Protein corona • Develop an understanding of relationship between nanoparticle design and these interactions. From this, design responsive agents. • Development of advanced imaging agent with improved sensitivity

We have developed several advanced MRI contrast agents with improved sensitivity, including particularly some biocompatible metal-free polymeric 19F contrast agents.

The Whittaker group has developed an innovative class of water-soluble fluorinated homopolymer (PFSAM) with high fluorine content that is suitable as a highly-sensitive 19F tracer for bioconjugation and in vivo tracking (Angew.

Chem. Int. Ed.2020, 59, 2–9). PFSAM is made of a carefullydesigned sulfoxide-containing fluorinated monomer (FSAM) and demonstrates interesting solution properties. Compared with previously-reported polymeric 19F CAs, PFSAM can enable more versatile biological applications such as in facile conjugation with therapeutics in various forms (e.g., peptides, proteins, or nanoparticles) to develop next-generation of self-trackable polymer therapeutic conjugates. Moreover,

PFSAM is low-fouling interacting weakly with biological system. This is particularly important for the development of long-circulating diagnostics and therapeutics with improved therapeutic outcomes.

Activities planned for 2020

In 2020, we plan to develop advanced molecular imaging agents that will include development of multimodal imaging agents, using molecular dynamics simulations to understanding interaction of imaging agents with biological systems such as proteins, cells and in vivo system, and development of long-circulating nanoparticular imaging agents for more efficient and targeted imaging.

Superposition of PET/CT images of a mouse with a brain tumour xenograft, after injection with a 64Cu labelled antibody.

PET/CT showing the distribution of a functional star polymer (S. Puttick/M.R. Whittaker), showing uptake in the bone marrow.

Snapshots of MD simulation of bovine serum albumin interacting with oligomeric polymer acrylic acid taken at the end of 20 ns of MD simulation. Modulating interaction of imaging nanoparticles with biological system using a highly hydrophilic lowfouling sulfoxide polymer as coating materials for nanoparticles. This will reduce unwanted nonspecific interaction with biological system and improve the accumulation of the imaging nanoparticles to the region of interest to further enhance imaging sensitivity and specificity for more precision detection of diseases.