Magnetotheranostics

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Magnetotheranostics From superparamagnetic nanoparticles to tools for the detection and treatment of cancer M. Mionic1, D. Bonvin1, H. Hofmann1, H. Richter2, B. von Rechenberg2, S. Barbieri3, H. Thöny3, J. Bastiaansen4, M. Stuber4, S. Ehrenberger5, O. Jordan5, G. Borchard5, M. Capstick6, E. Neufeld6, N. Kuster6 1EPFL, 2University of Zurich, 3Inselspital Bern, 4CHUV, 5University of Geneva, 6It’IS

Débora Bonvin, Institute of Materials, EPFL Nano-Tera Annual Meeting, 04th May 2015, Bern

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Prostate cancer stages Primary tumors

Early metastases (lymph nodes)

Late metastases (bones, lungs, ‌)

PSA* levels (ng/ml)

< 20

> 20 or Any

Any

5-year survival rate

90-100%

85-100%

40-80%

MRI* (>8mm)

PET/CT***, MRI**

50% metastases are missed

Easy detection BUT often too late

Detection method

*Prostate specific antigen **Magnetic resonance imaging ***Positron emission tomography/computed tomography

Goetz, 2008

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MagnetoTheranostics • Diagnostics of prostate cancer metastases in lymph nodes

(< 8 mm) by MRI with superparamagnetic nanoparticles Benign lymph node

Metastatic lymph node

Froehlich et al, 2012

Ø Difficult to distinguish healthy/metastatic part Ø Dark grey scale Ø Lack of specificity (< 100% metastatic lymph nodes)

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MagnetoTheranostics • Diagnostics of prostate cancer metastases in lymph nodes

(< 8 mm) by MRI with superparamagnetic nanoparticles Benign lymph node

Metastatic lymph node

Froehlich et al, 2012

• Treatment of prostate tumors by hyperthermia o Metastases in lymph nodes o Primary tumors

Andrade et al, 2011 Jordan et al, 2011

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Engineering ; ITIS, ANTIA

In-­‐vitro, Toxicity, imaging EPFL, ITIS, UNI GE, CHUV

Task 1 Existing and New Particle composition

Task 2 Development Temp.

Simulation tool Improvement of mag Generator

Task 3

Characterisation Tox screening

In vitro tests Heating capacity In vivo tests tumor treatment

Task 4 Functionalisation of Particle with Antibodies

Nanocomposite formulation

Toxicity Tests

Hyperthermia

Medical application CABMM, Inselspital

In vivo tests Theragnosis

In vitro tests Specific adsorption Metastasis In vivo tests metastasis detection

Molecular Imaging (MRI)

Physics, chemistry Material science; EPFL, UNI GE, CHUV

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EPFL

Task 1: Development of nanoparticles

Properties of new nanoparticles that have to be fulfilled o Physico-chemical requirements o Biomedical requirements

Selected materials: o Development based on iron oxide (i.e. γ-Fe2O3, SPIONs) o Exploration of new materials not yet used for medical applications

(e.g. doped transition metal oxides)

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EPFL

Task 1: Synthesis of γ-Fe2O3 Magnetic core

- Suitable for MRI - High heating for hyperthermia

Specific loss power (SLP): W / gFe2O3

!! !!! !" !! !! !! !! !

2!"! !"#!(!) = ! (coth!( )− ) ! !

1000!!"!!! !! ! !! !! !! 1 + (2!"!)

Brownian

Néel

3!!! !! = ! ! !! !

!! = ! !!

!! ! !!! !

f and H are limited (50<f<12000kHz; 0<H<15kA/m; f*H < 485 kHz*kA/m)

Relaxation time τ

1 1 1 =! +! ! ! !! !! η fluid viscosity, K particles anisotropy constant, Ho amplitude and f frequency of alternating magnetic field, µo magnetic permeability and Ms particles saturation magnetization

NANOPARTICLE SIZE!!!

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It’IS

Task 2: Development of generator

Magnetic field generator applicable to humans o Challenges and requirements ü Coils’ size suitable for humans (bore diameter 400mm) ü f = 300kHz: sufficient hyperthermia, but with clinically applicable conditions

(f*H < 485 kHz*kA/m)

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It’IS

Task 2: Development of generator

Magnetic field generator applicable to humans o Challenges and requirements ü Low voltage/current + homogeneous field strength to avoid hot spots

(field sensitivity 84uT/A)

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It’IS

Task 2: Development of generator

Temperature simulation software o Heating prediction (tumor, unwanted hot spots) -> safety and efficacy o New high-performance computing enabled thermal solver Ø Support of inhomogeneous heat source and tissue properties Ø Advanced perfusion models, generation of patient-specific vasculature

o Image-based heat source distributions Ø Information extraction from medical image data Ø Relationship between SPION density & field strengths and heating

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University of Geneva

Task 3: Tumor treatment by hyperthermia

Implant for local treatment of primary prostate cancer BLADDER

SPIONs Radio-opaque polymer DMSO

solid implant TUMOR liquid formulation PROSTATE

Solidifaction upon contact with aqueous solution

Liquid formulation

Implant

Scanning electron microscopy of precipitated implant

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University of Geneva

Task 3: Tumor treatment by hyperthermia Injectability (18wt% polymer)

Magnetically induced heat release

BLADDER

100kHz, 20mT

45

1600

1 2 3 4 5 6

1200

liquid formulation

PROSTATE 800

400 0 0

5

10

15

20

ΔT (°C)

TUMOR

SPIONs

Viscosity (mPa.s)

solid implant

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SPION concentration [wt%]

Viability (%)

105

PC3

95

Fibroblast

85 75 65

Polymer concentration (w/w%)

1

2

Time(min) 8

300kHz

6 ΔT (°C)

Cell viability (WST-1 test)

7nm-SPIONs in composite (20wt%)

0

12 mT 9 mT

4

6 mT

2

3 mT

0 0

0.5

1 Time (min)

1.5

2

CHUV, University of Zurich, EPFL, University of Geneva

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Task 4: Detection of LN metastases by MRI

Functionalization of nanoparticles with: o Coating o Targeting molecule towards tumor as specific as possible

MRI imaging protocol o Development of new sequences o Improvement of SPIONs localization

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CHUV, University of Zurich, EPFL, University of Geneva

Task 4: Functionalization (antibody) Requirements for biomedical applications o No use of organic solvents (only aqueous medium) o No use of catalysts o Targeting molecule has to stay active after coupling

Proof of principle of coupling o Coupling of SPIONs with IgG targeting Echinococcus o FTIR, ELISA Number %

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SPIONs Coated-SPIONs

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Antibody-SPIONs EmG11-SPIONs

10 0 1

10

100

1000

10000

Hydrodynamic diameter (nm)

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Conclusion o SPIONs for theranostics ü Maximization of heating for hyperthermia ü Aqueous synthesis without any toxic solvents

o Prototype of hyperthermia generator ü Size, frequency, current/voltage applicable to humans

o Suitable and injectable composite ü Biocompatible, promising heating

o Successful functionalization ü 11 coatings in aqueous medium ü Proof of principle of coupling with antibody

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Thank you for your attention !!