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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
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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 %
30
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 !!