Magnetotheranostics

From superparamagnetic nanoparticles to tools for the detection and

treatment of cancer

H. Hofmann1, B. von Rechenberg2, H. Thoeny3, M. Stuber4, O. Jordan5, N.

Kuster6, D. Bonvin1, P. Kircher2, H. Richter2, S. Barbieri3, J. Bastiaansen4, M.
Mionic Ebersold4, S. Ehrenberger5, G. Borchart5, M.Clapstick6, E. Neufeld6

1EPFL, 2University of Zurich, 3Inselspital Bern, 4CHUV, 5University of Geneva, 6 ItIS

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Magnetotheranostics January 2017
 Magnetotheranostics:
From Superparamagnetic Nano-particles until Tools for Detection
and Treatment of Cancer

Motivation:
Lymph node status is one of the most important prognostic factors
for prostate cancer
Early and complete lymph node staging is a big challenge for a
successful treatment
Major goals:
High-resolution MRI with superparamagnetic nanoparticles allows
detection of otherwise undetectable lymph node metastases.
Targeted treatment of metastases by hyperthermia

Research tasks:
Based on existing SPION-coating systems development of
SPION antibody systems
Specific adsorption of nanoparticles as MRI contrast agent
(molecular imaging)
In-vivo behaviour of SPION-Antibody-complexes
Dedicated software needs to be developed to perform
treatment planning and assisting hardware design

Magnetotheranostics January 2017

 Iron Oxide Nanoparticle
Best Particles

Primary size (nm) 17.4 4.7

Crystallite size (nm) 17.8

Hydrodynamic size (nm) 35.1 10.6

Zeta potential at pH 4 (mV) 49.3 2.4

New compositions:
ZnFe2O4; Ca, Mg, Mn or Ti doped Fe2O3; V doped TiO2;
Mn doped ZnO; Fe doped Al2O3 and TiO2).

For Mn doped Fe2O3 the SAR value could be increased from

10 nm 100 to 300 W/g (at 122kHz,18 mT) (first results)

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Magnetotheranostics January 2017
 IONP for MRI
20 nm IONP shows a very high relaxivity (high contrast) at 3Tesla clinical MRI
Further development of ultra-short echo time (UTE) MRI imaging.
Transfer of the sequences to partners
Diffusion-weighted MRI sequences alone and in combination with SPION for the detection of
lymph node metastases were further developed and the software for the processing of
diffusion-weighted MRI (mono-/bi- exponential model fitting) was developed.
Small lymph nodes (3 mm diameter) are detectable by MRI with SPION as contrast agents

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Magnetotheranostics January 2017
 Functionalization with targeting molecules
3 candidate ligands targeting the extracellular part of Prostate-specific membrane antigen (PSMA)
transmembrane receptor were chosen:
(i) Small urea molecule ACUPA (phase II clinical trial for docetaxel nanoparticles)
(ii) Aptamer A10 (phase I clinical trial for docetaxel-loaded nanoparticles)
(iii) Antibody J591 (phase II trials for PC immunotherapy, radiotherapy, imaging)

In vitro, the aptamer specifically binds to PSMA+ cells:

PSMA-positive LNCaP cells

PSMA-negative PC3 cells

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Magnetotheranostics January 2017
 In vivo tumor model
Most promising model: Grafting of MAT-LyLu prostate metastatic cell line in the rat.
Method: Incubation of MAT-LyLu with fluorescent aptamer-Cy5 and small molecule-BDP FL

aptamer-Cy5

binds surface of MAT-LyLu cells and is further internalized

Animal Tests started at Vetsuisse Zurich in November 2016.

Phase I: Development of the animal model (Tumor) sucsessfully finished
Phase II: Biodistribution (healthy rats and rats with tumors) in preparation (end of
Jan. 2017)
Phase III: Planned for May 2017

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Magnetotheranostics January 2017
 Task 2: Nano particle hyperthemia applicator
prototype
Field coils Amplifiers

Two amplifier units

- Each with 4 x
750W amplifier
modules
- Total of 6 kW RF
power at 300 kHz

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Magnetotheranostics January 2017
 Simulation Platform for TP
multiscale, multiphysics nanoparticle HT modeling:
electromagnetic field induced heating (incl. thermoregulation)
therapeutic impact
image integration: SPION density & anatomy for personalized
simulations,
novel FEM thermal solver with inhomogeneous & anisotropic
tissue models (perfusion & effective thermal conductivity)

The Sim4Life simulation platform for treatment

planning
Application of the treatment modeling software to simulate a
complete treatment using a human and a dog model

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Magnetotheranostics January 2017
Example: Modeling of dog NP HT

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Magnetotheranostics January 2017
 Conclusion
Milestones and delivery fulfilled as planned
Animal models and antibodies selected and tested
biological/medical part already started.

Next steps:
Finalizing animal tests
in vitro tets Tests of the magnetic field generator with INOP of
this project
Establishing of SOP for synthesis, modification, testing and
application of all products developed in Magnetotheranostics
Evaluation of GMP production of core nanoparticles ( 300 kCHF
for accereditation of the process, in contact with 3 companies)

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Magnetotheranostics January 2017
Disseminationofresults
Besidescientificpublicationswe
presentedourresultsalsotothe
public:
NanoWorldCancerDay2016
UniversityHospitalZurich
NanoWorldCancerDay2017,
UniversityofGeneva
"Imaginez unmonde,
http://www.rts.ch/play/tv
Dbora Bonvin,PhDstudent My
Thesisin180Secondscontest.
http://www.rts.ch/play/tv/lecourt
dujour/video/3minutespourla
sciencedeborabonvin?id=8078641

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MagnetotheranosticsJanuary2017
 Thankyouforyourattention
Investigator Institution Maintask
H.Hofmann,D.Bonvin, EPFL Particle andfunctionalisation
MMionic
B.vonRechenberg P. Vetsuisse Zrich animalexperiments
Kircher,
H.Richter
H.Thoeny, Inselspital,Bern MRIoflymph node
S.Barbieri, metastasis

M.Stuber,J.Bastiaansen, CHUV MRIsequences development

M.Mionic,
O.Jordan,G.Borchart , UNIGeneva, Implantandtargeting
S.Ehrenberger
N.Kuster, M.Clapstick ITIS Magnetic field generator and
E.Neufeld treatment modeling

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MagnetotheranosticsJanuary2017