Lausanne

26 April 2016

MagnetoTheranostics
Nano Particle Hyperthermia Applicator

Myles Capstick, Dimce Iliev

and Niels Kuster
ITIS Foundation, ETH Zurich, Switzerland

Development of the magnetic field applicator

AIMS
To develop a new applicator that improves the overall
efficiency for nano-particle heating - whilst considering the
unwanted heating of normal tissue and provide effective E-field
shielding.
Develop an applicator cooling system.
To design a high efficiency computer controlled RF source for
excitation of the applicator.
To provide experimental validation in simplified phantoms.

Second prototype

Applicator Second Prototype

8 field coil windings, each with 5 turns
Total 40 turns
Field sensitivity 84 T/A Bore diameter
400mm

Tuning and matching

High voltage capacitor stacks

Operates at 303 kHz

Input transformers for matching

PSU

System
Two amplifier
units
Each with 4 x
750W amplifier
modules
Each with 2 x
1.5kW power
supplies

Input 2fo
Power
Cotrol

PSU

PSU

One set of 8 field

coils
Series resonated
Fed at low
voltage point
PSU

System

System functions

Field coils
characterised

Equivalent circuit
model available

Basic control
software available

Field coil voltages

Field coil currents

Loss resistance
Calramic capacitors had
Tan = 0.002
Loss resistance between
0.23 and 0.30 at 300 kHz

Arlon Diclad 527

Tan = 0.001 at 1 MHz
r = 2.65
Loss resistance between
0.11 and 0.15 at 300 kHz

Oil cooled capacitors

Manufactured from a PTFE based material with some glass
fibre reinforcement with 254m thickness bonded to an oil
filled heat exchanger.
280mm x 212 mm
Can expect 200W
dissipation per
capacitor

Predicted field strength

For 750W per channel
Current is about 36 Arms
Field ~ 3mT

Cooling system
System has been defined, will use split cooling loops with a
liquid liquid heat exchanger.
Manifolds connect to all 8 coils
Coil cooling loop will use transformer oil which has very high
isolation of the high voltages and does not corrode or absorb
ions from the construction materials
The oil is pumped through the coils and heat exchanger in a
sealed and closed loop
Connections for an external water based cooling loop will be
provided the water will cool the oil

Cooling system

Treatment Planning for Magnetic NanoparticleBased Hyperthermia

Esra Neufeld, Hazael Montanaro, Myles Capstick,

Niels Kuster

Outline

background
method
application
impact:
width
shape
vasculature

conclusions

Image: Oxbridge Biotech

Background
SPIONS (superparamagnetic iron oxide
nanoparticles)
coated iron oxide core
can be functionalized, e.g., with antibodies

targeted visualization and therapy

(also secondary tumors &
metastases)
serve as MRI contrast agents

diagnosis and treatment guidance

heat in alternating magnetic field due to
remagnetization loss

hyperthermic cancer treatment

when targeting insufficient:
can be directly injected / integrated into bonecement used to treat brittle, tumor-affected
bone

Image: Sezer 2012

Introduction: Treatment Planning

personalized treatment planning permits
efficacy assessment
improved dosage (required particle density, field
strength, duration)
identification / avoidance of unwanted side effects
treatment optimization

requirements
efficient generation of personalized patient model
(anatomy, physiology, treatment setup)
precise modeling of physics
realistic modeling of physiological reaction
assessment of induced therapeutic effect /
collateral damage
treatment optimization
validation & uncertainty assessment

imaging provides information about

patient anatomy
nano particle distribution
potentially: tissue properties (perfusion maps)

Method
extend existing HTP platform (Sim4Life)
magneto-quasistatic solver to determine local magnetic field (FEM,
MPI-parallelized, rectilinear mesh)
modeling of in vivo induced magnetic field distribution from
applicator

Method (II)
combine computed field strength with image-based particle density
using derived relationship to determine deposited power
determine temperature increase using Pennes bioheat equation
perfusion impact
non-linear temperature dependence of perfusion
convective/Dirichlet boundary conditions for large vessels
possibility of coupling to advanced models
(body-core heating, vessel trees, CRD...)

Method (IV)
CEM43 thermal dose computation for effect assessment

Liver Tumor Targetting

Impact (I)
varied:
width of particle distribution
sharpness (step vs. gaussian)
proximity of major vessel
(Dirichlet, zero T increase)
observation
dominated by interplay between
diffusion & perfusion heat removal
little T impact when distribution
wider than characteristic Greens
function length
strongly perfused tissue (liver)
quickly reaches perfusion
dominated regime (perfusion &
particle density matter, distribution
only affects width)

Impact (II)

Conclusion

nanomedicine promises efficient, targetted therapies

comprehensive treatment planning platform has been created
supports image-based modeling (anatomy, particle distribution)
multiscale/multiphysics model (EM particle power loss thermal)
limitations: current implementation does not consider
modified macroscopic dielectric/thermal properties due to particles
interaction between multiple nanoparticles in proximity
ongoing:
extraction of quantitative particle density information from MRI data
experimental validation
used to:
optimize particle size / applicator frequency
gain understanding on impact of particle distribution, vasculature
model treatment

Acknowlegement
Funding
CTI HYCUNEHT
SNF, Nano-Tera.ch
Collaboration
EPFL Powder Lab
University Hospital Geneva
Veterinary Clinic, University Zurich
Centre Hospitalier Universitaire Vaudois
Center for BioMedical Imaging
Inselspital Bern

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.Capstick6, E.
Neufeld6
1EPFL, 2University of Zurich, 3Inselspital Bern, 4CHUV, 5University of Geneva, 6 ItIS

Magnetotheranostics Mid Term Report

April 2016

Project layout
Engineering ; ITIS, ANTIA
Physics, chemistry material
science; EPFL, UNI GE, CHUV
In-vitro, toxicity, imaging
EPFL, ITIS, UNI GE, CHUV

Development
temperatur
simulation
tool
Improvement
of mag
generator

Characterisation
toxicity screening
Functionalisation of
particle with
antibodies

Nanocomposite
formulation
In vitro tests
and heating
capacity
In vivo tests of
and tumor
treatment

Toxicity tests

Hyperthermia

Medical application
CABMM, Inselspital

In vivo tests
theragnosis
Magnetotheranostics Mid Term Report
April 2016

In vitro tests
specific adsorption
at metastasis
In vivo tests of
metastasis
detection

Molecular imaging (MRI)

Existing and new

particle composition

2
MagnetoTheranostics

SPION as Contrast agent

Functionalized nanoparticles for biomedical

application MSE 617

Mukesh G. Harisinghani, The new england journal of medicine 2003 vol. 348 no. 25, 2491

MRI sequences for IONP

Further development of ultra-short echo time (UTE) MRI
imaging.
visualization of the off-resonance portion of the MRI signals which are
present in areas surrounding the contrast agent,
visualization of short T2* components which are typically in closer
vicinity to the contrast agent.

basic MRI method

UTE MRI

novel IRON-UTE

Magnetotheranostics Mid Term Report

April 2016

(IRON) MRI
7

Magnetotheranostics Mid Term Report

April 2016

Functionalisation
Different types of molecules were used to
increase biocompatibility
higher colloidal stability
Act as linker for further functionalization with targeting molecules
Small biocompatible molecules with min 3 functional groups for:
-

retaining good MRI relaxivity (> thickness, < r2 relaxivity)

enabling heat transfer for hyperthermia treatment
enabling lymphatic retention (> for HDsize < 100 nm)
act as a linker for further functionalization with targeting molecules
Up-Take is controlled by the chemistry and charge of the coating.
Hard protein corona with different compositions detected (charge,
chemistry)
Magnetotheranostics Mid Term Report
April 2016

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

Magnetotheranostics Mid Term Report

April 2016

10

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

Adequate cell line for

in vivo targeting assay
small molecule

aptamer

merged

Magnetotheranostics Mid Term Report

April 2016

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Magnetic implant hyperthermia:

Potential applications to vertebroplasty

cement

Remaining
tumor tissue

Hyperthermic implant imaging:

CT-scan

Implant

Coronal cross section

3D reconstruction

SPION-containing implants easily seen

due to their X-ray absorption close to that of bone
Functionalized nanoparticles for biomedical
application MSE 617

13

Magnetic implant hyperthermia:

in vivo investigations
Equilibrium temperature depends on :

- magnetic field strength

- physiological cooling reflexes

Tumor site temperature (C)

50
48

Field strength

Tumoral ET

46

1212
mT
mT

46.2 C

44

1111
mT
mT

43.5 C

42

10.5
10.5mT
mT

42.7 C

40

1010
mT
mT

42.8 C

38

9 mT
9 mT

40.0 C

p<0.05
Fishers LSD

36
34
32
0

10

15

20

Time (min)
Functionalized nanoparticles for biomedical
application MSE 617

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Magnetic implant Hyperthermia

Implant

Functionalized nanoparticles for biomedical

application MSE 617

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Magnetic implant hyperthermia:

in vivo investigations

Kaplan-Meyer survival curves

endpoint : ten time initial tumoral volume

group

Median
survival
time : tm.

Control

12

1
0.9

n=6

0.7

implante
d control

0.6
12 mT

0.5
0.3

treated
n=7

10.5 mT

12 mT

Control

Implanted control

12

24

36

48

37

treated
n=11

0
0

27

p<0.05

10.5mT

0.1

21

n=7

0.4
0.2

p<0.001 p<0.05

Fractional survival

0.8

60

72

84
200

Days after therapy

*Significant differences between

curves with Wilcoxon test

45% of complete responses at one year

Functionalized nanoparticles for biomedical
application MSE 617

16

Magnetic fluid hyperthermia

Undergoing clinical trials

Phase II (efficacy): glioblastoma multiforme

and prostate carcinomas
Phase I (feasibility): esophageal cancer
Functionalized nanoparticles for biomedical
application MSE 617

17

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

Magnetotheranostics Mid Term Report

April 2016

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Simulation Platform for TP

multiscale, multiphysics nanoparticle HT modeling:
electromagnetic field nanoparticle losses induced heating (incl.
thermoregulation) therapeutic impact
image integration:
extraction of SPION density & anatomy for personalized
simulations, joint visualization of image data & models & results
advanced models of large vasculature impact;
novel vessel segmentation for large range of image data with
tunable interactivity/automatization
application: modeling complete treatment (human and dog model)
behavior study -> theoretical model: impact of particle distribution
(width, sharpness), diffusion vs. perfusion, nearby vessel
novel FEM thermal solver with inhomogeneous & anisotropic tissue
models (perfusion & effective thermal conductivity)
Magnetotheranostics Mid Term Report
April 2016

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Example: Modeling of dog NP HT

Magnetotheranostics Mid Term Report

April 2016

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Conclusion
Milestones and delivery fulfilled as planned
Engineering part developed so far, that the
biological/medical part can start.
Animal models and antibodies selected and tested
Next steps:

Finalizing in vitro tets

Animal tests
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
GMP production of core nanoparticles

Magnetotheranostics Mid Term Report

April 2016

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The other big challenges

Challenges

Measures (several
partners are involved)

Use of EMA/FDA approved chemicals and

solvents

Realized by using aqueous chemistry

Accepted methods for biocompatibility

tests of (inorganic) nanoparticles

Methods in parallel developed in CCMX

project VIGO and NanoScreen

Regulations for the use of inorganic

nanoparticles for diagnostic and
therapeutic applications

Active participation on NanoReg

(especially OECD Guidelines for the
characterization of inorganic NP

Good manufacturing practice at academic

level

Standard Operation Protocols for each

step established or in preparation

Reproducibility (at batch to batch and

research level)

Realized

Acceptance of nanotechnology

Organized the World Nano Cancer Day

(Swiss part), Papers targeting clinicians in
preparation*
22

*with Prof. S. Krishnan, Director, University of Texas MD Anderson Cancer Center, USA

Thank you for your attention

Investigator

Institution

Main task

H. Hofmann, D. Bovin,
M Mionic

EPFL

Particle and functionalisation

B. von Rechenberg P.
Kircher,
H. Richter

Vetsuisse Zrich

animal experiments

H. Thoeny,
S. Barbieri,

Inselspital, Bern

MRI of lymph node

metastasis

M. Stuber, J. Bastiaansen,
M. Mionic,

CHUV

MRI sequences development

O. Jordan, G. Borchart ,
S. Ehrenberger

UNI Geneva,

Implant and targeting

N. Kuster, M. Clapstick
E. Neufeld

ITIS

Magnetic field generator and

treatment modeling

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April 2016

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