Magnetotheranostics - Nano-Tera 2016

8/18/2019 Magnetotheranostics - Nano-Tera 2016

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MagnetoTheranosticsNano Particle Hyperthermia Applicator

Myles Capstick, Dimce Iliev

and Niels Kuster IT’IS Foundation, ETH Zurich, Switzerland

Lausanne 26 April 2016


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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.


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Second prototype


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Applicator Second Prototype

• 8 field coil windings, each with 5 turns• Total 40 turns

• Field sensitivity 84 μT/A Bore diameter

400mm


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Tuning and matching

• High voltage capacitor stacks Input transformers for matching

• Operates at 303 kHz


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System

• Two amplifierunits

– Each with 4 x

750W amplifier

modules

– Each with 2 x1.5kW power

supplies

• One set of 8 field

coils

– Series resonated – Fed at low

voltage point

PSU

Input 2fo

Power

Cotrol

PSU

PSU

PSU


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System

• System functions

• Field coils

characterised

• Equivalent circuitmodel available

• Basic control

software available


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Field coil voltages


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Field coil currents


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Loss resistance

• Calramic capacitors hadTanδ = 0.002

• Loss resistance between

0.23 and 0.30 Ω at 300 kHz

• Arlon Diclad 527

• Tanδ = 0.001 at 1 MHz

• εr = 2.65

• Loss resistance between

0.11 and 0.15 Ω at 300 kHz


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Oil cooled capacitors

• Manufactured from a PTFE based material with some glassfibre reinforcement with 254µm thickness bonded to an oil

filled heat exchanger.

280mm x 212 mm

• Can expect 200W

dissipation per capacitor


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Predicted field strength

For 750W per channel

Current is about 36 ArmsField ~ 3mT


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Cooling system

• System has been defined, will use split cooling loops with aliquid – 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


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Cooling system


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Treatment Planning for Magnetic Nanoparticle-Based Hyperthermia

Esra Neufeld, Hazael Montanaro, Myles Capstick,Niels Kuster


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Outline

• background• method

• application

• impact:

– width – shape

– vasculature

• conclusions

Image: Oxbridge Biotech


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Background

• SPIONS (superparamagnetic iron oxidenanoparticles)

• 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 toremagnetization loss

–hyperthermic cancer treatment• when targeting insufficient:

can be directly injected / integrated into bone-

cement used to treat brittle, tumor-affectedbone

Image: Sezer 2012


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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…)


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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 fromapplicator


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Method (II)

• combine computed field strength with image-based particle densityusing 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...)


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Method (IV)

• CEM43 thermal dose computation for effect assessment


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Liver Tumor Targetting


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Impact (I)

varied:

• width of particle distribution• sharpness (step vs. gaussian)

• proximity of major vessel(Dirichlet, zero T increase)

observation

• dominated by interplay betweendiffusion & perfusion heat removal

–little T impact when distributionwider than characteristic Green’sfunction length

–strongly perfused tissue (liver)

quickly reaches perfusiondominated regime (perfusion &particle density matter, distributiononly affects width)


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Impact (II)


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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


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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


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Magnetotheranostics

From superparamagneticnanoparticles 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 It’IS

Magnetotheranostics Mid Term Report

April 2016

1


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Project layout

Existing and newparticle composition

Functionalisation ofparticle with

antibodies

Characterisation

toxicity screening

In vitro tests

specific adsorption

at metastasis

Nanocomposite

formulation

In vitro tests

and heating

capacity

In vivo tests of

and tumor

treatment

In vivo tests of

metastasis

detection

In vivo tests

theragnosis

Improvement

of mag

generator

Developmenttemperatur

simulation

tool

Engineering ; ITIS, ANTIA

Physics, chemistry material

science; EPFL, UNI GE, CHUV

In-vitro, toxicity, imaging

EPFL, ITIS, UNI GE, CHUV

Medical application

CABMM, Inselspital

T o x i c i t y

t e s t s

M o l e c u l a

r i m a g i n g ( M R I )

H y p

e r t h e r m i a

MagnetoTheranosticsMagnetotheranostics Mid Term ReportApril 2016

2


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SPION as Contrast agent

Functionalized nanoparticles for biomedicalapplication MSE 617

4

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


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MRI sequences for IONP

• Further development of ultra-short echo time (UTE) MRIimaging.

– 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 closervicinity to the contrast agent.


April 2016

7

basic MRI method UTE MRI novel IRON-UTE (IRON) MRI


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Magnetotheranostics Mid Term ReportApril 2016

8


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Functionalisation


April 2016

9

Different types of molecules were used to

• increase biocompatibility• higher colloidal stability

• Act as 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)

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


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Functionalization with targeting molecules


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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-negative PC3 cells

PSMA-positive LNCaP cells


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In vivo tumor model


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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

B

binds surface of MAT-LyLu cells… and is further internalized

small molecule aptamer merged

Adequate cell line forin vivo targeting assay

aptamer-Cy5

M ti i l t h th i


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cement

Remaining

tumor tissue

Magnetic implant hyperthermia:Potential applications to vertebroplasty


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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


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M i i l h h i


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Magnetic implant hyperthermia:

in vivo investigations

Equilibrium temperature depends on : - magnetic field strength

- physiological cooling reflexes

p


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Magnetic implant Hyperthermia

Implant

15Functionalized nanoparticles for biomedicalapplication MSE 617


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Magnetic implant hyperthermia:

in vivo investigations

• Kaplan-Meyer survival curvesendpoint : ten time initial tumoral volume

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 12 24 36 48 60 72 84

Days after therapy

F r a c t i o n a l s u r

v i v a l

ControlImplanted control

10.5 mT

12 mT

200

group Median

survival

time : tm.

Controln=6

12

implante

d controln=7

21

10.5mTtreated

n=7

27

12 mTtreated

n=11

37

*Significant differences betweencurves with Wilcoxon test

p


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Magnetic fluid hyperthermia

• Undergoing clinical trials

– Phase II (efficacy): glioblastoma multiforme

and prostate carcinomas

– Phase I (feasibility): esophageal cancer


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Task 2: Nano particle hyperthemia applicator

prototype

• Two amplifier units

-Each with 4 x750W amplifiermodules

- Total of 6 kW RFpower at 300 kHz

• Field coils Amplifiers


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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 withtunable 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 tissuemodels (perfusion & effective thermal conductivity)


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Example: Modeling of dog NP HT

Magnetotheranostics Mid Term ReportApril 2016 20


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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 andapplication of all products developed in Magnetotheranostics

– GMP production of core nanoparticles


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

The «other» big challenges

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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 andresearch level)

Realized

Acceptance of nanotechnology Organized the World Nano Cancer Day

(Swiss part), Papers targeting clinicians in

preparation*


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Thank you for your attentionInvestigator Institution Main task

H. Hofmann, D. Bovin,M Mionic

EPFL Particle and functionalisation

B. von Rechenberg P.

Kircher,

H. Richter

Vetsuisse Zürich animal experiments

H. Thoeny,S. Barbieri, Inselspital, Bern MRI of lymph nodemetastasis

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

Magnetotheranostics - Nano-Tera 2016

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