Magnetic Hyperthermiausers.auth.gr/agelaker/index_htm_files/Angelakeris3-PAM3...Hyperthermia differs...

M . A n g e l a k e r i s : M a g n e t i c H y p e r t h e r m i a : A v e r s a t i l e p l a t f o r m f o r h e a t - t r i g g e r e d m o d a l i t i e s 1 / 3 0P H Y S I C SA U T h - G r e e c ePAMS-3

3rd PAM International School on Application of Nanomaterials in Medicine, 2-4 November, 2016, Tehran, Iran

Magnetic Hyperthermia:

A versatile platform for heat-triggered modalities

Principle

Parameters

Conditions

Functions

M. Angelakeris, associate professorDepartment of Physics, Aristotle University

54124, Thessaloniki-Greece

[email protected]

http://multigr.physics.auth.gr



Introduction-Heat treatmentsPrinciple

Parameters

Conditions

Functions

1891: A century ago, Dr. William Coley an innovative New York surgeon induced

a fever in the body of a cancer patient to stimulate the immune response and

cause cancer remission.

Coley’s toxins: Bacteria used to treat patients with a variety of types of cancer

up until the early 1950s. More than 1,000 patients over 40 years.

“What medicine cannot cure,

iron (the knife) cures;

what iron cannot cure, fire cures ;

what fire does not cure, is to be considered incurable”

Hyperthermia is elevated body temperature due to failed thermoregulation that occurs when

a body produces or absorbs more heat than it dissipates.

Hyperthermia differs from fever in that the body's temperature set point remains unchanged.

500 BC: Hippocrates



Introduction-Hyperthermia typesPrinciple

Parameters

Conditions

Functions

Hyperthermia: Treatments at temperatures of 41–45 ◦C

for up to few hours—actually denoted as

hyperthermia—need a combination with other assisting

toxic agents (mostly irradiation or chemotherapy) for

reliable damage of tumor cells.

Local hyperthermia: the local temperature increase with respect to standard temperature of the human

body is considered to be therapeutically useful over a relatively broad temperature range where different

mechanisms of cell damaging occur with increasing temperature.

Local intracorporal heat generation by: microwave radiation, capacitive or inductive coupling of

radiofrequency fields, implanted electrodes, ultrasound, lasers.

Thermoablation: aims for the thermal killing

of all tumor cells by applying temperatures

in excess of at least 50 ◦C in the tumor

region for exposure times of at least few

minutes.

Whole body hyperthermia: the

systemic temperature has to be

carefully controlled to ~41.8 ◦C

by a heat bath.



Magnetic HyperthermiaPrinciple

Parameters

Conditions

Functions

Magnetism + hyperthermia:

1957: Gilchrist and others proposed the use of magnetic materials in

hyperthermia.

Today: MPH: Magnetic Particle Hyperthermia: The use of magnetic

nanoparticles improves hyperthermia cancer treatment.

Hyperthermia vs cancer:

Many tumors thrive in a hypoxic environment in which the

oxygenation of the tumor is much lower than in normal tissue.

Because tumors cannot dissipate heat as quickly as healthy tissue, they

can get hotter than that tissue if enough heat is applied.

Hyperthermia at relatively low levels — as in the early clinical use of

thermal medicine — ends up increasing the amount of blood flow and

oxygenation of the tumor, making it more sensitive to radiation and

chemotherapies.



Principle

Parameters

Conditions

Functions

Field Frequency: 100-1000 kHz

Field Amplitude: 10-100 kA/m

Magnetic Hyperthermia-Setup



Magnetic hyperthermia-MechanismsPrinciple

Parameters

Conditions

Functions

Γ=KV/kBT

A=αμοMSHC

Co

erc

ive

fie

ld

Su

pe

rpar

amag

ne

tism

ferromagnetism

monodomain multidomain

Particle Diameter



Principle

Parameters

Conditions

FunctionsMagnetic hyperthermia-Parameters

Magnetic losses

Hysteresis losses

~2 K

Néel relaxation

τΝ=τ0eKV/kT

Brown relaxation

τΒ=4πnrh3/kT

Viscous losses

~2πμ0ΜRHV

Induced Heating Power

~ H2 f2 D2

Effective relaxation

τeff=τΝτΒ/(τΝ+τΒ)

Ferromagneticparticles

Superparamagneticparticles

Magnetic losses

to be utilized for heating

different processes of

magnetization reversal

different manners on

the applied magnetic AC: field amplitude and frequency.

the structure: mean size, width of size distribution, particle

shape and crystallinity.



Magnetic hyperthermia-ProcessPrinciple

Parameters

Conditions

Functions

Obtained data corrected for heat losses

Coil heating effect

Environmental losses

ΔΤ/Δt

Τ=Το+be-Kt

Specific Loss Power

(SLP) calculation

J. Magn. Magn. Mater. 323 775-780 (2011).J. Appl. Phys. 114, 103904 (2013).



Principle

Parameters

Conditions

FunctionsMagnetic hyperthermia-Parameters

Size: 10 < D < 30 nm

Saturation Magnetization: 60 < Ms < 100 A m2/kg

Anisotropy: 5 < Keff < 40 KJ/m3

heat⇔SLPmax

Material

DosageConditions

M . A n g e l a k e r i s : M a g n e t i c H y p e r t h e r m i a : A v e r s a t i l e p l a t f o r m f o r h e a t - t r i g g e r e d m o d a l i t i e s 1 0 / 3 0P H Y S I C SA U T h - G r e e c ePAMS-3


Principle

Parameters

Conditions

FunctionsTypes of materials-Sizes

28

SLP

(W/g

Fe) SPM

maximum

FM maximum

22 KA/m

Fe3O4: IEEE Trans. on Magn. 48 1320,( 2011).MnFe2O4: Dalton Trans. 44 5396 (2015).

further increase of particle size:

MonodomainMultidomain

coercivity & remanence decrease

decrease of hysteresis losses

Iron oxide particles

below ~ 20 nm become

superparamagnetic

a maximum of hysteresis losses

may be expected

for single domain iron oxide particles

near ~ 30 nm

PSPM = μ0πf χ’’H2

HdMf0 FMP



Principle

Parameters

Conditions

FunctionsTypes of materials-Sizes

R. Hergt et al. J. Phys.: Condens. Matter 20 385214 (12pp) (2008).

Narrow size distribution (w=0.7 nm)

Broad size distribution (w=7 nm)

Reduction of field amplitude below saturation

decrease of heat output.

The amount of decrease depends specifically on the

mean size and the distribution width.

Broad size distribution not very sensitive to changes

of mean size.

Narrow size distribution depression of losses for

medium sizes.

The maximum loss may be gained only if Ho > Hc is above

the coercivity of the majority of particles.



Principle

Parameters

Conditions

FunctionsTypes of materials-Shapes

Tuning of magnetic anisotropy via shape anisotropy in magnetite particles

Scientific Reports | 3 : 1652 | DOI: 10.1038/srep01652 (2013).

-1.0 -0.5 0.0 0.5 1.0

-100

-50

0

50

100

20 nm spheres

20 nm squares

40 nm squares

Ma

gn

eti

za

tio

n (

Am

2/k

g)

Magnetic field (T)

300 K

50 nm



Principle

Parameters

Conditions

FunctionsTypes of materials-Combinations

single-core

core-shell arrays

50 nm



Principle

Parameters

Conditions


Metallic Fe

hard/softinterface

Fe3O4 or γ-Fe2O3

Tuning the magnetism of ferrite nanoparticles

Sample Target (%wt) Chamber’s

pressure/Gas

Composition (%wt) XRD/Mossbauer analysis Average Size

(nm)

Morphology*

Fe Fe3O4 Fe FeO Fe3O4 γ-

Fe2O3 Core/Shell(s)

(nm) Scheme

F01 100 - 70 torr/Ar 79.4

77.7 -

20.6

22.3 50 44/3

F02 75 25 70 torr/Ar 58.6

69.8

10.1

5.2

31.3

25.0 52 42/2/3

F03 75 25 50 torr/Ar 53.6

67.5

11.8

13.1

34.6

-

-

19.3 33 25/1/3

F04 50 50 70 torr/Ar 12.9

11.1

14.7

8.4

72.4

80.6 48 24/4/8

F05 - 100 80 torr/Ar 9.1

5.9 -

90.9

94.1 78 30/24

F06 - 100 80 torr/Ar-O2 - -

4.6

-

58.0

100

37.4 43 43/-

Sample Target (%wt) Chamber’s

pressure/Gas

Composition (%wt) XRD/Mossbauer analysis Average Size

(nm)

Morphology*

Fe Fe3O4 Fe FeO Fe3O4 γ-

Fe2O3 Core/Shell(s)

(nm) Scheme

F01 100 - 70 torr/Ar 79.4

77.7 -

20.6

22.3 50 44/3

F02 75 25 70 torr/Ar 58.6

69.8

10.1

5.2

31.3

25.0 52 42/2/3

F03 75 25 50 torr/Ar 53.6

67.5

11.8

13.1

34.6

-

-

19.3 33 25/1/3

F04 50 50 70 torr/Ar 12.9

11.1

14.7

8.4

72.4

80.6 48 24/4/8

F05 - 100 80 torr/Ar 9.1

5.9 -

90.9

94.1 78 30/24

F06 - 100 80 torr/Ar-O2 - -

4.6

-

58.0

100

37.4 43 43/-



Principle

Parameters

Conditions


MFe2O4, M=Mn, Co

hard/softinterface

MFe2O4, M=Co, Mn or Fe

J. Magn. Magn. Mater. 81 179 (2015)J. Mag. Magn. Mater. 415, 20 (2016)RSC Adv., 6, 53107 (2016)RSC Adv. 6, 72918 (2016)




Principle

Parameters

Conditions



Cluster size dependent magnetic losses

50 nm

100 nm

40 50 60 70 80 90 100100

200

300

400 SLP

SL

P (

W/g

)

Size (nm)

H=25kA/m -f=765kHz

100

200

300

400

H.L.

Hyste

resis

Lo

sse

s (W

/g)

50 nm

Mat. Sci. Eng. C 58, 187–193 (2016)



Principle

Parameters

Conditions



Scientific Reports, Nature, accepted for publication, 2016



Conditions-Field effectPrinciple

Parameters

Conditions

Functions

Out of plane component of ac susceptibility: χ’’=χοωτ/(1+(ωτ)2)

experimental time constant: ω-1=(2πf)-1

ω-1=τ: determination of TBω-1>τ : thermal relaxation takes place

ω-1




Parameters

Conditions

Functions

H

(kA m-1)

f

(kHz)

Hf

(109A m-1 s-1)Reference

18 100 1.8 1

10 410 4.1 2

32 183 5.9 3

19 435 8.3 4

37.3 500 18.7 5

A restriction limits the range of frequency that can be

employed, considering the safety and patient tolerance

limits below which the eddy current effects are

affordable.

Originally, a maximum field - frequency product

Hf ≤ 4.85 × 108 A m-1s-1 called the Atkinson-Brezovich

limit was proposed in 1984, based on micron-sized

magnetic implants.

However, up to date practice, has shown that such a

limitation is rather stringent and should be reconsidered

by including both the nanoscale character of the particles

and the treatment itself.

1. B. Thiesen & A. Jordan (1st clinical magnetic hyperthermia

application) Int. J. Hyperthermia, September 2008; 24(6): 467–474

2. R. Hergt et al. J. Magn. Magn. Mater. 2005, 293, 80–86.

3. E. Alphandéry et al. ACS Nano 2011, 5 (8), 6279–6296.

4. S. Kossatz et al. Pharm Res (2014) 31:3274–3288

5. H. Mamiya, Journal of Nanomaterials 2013, Article ID 752973



Conditions-Concentration effectPrinciple

Parameters

Conditions

Functions

140 160 180 200 220 240 260 2800

100

200

300

400

500

600

Ø18 nm

c/7

c

Ø10 nm

c/7

c

SA

R (

W/g

Fe)

H (Oe)

Iron Oxide MNPs

c=1.2 mg/ml

ΔSAR=255

ΔSAR=328

SLP

ΔSLP

ΔSLP

SLP decreases with increasing concentration

Static susceptibility decrease

Néel relaxation time decrease

faster τ dominates



Conditions-Concentration effectPrinciple

Parameters

Conditions

Functions

J. Appl. Phys. 108, 073918 (2010).

Adv. Funct. Mater. DOI: 10.1002/adfm.201200307, 2012.

Sci.Rep. 2016, Accepted for publication

Single-domain metallic Fe MNPs

Effective uniaxial magnetic anisotropy Keff

Uniform magnetization and composition

decrease in the initial susceptibility with increasing c, so that the

stronger the interaction between particles, the lower the SLP.

SLP saturates to a constant value for large fields

the saturation taking place at larger values for larger concentrations.

Ha (larger the higher the concentration) gives the upper limit for the

field amplitude for larger SLP.

Ha=2 K/MSanisotropy field

SLP

/f (

J/k

g)




Parameters

Conditions

Functions

In-vitro Hyperthermia

Versatile in-vitro hyperthermia protocol

(two hyperthermia runs separated by a

48 h incubation stage).

Single-pulse or a multi-pulse AC field

exposure with tunable time duration in

order to maintain the cells as long as

possible between 41 and 45oC, i.e. the

hyperthermia region.

Check in-vitro performance in human

osteosarcoma cell line (SaOs-2) and in two

reference healthy cell lines (C2C12 skeletal

myoblasts and 3T3-L1 fibroblast-like

preadipocytes).

(a) (b) (c)

0 200 400 600

41

43

45

Te

mpe

ratu

re (

oC

)

Time (sec)

Co+Fe

Mn+Fe

(b)

0 200 400 600 800 1000

34

36

38

40

42

44

46

hyp

ert

he

rmia

leve

ls 4

1-4

5oC

Control

Mn+Fe

Co+Fe

Te

mp

era

ture

(oC

)

Time (sec)

Mn+Fe Co+Fe Control(a)

0 200 400 600 800 1000

34

36

38

40

42

44

46 Mn+Fe Co+Fe Control

Control

Tem

pera

ture

(oC

)

Time (sec)

Co+Fe

Mn+Fe

hyp

ert

he

rmia

leve

ls 4

1-4

5oC

(e)

0 200 400 600

41

43

45

Mn+Fe

Co+Fe

Te

mp

era

ture

(oC

)

Time (sec)

(f)

Saos-2 sample Prusian Blue stained

(a) control sample

(b) with Mn+Fe MNPs

(c) With Co+Fe MNPS

Int J Hyperthermia 2016, 32(7):778-85.



Functions-Tuning hyperthermia responsePrinciple

Parameters

Conditions

Functions

K. L. McNerny et al. J. Appl. Phys. 107 09A312 (2010).

Fe27Pt73, Ni28Pd72, TC~45oC

Ni alloys: Ni-Cu, Ni-Pd, Ni-Pt

Fe-Pt alloys, Co-Pd alloys

Ferrites: Fe1-xMnxFe2O4

Magnetic nanoparticles possessing low Curie temperatures

(TC) offer the possibility for self regulated heating of cancer

cells, where the TC acts as an upper limit to heating to

prevent damage to neighboring healthy tissues.

Once they reach the Curie temperature, the Ms drops to zero

and heating stops.

Thus if the Curie temperature is fixed by judicious selection of

particle composition and size hyperthermia response is

eventually fixed below a certain temperature level preventing

excessive temperatures.

Self-regulated hyperthermia



Principle

Parameters

Conditions

Functions

To investigate the usefulness of a method for controlling the

temperature rise in magnetic hyperthermia (MH) using an external

magnetic field to manipulate the energy dissipation of magnetic

nanoparticles in the presence of both fields

Functions-Tuning hyperthermia response

High-Performance Iron Oxide Nanoparticles forMagnetic Particle Imaging – Guided Hyperthermia(hMPI)

Appl. Field (f=380kHz, Ho=16kA/m)

To mimic the magnetic environment during an MPI imaging Process -

external magnetic field gradient (0.47T/m gradient across the

hyperthermia coil with a null point near the center

L. M. Bauer et al. Nanoscale, 2016,8, 12162-12169

Control of the temperature rise in magnetichyperthermia with use of an external static magneticfield K. Murase et al. Phys Med. 2013;29(6):624-30



Functions-NanoplatformsPrinciple

Parameters

Conditions

Functions

A. Ito et al. Cancer Immuniol. Immunother. 55 320-328 (2006).

Interaction with the Immune System

Hyperthermia based controlled drug-delivery

Hyperthermia & Diagnosis

Μultifunctional NPs with a γ-Fe2O3 core and

labeled with a targeting agent LHRH

(Luteinizing Hormone Release Hormone)

ensured specific targeting to cancer cells of

breast and prostate in addition to having a

two-photon fluorescent probe to aid in

optical tracking.

Delivery through Bond Breaking (DBB)

Delivery through Enhanced Permeability (DEP)

C. S. S. R Kumar et al. Advanced Drug Delivery Reviews 63 789-808 (2011)



Principle

Parameters

Conditions

Functions

Magnetic-hyperthermia triggered drug release system

RSC Adv. 3, 24367 (2013).

Functions-Nanoplatforms

Highly faceted IOs

Encapsulation in biodegradable block copolymers

Hyperthermia & Taxol drug release



Principle

Parameters

Conditions

Functions

The major advantage of such a study is that an optimum system

directly addresses the multifunctional role in modern

theranostics and may be further implemented in therapies with

faster steps since major tasks have already been undertaken.

A series of commercially available magnetic iron oxide nanoparticles (Nanomag®-D-spio,

FeraSpin R and FluidMag-DX) as multifunctional biomedical carriers combining their initial

modality (i.e. MRI contract agents or drug carriers) with heat triggered actions.

J. Magn. Magn. Mater. 380 360-364 (2015).

EPJ Web of Conferences 75, 08002 (2014).

Functions-Nanoplatforms



Functions-Multimodal Cancer RegimensPrinciple

Parameters

Conditions

Functions

Radiation sensitizers

Chemo-therapeutic

cocktails

Surgery

Targeted therapeutic

agents

Platinum therapeutics

Multimodal

Regimens

• Radiation and chemotherapy induce

DNA damagedouble strand breaks oxygen radicals

• Hyperthermia increases

• oxygenation levels in cancer cells

• Hinders the ability of cancer cells to sense DNA

destruction

• Impedes DNA repair mediators

Hyperthermia synergizes with

Radiation therapy

Chemotherapy: (arsenic trioxide, tirapazamine, cisplatin)

+ hyperthermia



Magnetic hyperthermia-Questions Principle

Parameters

Conditions

Functions

In vivo studies

Cell: 10-100 μm,

Virus: 20-450 nm

Gene: 2nm wide, 10-100 nm long

Hydrodynamic parameters

Blood flow rate

Ferrofluid concentration

Infusion route

Circulation time

Psysiological parameters

Tissue depth & perfusion

Tumour volume

Strength of carrier/binding in varying enrnoment

Side-effects of high frequency magnetic fields

Stimulation of peripheral or skeletal muscles

Possible cardiac stimulation and arrythmia

Non-specific inductive heating of tissue

Circulation & Accumulation

Circumvention of rapid kidney clearance and reticular endothelial system (RES)

Design to avoid rapid opsonization and subsequent macrophage phagocytosis

Slow accumulation through the leaky vasculature in a variety of lesions

Metallic Iron upon metabolism – oxidative stress through harmful reactive oxygen species



Colleagues

M. Farle & group members, Germany

Ll. Balcels, C. Boubeta, D. Serantes, Spain

K. Chliclia, K. Spriridopoulou, M. Tziomaki, M. Yavropoulou, Greece

K. Dendrinou-Samara, O. Kalogirou, T. Samaras, AUTh-Greece

Group members

K. Simeonidis, Dr.

D. Sakellari, Dr.

A. Makridis, PhD student

E. Mirovali, PhD student

N. Maniotis, PhD student

Acknowledgements

Magnetic Hyperthermiausers.auth.gr/agelaker/index_htm_files/Angelakeris3-PAM3...Hyperthermia differs...

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