Magnetic Nanoparticles - auth

http:// multigr.physics.auth.gr

Magnetic Nanoparticles: Biomedical Applicability as heating mediators

M. Angelakeris Associate Professor

Department of Physics Aristotle University of Thessaloniki, Greece


Contents

Magnetic Nanoparticles: Biomedical Applicabil ity as heating mediators


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M. Angelakeris

Introduction • Magnetic nanoparticles

• Biomedical Applications

• Magnetic Particle Hyperthermia

Design Rules • Material selection

• Particle Properties

• Interactions

Perspectives • Clinical Practice

• Side-effects

• Theranostic Particles


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

inducing 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.

500 BC: Hippocrates:

“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.

Heat treatments

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

hyperthermia in 1957.

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

nanoparticles improves hyperthermia cancer treatment.

• 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.

Introduction

http:// multigr.physics.auth.gr Magnetic Nanoparticles


varying stoichiometry

structure & morphology

tunable

nano-

micro-

macro-

scopic magnetic behavior.

Spheres with diameter < 50 nm, < 100.000 atoms

Reproducibility

Stability

Arrangement

Morphology

Nanomagnetism Spin configuration

Co-ordination Dipolar Interactions

Uniformness

Exchange Interactions

Introduction


http:// multigr.physics.auth.gr Magnetic Nanoparticles

1G: Physics

• To design, control and measure magnetic response at the nanoparticle unity.

2G: Chemistry

• To achieve and reproduce nanoscale multicomponent fabrication.

3G: Biology

• To introduce multifunctionality without sparing enhanced performance.

4G: Medicine

• To increase biocompatibilty and sustain enhanced mulifunctionality in-vivo.

Introduction



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Biomedical Applications

Magnetic Hyperthermia

Cell Regeneration Drug Delivery

Bioseparation

BioSensing

MRI

Cell Capture

Cellural Proteomics

Cell Tracing

Introduction


http:// multigr.physics.auth.gr Magnetic Particle Hyperthermia

Γ=KV/kBT

A=αμοMSHC0

fH

SARILP

2

)1()( Bt

f et

tm

mc

mt

Q

m

WSARSLP

magn

f

magnmagn

or

PSPM = μ0πf χ’’H2

HdMf0FMP

M. Kallumadil et al. J. Magn. Magn. Mater. 321 1509 -1513 (2009). A. Chalkidou et al. J. Magn. Magn. Mater. 323 775-780 (2011). K. Simeonidis et al. J. Appl. Phys. 114, 103904 (2013).

Introduction



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Magnetic Particle Hyperthermia

Constant frequency: 200, 765 kHz

Varying magnetic field: 8-40 kA/m

Varying ferrofluid concentration: 0.1-50 mg/mL

GaAs (SCBG) technology OTG series optical sensor Temperature-dependent bandgap of GaAs crystal Dimensions: 0.170mm OD Response time <10ms. Accuracy: ± 0.3°C Resolution: 0.05°C

Introduction


Contents



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M. Angelakeris






• Interactions


• Side-effects




Anisotropy: 5 < Keff < 40 KJ/m3

Size: 10 < D < 30 nm

Saturation Magnetization: 60 < Ms < 100 emu/g

Material Selection

Magnetic Nanoparticles: Biomedical Applicabil ity as heating mediators 10

M. Angelakeris

Design Rules



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Material Selection

• Region between bulk and atomic scale

– Increase of surface atoms

– Surface structure modulation

– Tunable electronic, optic, magnetic and catalytic

properties

• Reduced dimensionality effects

– Mono-Multidomain Limit

– Superpamagnetic Limit

• Surface effects

– Magnetization tuning

– Magnetic anisotropy increase(shape, interface)

– Magnetic coupling effects (intra, or inter particle)

Co

erc

ive

fie

ld

Sup

erp

aram

agn

eti

sm

ferromagnetism

monodomain multidomain

Particle Diameter

CoFe2O4

γ-Fe2O3

Fe3O4

FeCo

FePt

CoPt

Ni

Co

200 kJ/m3

4.7 kJ/m3

5 kJ/m3

412 kJ/m3

Design Rules


28

SLP

(W/g

Fe) SPM

maximum

FM maximum

22 KA/m

K. Bakoglidis et al., IEEE Trans. on Magn. 48 1320,( 2011).

further increase of particle size:

Monodomain Multidomain

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

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M. Angelakeris


Size of Magnetic Nanoparticles

Particle Properties Design Rules

PSPM = μ0πf χ’’H2

HdMf0FMP


Tuning of magnetic anisotropy via shape anisotropy

Particle Properties Design Rules

C. Boubeta et al. Scientific Reports | 3 : 1652 | DOI: 10.1038/srep01652 (2013).

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M. Angelakeris




Dipolar interactions

Design Rules-Interactions

Magnetic nanoparticles are stabilized in agarose matrices of varying density under an external static magnetic field

(0.1 T) to facilitate orientation in long-range chains to facilitate orientation in long-range chains.

The level of specific loss power is defined by the strength and frequency of the applied AC magnetic field, but also

the dispersion’s concentration due to the appearance of dipole-dipole interactions.

The alignment of nanoparticle chains gradually disappears at higher agarose concentrations due to limitations in

particle mobility raised by the matrix viscosity.

Agarose network also simulates heat transfer in a typical in-vivo environment. E. Mirovali et al. under preparation

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M. Angelakeris



D. Serantes et al., J. Apl. Phys. 108, 073918 (2010).

C. Boubeta et al. Adv. Funct. Mater. DOI: 10.1002/adfm.201200307, (2012).

D. Serantes et al., J. Phys. Chem. C, 118 (11), pp 5927–5934 (2014).

Single-domain metallic Fe MNPs

Effective uniaxial magnetic anisotropy Keff

Uniform magnetization and composition

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.

Tuning of dipolar interactions

Interactions Design Rules

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Different dependences of SLP on AC field parameters for different loss types

Field amplitude and frequency favorably chosen depending on particle choice

Particle type dependent magnetic losses

50 nm

85 nm

50 nm

90 nm Tuning of dipolar interactions

Interactions Design Rules

50 nm

D. Sakellari et al., submitted for publication

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)



M. Angelakeris

Exchange interactions

Interactions

The effect of incorporating core-shell morphologies as an alternative approach in enhancing AC magnetic particle

hyperthermia efficacy via nanomagnetism tuning.

Initially, we studied pure (MnFe2O4 and CoFe2O4) ferrite particles and then

attempted to synthesize bimagnetic core-shell particles with a seed-mediated growth where initial nanoparticles

were used as substrates.

The use of core-shell bimagnetic morphology instead of careful control of size and homogeneity in single phase

particles seems to address the issue of enhanced hyperthermia agents more successfully since bimagnetic

particles exhibit scores one order of magnitude higher that initial materials.

M. Angelakeris et al. submitted for publication

Design Rules

http:// multigr.physics.auth.gr Contents



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M. Angelakeris






• Interactions


• Side-effects



C. Martinez-Boubeta et al. Nanomedicine: Nanotechnology, Biology, and Medicine 6, Issue 2, 362-370 (2010). A. Chalkidou et al. J. Magn. Magn. Mater. 323 775–780 (2011).

Spherical iron nanoparticles of 75 nm.

Biocompatible MgO shell and bcc Fe core.

Significant uptake for the different cell lines (42 -126 pg Fe/cell).

Concentration-dependent cytotoxity profile

SLP was estimated to be in the region of 100-500 W/g Fe.

Fast thermal response (15 oC/ 10 min)

Three different MDA-MB-231, SkBr3 and MCF7 breast cancer cell lines with different hormonal status and

HER2/neu

Clinical Practice Perspectives

In-vitro tests

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M. Angelakeris




Saos-2

10x

Control2: cells only

Saos-2 with Field

10x Control3: cells+field, no MNPs

M1-8 mg/mL

10x

Control4: cells+ MNPs, no field

MnFe₂O₄ nanoparticles

are good candidates for hyperthermia purposes since

they present a moderate magnetic moment,

chemical stability and

high specific loss power (SLP)

Magnetic field of 300 Oe & 765 kHz (~2 x 1010 m-1 s-1)

had small influence on cell viability

enhances cell uptake by activating heat shock proteins

Even without surfactants → very low cytotoxic effect

Successful in-vitro hyperthermia in Saos-2 cancer cells

Clinical Practice Perspectives

In-vitro tests

A. Makridis et al.,

submitted for publication



M. Angelakeris

Commercial Ferrofluids


Clinical Practice

A series of commercially available magnetic iron oxide nanoparticles (Nanomag®-D-spio[i], FeraSpin R[ii] and FluidMag-DX[iii]) as possible candidates for magnetic particle hyperthermia applications and their exploitation as multifunctional biomedical carriers combining their initial modality (i.e. MRI contract agents or drug carriers) with heat triggered actions. 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.

[i] http://www.micromod.de/ [ii] http://www.nanopet-pharma.com [iii] http://www.chemicell.com/home/index.html

Perspectives



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Side-effects The toxicity of magnetic particles depends on materials and morphological

parameters including composition, degradation, oxidation, size, shape, surface

area and structure.

When compared to micron-sized particles, nano-sized particles

can be generally more toxic because they have larger surface

area (hence, more reactive), for a given mass, to interact with

cell membranes and deliver toxicity.

They are also retained for longer periods in the body (more

circulation or larger clearance time) and, in principle, can be

delivered deeper into the tissue due to their size.

The surface coating and their morphology play an important role

in determining nanoparticle toxicity.

Perspectives



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M. Angelakeris


Theranostic Particles

Radiation sensitizers

Chemo-therapeutic

cocktails

Surgery

Targeted therapeutic

agents

Platinum therapeutics

Multimodal

Regimens

• Hyperthermia synergizes with

– a variety of materials (arsenic trioxide,

tirapazamine, cisplatin)

– Radiation therapy

• Radiation produces

– oxygen radicals-double stand breaks-

cancer cell destruction

• Hyperthermia increases

– oxygenation levels in cancer cells

– Hinders the ability of cancer cells to

sense DNA destruction

– Impedes DNA repair mediators

Perspectives



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M. Angelakeris



Theranostics arises from the combination of the terms "Therapeutics" and "Diagnostics" and is used to describe a proposed process of diagnostic therapy for individual patients - to test them for possible reactions when taking a new medication and to tailor a treatment for them based on personalized test results.

A major challenge in Theranostics for the 21st century is to be able to detect disease biomarkers non-invasively at an early stage of disease progression and choose and administer personalized medical treatment factoring individual genetic and phenotypic characteristics.

Perspectives



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M. Angelakeris

Magnetic Particle Hyperthermia & Drug Relase



Highly faceted IOs

Encapsulation in biodegradable block copolymers

Hyperthermia & Taxol drug release

M. Filipousi et al. RSC Adv. 3, 24367 (2013).

Perspectives



Conclusions

cancer cells absorb MNPs thereby increasing the effectiveness of treatment.

MNPs can be targeted through cancer-specific binding agents making the treatment

much more selective and effective.

the frequencies, intensities of magnetic fields generally utilized pass harmlessly

through the body.

MNPs can also effectively cross blood-brain barrier (BBB) and hence can be used for

treating brain tumors.

effectively and externally stimulated can be delivered at cellular levels through

magnetic field.

with the possibility to obtain stable colloids using MNPs, they can be administered

through a number of drug delivery routes.

only few tens of nanometer in size and therefore, allows easy passage into several

tumors whose pore sizes are in 380–780 nm range.

compared to macroscopic implants, MNPs provide much more efficient and

homogeneous treatment.

MNP-based hyperthermia treatment may induce antitumoral immunity.

Multifunctional and multi-therapeutic approaches for treating a number of

diseases. 26


http:// multigr.physics.auth.gr Acknowledgements

Synthesis

K. Dendrinou-Samara, Assoc. Prof. ,Chemistry-AUTh

Ll. Balcels, Dr. ICMAB-Spain

M. Hilgendorff, Freie Univ. Germany

K. Simeonidis, Dr. Physics-AUTh

Structure & Morphology

M. Filipousi Dr. EMAT Univ. Antwerp, Belgium

Zi-An Lee, Univ. Duisburg-Essen, Germany

P. A. Migley, Dr. Univ. Cambridge

I. Tsiaousis, Dr. Physics-AUTh

Magnetism

C. Boubeta, Dr. IN2UB-Dept. d’Electrònica, UBCN

O. Kalogirou, Prof. Physics-AUTh

M. Farle, Prof. Dr. Unin. Duisburg-Essen

Magnetic Hyperthermia

Z. Kalpaxidou, V. Ntomprougidis, BSc students

S. Mathioudaki, O. Patsia, MSc students

A. Makridis, E. Mirovali, PhD Students

D. Sakellari, Dr. Physics-AUTh

In-vivo experiments

A. Chalkidou, MSc, Oncologist., Theageneio Hosp.

K. Papazisis, Dr. Oncologist, Theageneio Hosp.

D. Topouridou, Dr. AHEPA-AUTh Hospital Clinic

M. Tziomaki, PhD student AHEPA-AUTh Hospital

M. Yavropoulou, Dr. Endocr. AHEPA-AUTh Hospital

Modeling

Th. Samaras, Assoc. Prof., Physics-AUTh

27

M. Angelakeris Magnetic Nanoparticles: Biomedical Applicabil ity as heating mediators

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