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M . A n g e l a k e r i s : B i o m e d i c a l N a n o m a g n e t i c s : A d v a n c e s , c u r r e n t t r e n d s a n d c h a l l e n g e s 1 / 2 3P 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

Biomedical Nanomagnetics:

Advances, current trends and challenges

Particles

Ensembles

Systems

M. Angelakeris, associate professor

Department of Physics, Aristotle University

54124, Thessaloniki-Greece

[email protected]

http://multigr.physics.auth.gr



magnetics

medical

NanoBioNano: only few tens of nanometer in size and therefore,

allows easy passage into several regions (cross blood-brain

barrier).

Homogenous: compared to macroscopic implants, provide

much more efficient and homogeneous treatment.

Less invasive: the frequencies, intensities of magnetic fields generally

utilized pass harmlessly through the body.

External: effectively and externally stimulated can be delivered at cellular

levels through magnetic field.

Alternative: administered through a number of

drug delivery routes.

Selective: specific cell targeted through specific

binding agents.

Synergy: Multifunctional and multi-therapeutic approaches for treating a number of diseases.

Stimulation: Positive side-effects (Immune system activation).

Bio+medical+Nano+magnetics

Why so important?



Biomedical Applicability

Magnetic Hyperthermia

Cell Fate Control Drug Delivery

Bioseparation

BioSensing

MRI

Cell Capture

Cellular Proteomics

Cell Tracing

Types of Treatments



Magnetic Nanoparticles

varying stoichiometry

structure & morphology

tunable nano- micro- macroscopic magnetic behavior.

Spheres with diameter < 50 nm,< 100.000 atoms



NanomagnetismSurface & Interface Magnetism

in 3 nm particles (~1400 atoms) 40% of atoms is located at surface

weak ferromagnetism

exchange-spring magnets

superparamagnetism exchange bias



KV: Magnetic Anisotropy Energy vs kBT: Thermal Energy

Nanomagnetism



Magnetic field (T)

Mag

ne

tiza

tio

n (

em

u/g

)

Size D<Dcrit superparamagnetism

D>Dcrit ferromagnetism

Temperature TBmaximum susceptibility

T<TB ferromagnetism

T>TB superparamagnetism

Temperature (K)

Mag

ne

tiza

tio

n (

arb

. un

its)

Shape Shape anisotropy ferromagnetism

Interface anisotropy ferromagnetism

Iron Oxide Nanoparticles

C. Martínez-Boubeta et al., Phys. Rev. B 74 054430 (2006).

Nanomagnetism



Particles

Properties



Particles

1st choice USPIOS < 10 nm SPIOS 10 nm < < 30 nm Large > 30 nm

Magnetic iron oxides Fe3O4 (magnetite) and γ -Fe2O3 (maghemite) well tolerated by the human body

Magnetic field (T)

Mag

ne

tiza

tio

n (

em

u/g

)

Phys. Rev. B 74, 054430 (2006). IEEE Trans. Magn. 48, NO. 4, 2012, 1320

M . A n g e l a k e r i s : B i o m e d i c a l N a n o m a g n e t i c s : A d v a n c e s , c u r r e n t t r e n d s a n d c h a l l e n g e s 1 0 / 2 3P H Y S I C SA U T h - G r e e c ePAMS-3


Particles

Co

erc

ive

fie

ld

Su

pe

rpar

amag

ne

tism

ferromagnetism

monodomain multidomain

Particle Diameter (nm)

0

SM HM

SPM

0 20 100

Size ↓

↑ % surface atoms

Surface & Interface Magnetism

Size Issues



Particles

CoFe2O4

γ-Fe2O3

Fe3O4

FeCo

FePt

CoPt

Ni

Co

Alternatives

Metallic particles, spinel ferrites or special magnetic alloys

Other Choices 200 kJ/m3

Nanoparticle Diameter (nm)

0 20 40 60 80 100 120

4.7 kJ/m3

5 kJ/m3

412 kJ/m3



Particles

Ensemble

Conditions

Add-ons

Bio-practice

Particles

NiFe2O4

Tuning magnetization by sizeMnxFe1-xO4

Other Choices

IEEE Trans on Magn. 50, 12, 2014, 4601207

Composition and hydrophilicity control

Dalton Transactions 44, Issue 12, 28, 5396-5406 (2015)

metallic Fe/MgO

high-yield one step synthesis

Nanomedicine: Nanotechnology, Biology, and Medicine

6 (2010) 362–370



Ensemble

Water Transfer

A versatile large-scale and green process for synthesizing magnetic nanoparticles with tunable magnetic hyperthermia features

accepted for publication in RSC Advances, 2016



Ensemble

single-core

core-shell arrays

50 nm

Interactions



Ensemble

Interactions

MFe2O4, M=Mn, Co

hard/softinterface

MFe2O4, M=Co, Mn or Fe

J. Magn. Magn. Mater. 81 179–187 (2015).J. Magn. Magn. Mater, RSC Adv. accepted for publication, 2016

Tuning the magnetism of ferrite nanoparticles by nanoscale mixing and matching

Mn@Co

Co@Mn



Ensemble

Interactions

J. Appl. Phys. 108, 073918 (2010).Adv. Funct. Mater. DOI: 10.1002/adfm.201200307, 2012.

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 saturation taking place at larger values for larger concentrations.



Ensemble

Interactions

Sci. Rep. accepted for publication, 2016



Ensemble

Interactions

Cluster size dependent magnetic properties

50 nm

86 nm

50 nm

98 nm

Tuning of dipolar interactions

50 nm

Mat. Sci. Eng. C 58, 187–193 (2016)

13 nm 45 nm

50 nm 62 nm

86 nm 98 nm



In-vitro testing

Cell fate control with magnetic field dancing modes

Magnetic nanoparticles may also be used to generate mechanical stimulations on cells

which can induce changes in cell activity such as differentiation, growth and death.

1 10

50

60

70

80

90

100 200mT

50mT

100mT

60mT

40mT

Force/MNP100nm

(pN)

Ce

ll V

iab

ility

(%

)

Force/Cell (pN)

1E-4 1E-3

SystemsParticles

Ensemble

Conditions

Add-ons

Bio-practice

Nano-screenMAG-D, Chemicell GmbH on HT.29 cells (human colorectal adenocarcinoma)

Blue : cell nucleusRed : Lysosomes

Hetero-nanocomposites: 30 nm Cu2O nanoparticles with antifungal properties

functionalized with 9 nm NiFe2O4 magnetic nanoparticles as a platform for

magnetomechanical stress in Saccharomyces cerevisiae: J. Mater. Chem. B, 2015, 3, 5341



In-vitro testing

Particles

Ensemble

Conditions

Add-ons

Bio-practice

Systems

Dose-dependent proliferation assay on 3T3 cells bymonitoring the 24-hour cell growth. Normalproliferation rates were obtained at all concentrationstested.

T2-weigthed MR images of mouse body before (left) and after injection of NPs.Because of the negative contrast properties of the solution, the liver appearshypointense in images after contrast injection (see arrow). (B) Color-coded T2maps, from yellow (high T2) to green (low T2). (C) Comparison of magnetic signalfrom targeted liver at the same time points as imaged by MRI. Maximumconcentrations (~ 90% of the injected dose) were observed 24 hours after injection.

Nanomedicine: Nanotechnology, Biology, and Medicine 6 (2010) 362–370

Fe/MgO nanoparticles



Systems

To detect small sized pathogenic targets precisely at an early stage, MRI contrast agents are often used to highlight

those specific areas of interest.

One of the most effective ways to increase the MR contrast effects is the optimization of saturation magnetization

(Ms) which is directly related to the relaxivity coefficient (r2).

The magnetism engineering of iron oxide nanoparticles has already been

reported where substitution of one of the Fe ions with different magnetic

atoms such as Mn can increase the Ms.

Substituting Fe2+ in the Td holes with non-magnetic Zn2+ (0 μB).

For (Zn0.4Mn0.6)Fe2O4 nanoparticles with a high Ms value of 175 emu/g, the

r2 reaches up to 676 mM-1 s-1 which is 6 times higher than that of Feridex

which is one of the most representative iron oxide based contrast agents.

D. YOO et al. Accounts of Chemical Research 44 863 (2011)

D. Yoo et al. Accounts of Chemical Research 44 863 (2011)



Conventional MRI contrast agents are mostly effective only in a single imaging mode of either T1 or T2 and

frequently suffer the ambiguities in diagnostics especially for small biological targets.

The combination of simultaneously strong T1 and T2 contrast

effects in a single contrast agent can be one of the new

breakthroughs, since it can potentially provide more accurate MR

imaging via self confirmation with better differentiation of normal

and diseased areas.

When the SiO2 layer is 16 nm, both T1 and T2 contrast effects

become larger than the effects of the well-known single mode

contrast agents, Gd-DTPA and Feridex.

Due to the simultaneously high T1 and T2 effect, DMCA can now

be used effectively to perform “AND” logic in MRI.

D. Yoo et al. Accounts of Chemical Research 44 863 (2011)

Systems



1. Magnetic Nanoparticles directly address the current trends of theranostics since they

combine imaging with therapeutic capabilities and allow a large degree of control

over the treatment efficacy.

2. Magnetism: Effective, Externally stimulated, Specific response to external magnetic field

at cellular level, Easy passage into several tumors .

3. Functionalization: Selective targeting via cancer-binding agents, Multifunctional and

multi-therapeutic approaches.

4. Biocompatibity: Field parameters pass harmlessly through the body, Nanotoxicity

control, efficient and homogeneous treatment with smaller dose.

Biomedical Nanomagnetics: Advances, current trends and challenges



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

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