nanomagnetism & biomedical applicability

M . A n g e l a k e r i s : N a n o m a g n e t i s m a n d B i o m e d i c a l A p p l i c a b i l i t y 1 / 2 3P h y s i c sA U T h

Workshop: Materials at the Nanoscale, 3-4 November, 2018, Thessaloniki-Greece

Hellenic Society for the Science and Technology of Condensed Matter

Nanomagnetism &

Biomedical applicability

M. Angelakeris, Associate Professor

Magnetic Nanostructure Characterization Group:

Technology & Applications

Department of Physics, Aristotle University of Thessaloniki,

54124 Thessaloniki, Greece

http://magnacharta.physics.auth.gr

email: [email protected]




Magnetism around us

Though some are plainly

visible, others are often

tucked inside the inner

workings of appliances

and other household,

medical and commercial

items, doing their job

silently and unseen.

▪ You come into contact with magnets many times in the

course of your daily life.

▪ They play an important role in a wide range of devices

including simple toys, computers, credit cards, MRI

machines and business equipment.

▪ Magnets range in size from barely-visible specks to

industrial monsters weighing tons.




The origin of Magnetism

Since electric current is the guided motion of electrons, electrons orbiting around a nucleus or spinning

around themselves are actually electric currents producing magnetic fields.

Each electron holds an orbital magnetic moment (rotation)

and a spin magnetic moment (spinning). Each electron is thus a tiny magnet.

Adding these microscopic magnetic moments for an atom, molecule,

crystal, body results to a macroscopic magnetization value.

In a typical electromagnet, the magnetic field is originated due to the electric current flowing in a

conductor.

What happens in a typical bar magnet?




Magnetism & Periodic Table

Antiferromagnetism Diamagnetism Ferromagnetism Paramagnetism

Elements of the periodic table are

split in 4 major categories with

respct to the value of their

magnetic susceptibility

Most materials of the

periodic tables are

diamagnetic and

paramagnetic materials at

room temperature.

In most of materials, the

total magnetic moment, is

zero due the organization of

electrons in couples.




Types of Magnetism𝜒 =

Μ

Ηχ=0

Diamagnetism: χ<0

Paramagnetism: χ>0

Ferromagnetism: χ>>0

Superconductivity

Ferrimagnetism

Antiferromagnetism

Magnetic

Order

Magnetic

Disorder




2D: magnetic arrays

3D: magnetic nanoparticles1D: magnetic multilayers

Nanomagnetic Materials

0 20 40 60 80 100

Co

Fe

Ni

Mn-ferrite

Co-ferrite

Ni-ferrite

Magnetite

Maghemite

CoPt

FePt

FeCo

10

20

30

4.3

10

20

25

35

3

4

16

Nanoparticle Diameter (nm)

3 kJ/m3, 110 A m2/kg

6.2 kJ/m3, 47 A m2/kg

Alloys

Ferrites

Elements

9 kJ/m3, 89 A m2/kg

4.7 kJ/m3, 85 A m2/kg

4000 kJ/m3, 46 A m2/kg

7000 kJ/m3, 75 A m2/kg

1.5 kJ/m3, 201 A m2/kg

200 kJ/m3, 85 A m2/kg

5 kJ/m3, 59 A m2/kg

412 kJ/m3, 163 A m2/kg

48 kJ/m3, 222 A m2/kg

SPM ⇒ SD SD ⇒MD




Ferrofluids

A ferrofluid (a composite word from

ferromagnetism and fluid) is a fluid magnetized

strongly in the presence of magnetic field.

Ferrous materials are colloidal fluids made of magnetic

micro- or nanoparticles suspended in a fluid carrier

(usually an organic solvent or water).




https://www.youtube.com/watch?v=uva1fixU_zg

https://www.youtube.com/watch?v=6Kzrwq2WJkY

Nanoparticle Synthesis

Magnetic nanoparticles

Magnetic nanoparticle suspensions

https://www.youtube.com/watch?v=uva1fixU_zg

https://www.youtube.com/watch?v=6Kzrwq2WJkY

10

1. Alternative: with the possibility to obtain stable

colloids using MNPs, they can be administered

through a number of drug delivery routes.

2. Selective: MNPs can be targeted through

specific binding agents making the treatment

much more selective and effective.

3. Cancer-specific: cancer cells absorb MNPs

thereby increasing the effectiveness of

treatment.

4. Brain tumors: MNPs can also effectively cross

blood-brain barrier (BBB) and hence can be used

for treating brain tumors.

5. Homogenous: compared to macroscopic

implants, MNPs provide much more efficient

and homogeneous treatment.

M . A n g e l a k e r i s : N a n o m a g n e t i s m a n d B i o m e d i c a l A p p l i c a b i l i t y 1 1 / 2 3P h y s i c sA U T h



Biomedical Applicability

Magnetic Hyperthermia

Cell Fate Control Drug Delivery

Bioseparation

BioSensing

MRI

Cell Capture

Cellular Proteomics

Cell Tracing

Types of Treatments




Nanotheranostics

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. The prefix Nano means that nanomaterials deliver the treatments.

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.




Issues to considerNanotheranostics

Adjusting the

conditions

From lab to clinical trials

Short & Long term

side effects

Choosing the proper

agent Optimizing the treatment

• biocompatibilty• toxicity• In-vivo

efficiency

the side-effects• Short-term• Long-term• extraction

Optimizing the carrier

• Material Choice• Size• Shape• Magnetic profile• Concentration• Colloidal Stability

the conditions• Frequency• Field intensity

Clinical Application

Colloidal Particles




NanorobotsNanotheranostics

• Scientists and researchers are discovering new ways that nanotechnology

can be used in the near future. It will be used for drug delivery, treatment

and detection of cancer and other diseases, imaging, and much more.

• One of the more interesting uses of nanotechnology in medicine is the

"nanorobot." The nanorobot is a microscopic robot that can be used

for cancer treatment, drug delivery, or even heart bypass surgery.

• As it enters the bloodstream through a tiny incision and travels through

the many veins and arteries it has the capability of finding specific cancer

cells and treating them.

• This could effectively eliminate the side effects of radiation and

chemotherapy as they would not be needed. Nanorobots could also cut

down on surgery time, recovery time, and the various-side effects related

to procedures such as heart bypass surgery.




Controlled Drug-releaseNanotheranostics

Cargo can be released in response to

Magnetically triggered drug release system

No cell death is observed prior toapplying a magnetic field.

16% of the cells were killed upon theapplication of an oscillatingmagnetic field without doxorubicinloaded in the pores

When MNPs are loaded with doxo-rubicin and exposed to anoscillating magnetic field, 37% of thecells are killed, with apoptoticbodies indicated by arrows

MDA-MB-231 breast cancer cells

external stimuli:light or a magnetic field

internal stimuli:natural biochemistry

inside cells using redox, enzymes, or a pH change in the cellular

compartments

MNPs which generateheat upon exposure toan oscillatingmagnetic field,causing the CB rings toslip off the stalks, thusreleasing a cargo ofeither rhodamine B ordoxorubicin.




Nanotheranostics

Controlled Drug-release




Activation of cell signals

T. R. Pisanic II, Biomaterials 28 2572-2581 (2007)

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.

Under an external magnetic field, magnetic nanoparticles

can move around on cell membrane surfaces and exert

translational forces. Simultaneously, by attaching proper

ligands on MNPs binding of MNPs to special cell-surface

receptors may be achieved and heat-triggered mechanical

stimulations can activate cellular signaling pathways.

a. Clusterisation

b. Translational Force

c. Heat generation

Advantages

a. Spatial

b. Temporal

c. Remote

Control of Cellular ActivitiesMagnetic stimulation in human endothelial cells

Cellular morphology tubular shape = prestage of angiogenesis

Nanotheranostics




Magnetic HyperthermiaHyperthermia 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.




Magnetic Hyperthermia

Magnetic implants

+ 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:

Καταπολεμώντας τον καρκίνο με νανοσωματίδιαMagForce: NanoCancer Therapy Fighting Cancer with magnetic

NanoparticlesΗ κεντρική ιδέα της θεραπείας καρκίνου MagForce είναι το

νανοσωματίδιοπου αποτελείται από ένα πυρήνα οξειδίου του σιδήρου και

μια πατενταρισμένη επικάλυψη πουδιασφαλίζει τη χημική σταθερότητα των σωματιδίων και τη

διασποράτους στους προβληματικούς ιστούς (όγκους).Η επικάλυψη αυτή διευκολύνει την προσρόφηση των

νανοσωματιδίων επιλεκτικά από τα καρκινικά κύτταρα,ενώ το μικρό τους μέγεθος είναι καθοριστικής σημασίας για το

θεραπευτικό πρωτόκολλο.Η διάμετρος τους είναι ~ 20 nm και είναι 500 φορές μικρότερη

απόερυθρό αιμοσφαίριο.1 ml από το διάλυμα των σωματιδίων

περιέχειπερίπου 17 τρισεκατομμύρια νανοσωματίδια, καθιστώντας

λειτουργική τη συγκεκριμένη θεραπεία.Στο πρώτο στάδιο της θεραπείας τα νανοσωματίδια εγχέονται

απευθείαςστον όγκο, που στην προκειμένη περίπτωση είναι ένα

γλοιοβλάστωμαένας κακοήθης εγκεφαλικός όγκος, που χαρακτηρίζεται από

επιθετική ανάπτυξη κυττάρων.Σε μικροσκοπικό επίπεδο, διακρίνονται τα υγιή κύτταρα

αριστερά και τα καρκινικά στα δεξιάΜετά την έγχυση τους τα νανοσωματίδια εξαπλώνονται στα

ενδιάμεσα κενά μεταξύ των καρκινικών κυττάρων.Ο ασθενής εισέρχεται σε μια συσκευή παραγωγής μαγνητικών

πεδίων,τα οποία χαρακτηρίζονται εναλλασσόμενα λόγω συχνότητας

(kHz), χωρίς επιπλέον τοξικολογική επιβάρυνση του ασθενούς

Η επίδραση του πεδίου που εναλλάσσει τους πόλους του 100,000 φορές το δευτερόλεπτο πάνω στα μαγνητικά νανοσωματίδιαοδηγεί στην εμφάνισηθερμότητας (μετατροπή μαγνητικής ενέργειας σε θερμική)

δημιουργώντας ένα θερμό περιβάλλονπου καταρχήν ευνοεί την προσρόφηση των νανοσωματιδίων

από τα καρκινικά κύτταρακαι καθώς η θεραπεία επαναλαμβάνεταιτο θερμικό αποτέλεσμα ενισχύεται εμφανώς

ενώ τα νανοσωματίδια αρχίζουν να ταλαντώνονται (ακολουθώντας το εξωτερικό πεδίο οδηγώντας τα καρκινικά κύτταρα σε μηχανισμούς καταστροφήςδιαφορετικής έντασης που τελικά οδηγούν στην πλήρη

αναστολή της ανάπτυξης του όγκου.Η ανάπτυξη του όγκου αναστέλλεται και τα κατεστραμμένα

κύτταρα και τα νανοσωματίδια αποβάλλονταιαπό το σώμα του ασθενούς με φυσικές διαδικασίες. Η μη

επεμβατική αυτή θεραπείαεπαναλαμβάνεται έξι φορές,παρόλο που τα νανοσωματίδια εισέρχονται στον ασθενή μια

φορά στην αρχή της 1ης αγωγής, καθιστώντας τηελάχιστα επιβαρυντική για τον ασθενή.




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).

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.

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

Nanotheranostics Contrast Agents in MRI




Dose-dependent proliferation assay on 3T3 cells bymonitoring the 24-hour cell growth. Normal proliferationrates were obtained at all concentrations tested.

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 magneticsignal from targeted liver at the same time points as imaged by MRI. Maximumconcentrations (~ 90% of the injected dose) were observed 24 hours afterinjection.

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

Fe/MgO nanoparticles

Nanotheranostics Contrast Agentsin MRI




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, M. Spasova, U. Wiedwald, Germany

▪ Ll. Balcels, C. Boubeta, M. P. Morales, D. Serantes, Spain

▪ K. Chliclia, K. Spriridopoulou, 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 Nanostructure Characterization Group:

Technology & Applications

Department of Physics, Aristotle University of Thessaloniki,

54124 Thessaloniki, Greece

http://magnacharta.physics.auth.gr

email: [email protected]

nanomagnetism & biomedical applicability

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