Helena Gavilán Rubio - Deutsche Physikalische … · Helena Gavilán Rubio M H Response to a...

Instituto de Ciencia de Materiales de Madrid, ICMM/CSICDepartment of Energy, Environment and Health

Magnetism in Life Sciences

Helena Gavilán Rubio

Response to a magnetic field

Thermal

energyAlter NMR signal

Summer School "Magnetism: From Fundamentals to Spin based

Nanotechnology “, September 2017

OUTLINE

1- Nanoparticles for medicine

2- Basic principles in magnetism

4- Requirements

4- Toxicity

5- Synthesis

3- Biomedical applications: Diagnosis and Therapy

Applications

• Surgery• Therapy• Diagnostics• Biosensors/biodetection• Implantable materials/devices: Tissue engineering• Textiles and wound care products• Drug/gene delivery materials and devices

MaterialsNano-porousNano-crystalsNano-reinforcedNano-structured surfaces

PropertiesTissue ingrowth, transport of substancesPhysical, electrical, optical, mechanicalpropertiesMechanical properties, Biocompatibility

Bandages with silver nanoparticles

Curad® (www.curadusa.com)

antibacterial agent.

Patrick Couvreur et al., Chem. Rev. 112, 5818, 2012

He was the first to develop nanometric capsules able to penetrate cells to deliver medicine

Nanosystems in medicine

(Compound annual growth rate)

Nanoparticles in Biotechnology, Drug Development & Drug Delivery (BIO113B) by Jackson Highsmith, and Nanotechnology in

Medical Applications: The Global Market (HLC069B) by Paul Evers. For more information, visit www.bccresearch.com. and

www.drug-dev.com.

Drug delivery

- Drug release control- Drug solubility problems- DNA carriers- Tissue regeneration

Global Market for Nanoparticles

Areas: CancerNeurodegenerative Cardiovascular

Infection

Nanotechnology and heath care, huge potential and some risks.

Consequences: The oncology market is the third largest pharmaceutical market,

behind the cardiovascular and central nervous system therapy areas.

These treatments affect both tumors and healthy tissue.

Consequences: Multi-billion markets in medical and palliative expenses because

systemic toxicity and undesirables side effects.

Oncology

High mortality without effective treatment

Treatment of cancer with traditional medicine involvessurgery, ionizing radiation, and chemotherapy

Product Nanosystem Application Status Company

Doxil(Barenholz, 2012)

Doxorrubicina encapsulada en liposomas PEGilados

Cáncer de ovarios Aprobado 11/17/1995

FDA50718

Ortho Biotech

(adquirida por JNJ)

Myocet(Waterhouse et al., 2001)

Doxorrubicina encapsulada en liposomas No PEGilados

Cáncer de mama metastásico

Europa y Canadá, en combinación con

ciclofosfamida

Sopherion Therapeutics, LLC EEUU y Cephalon,

Inc. en Europa

DaunoXome(Forssen, 1997)

Daunorrubicina encapsulada en liposomas

Tratamiento de sarcoma de Kaposi avanzado

asociado al VIH

Aprobado en E.E.U.U Galen Ltd.

ThermoDox(Dromi et al., 2007)

Doxorrubicina encapsulada en liposomas (liberación mediada

por calor)

Cáncer de mama y primeras etapas de cáncer

de hígado

Aprobación esperada para el año 2013

Celsion

Abraxane(Guarneri et al., 2012)

Nanopartículas de albúmina-paclitaxel

Diferentes tipos de cáncer Aprobado 1/7/2005

FDA21660

Celgene

Rexin-G(Gordon and Hall, 2010)

MicroRNA-122 encapsulado en liposomas

Sarcoma, osteosarcoma, cáncer de páncreas, y otros tumores sólidos

Aprobado en Filipinas, Fase II y III en E.E.U.U

Epeius BiotechnologiesCorp.

Oncaspar(Avramis and Tiwari, 2006)

Asparaginasa PEGilada Leucemia linfoblástica aguda

Aprobado 24/06/2006

Enzon Pharmaceuticals, Inc.

Resovist(Hamm et al., 1994)

Nanopartículas de óxido de hierro recubiertas de

carboxidextrano

Agentes de contraste para hígado y bazo

Aprobado en Europa en 2001

Bayer Schering PharmaAG

Feridex(Weissleder et al., 1989)

Nanopartículas de óxido de hierro recubiertas de dextrano

Aprobado por la FDA en E.E.U.U en 1996

Berlex Laboratories

Endorem(Weissleder et al., 1989)

Nanopartículas de óxido de hierro recubiertas de dextrano

Aprobado en Europa Guerbet

Nanoformulations approved by different regulatory agencies

Chemical Design of Biocompatible Iron Oxide Nanoparticles for Medical Applications,

Daishun Ling a nd Taeghwan Hyeon , Small 2013, 9, No. 9–10, 1450–1466,

Chem. Soc. Rev., 2012, 41, 4306

Schladt, T. D.; Schneider, K.; Schild,

H.; Tremel, W. Dalton transactions

2011, 40, 6315

Figuerola, A.; Corato, R. Di; Manna,

L.; Pellegrino, T. Pharmacological

Research 2010, 62, 126

Iron Oxide

Magnetic nanoparticles

Acc. Chem. Res. 2015, 48, 1276−1285

Advantages of using magnetic nanoparticles

Target, Detect by MRI and Heat

Size, surface and magnetic properties

Response to a magnetic field Interaction with bio-entities

Before and after injection

SUPERPARAMAGNETIC PARTICLES

Thermal

energyHeating power= m0.p.f.H2.X´´

Basic principles in magnetism

Reversible

behaviour

No particle

aggregation

Superparamagnetism

Relaxation time

aexp10

Jump frequency

Small particle size

DE= KaV kBT

Rotation of the moment within the NP

Mechanical rotation of the NP

Movement of domain walls in multidomain

Dispersion media

MECHANISM OF MAGNETIZATION ROTATION

Comparison of the normalised minor loops for mobile MNPs (fluid), immobilised MNPs (gelatine), and MNPs inside the tumour (tumour) at a magnetic field amplitude of 25 kA/m measured under quasistatic conditions.

Silvio Dutz and Rudolf HergtInt J Hyperthermia, 2013 DOI: 10.3109/02656736.2013.822993

Instituto de Ciencia de Materiales de Madrid

COLLOIDAL

SUSPENSIONS

In vitro

In vivo

REQUIREMENTS

- Size

- Surface

- Properties

APPLICATIONS

- Stable

- Biocompatible

- Reversible

NANOPARTICLES

No toxic!!

Requirements for biomedical applications

Detected by the immune system and eliminated

Small response to a magnetic field

Remain in the body long enough to be circulated

through the blood stream

5-50 nm = Ideal diameter for most forms of therapy

Hydrodynamic size

Core + Molecules around

Surface Modification of the particle´s surface to make it biocompatible

and specific

=> Biocompatible = Hydrophilic coating make

the particle look friendly to the immune system

- Polymer

- Inorganic

=> Specific = Coated with a biological entity to

make the particles function in a specific manner

=> Carrier = to transport and deliver a biological

active agent

• They must constantly and rapidly

“flip” magnetic states.

=> Mr=0

• Saturation magnetisation (Ms) should

be strong enough to be manipulated by

an external magnetic field

• Resonant respond to a time-varying

magnetic field should be enough to heat

Magnetic properties

Biomedical applications

• Goal: Separate/detect/isolate one type of cell or biomolecule from others, often when the target is present in very small quantities

Reduce the time

Detect lower concentrations

Separation/selection

Nobel Prize 2003

Paul C. Lauterbur and Sir Peter Mansfield

"for their discoveries concerning magnetic

resonance imaging"

The most powerful technique for diagnosis

Advantage: not use X-Rays nor any other type of "ionizing“ radiation

Instead: it is a technique that combines a large magnetic field and some radio frequency antennas

Measure the relaxation rate of protons in the atoms of waterwithin the patient from their excited state to the ground state

NMR Imaging

protons of water "line-up"

magnetic fieldhigh-frequency

electro-magnetic pulse

protons out of alignment

image reflects the water protons in the patient and their chemical association with

proteins

"resonance" signal as the proton goes back

into alignment

NMR Imaging

Instituto de Ciencia de Materiales de MadridMRI made easy

NMR imaging

NMR Imaging

Slow Fast Slow

0 50 100 150 200 2500

Bibliog

r 2 (m

Hydrodynamic size (nm)

EndoremSinerem

Resovit

Commercial

products = 5-10 nm

NMR imaging

Basic Res Cardiol 103:122–130 (2008)

Ralph Weissleder

Challenges

R. Weissleder et al. 2001 Angew. Chem., Int. Ed. 40 3204

NMR Imaging

C. Sun et al. / Advanced Drug Delivery Reviews 60 (2008) 1252–1265

tumorTargeted imaging

NMR Imaging

T1 Contrast Image agents

Multifunctional contrast agents

NMR Imaging

DRUG DELIVERY Targeting of a drug immobilised on magnetic

nanoparticles under the action of an external

magnetic field.

• Specific -> Reducing side effects

• High local concentration -> Reducing the dosage

• Problem -> Field strength

Deep tissue

Driven

with a

magnet

Release drug by

photolysis, pH..

Reverse

Human prelimirary test

Drug delivery

IONP ionically orcovalently binding a

Drug delivery

Drug carrier systems

IONP ionicallyor covalently

binding a drug

Polymer coatednanosystems

loaded with drugsand IONPs

Drug loadedmagneticmicelles

Lipid vesiclesloaded withdrugs and

Five-step in targeted cancer drug delivery.

Sun, Q. H.; et al.. Integration of Nanoassembly Functions for an

Effective Delivery Cascade for Cancer Drugs. Adv. Mater. 2014, 26, 7615−7621.

Drug delivery

Cancer inmunotherapy : Activating immune response

to removal primary tumor and prevent metastases.

Cytokine: small protein produced by macrophages

and T lymphocytes

Activity:

- Activate macrophages production

- Induce cancer cell apoptosis

IFN- the most effective cytokine in tumor elimination

Magnetic nanoparticles: Controlled local release of cytokines

Cytokine

R. Mejías, Journal of Controlled Release 130,168, 2008

Drug delivery

Tumor size

Also for induced tumours

with 3-methylcholanthrene (MCA)

Drug delivery

Biomaterials 32, 2938, 2011.

200 nm

Accumulation

in liver and spleen

<5.5 nm

Removable

through kidney

EXTERNAL

MAGNETIC FIELD

Specific Targeting with Magnetic Fields 100-10 nm MNPs

• Large MNPs (> 200 nm) will be easily detected by the immune system and removed from the blood and delivered to the liver and the spleen.

• Very small MNPs (< 5.5 nm) can be excreted through the kidneys.

• Different magnetic biocomposites can be transported to reach the tumor area inside the body thanks to the applied magnetic field.

Main limitation

Drug delivery

Challenges

Drug delivery

Hyperthermia = Greek words: HYPER (rise) and THERME (heat)

= increasing body temperature to achieve a therapeutic effect.

42-43ºC

Conventional

Hyperthermia

Heating method External heating

Internal heating

Heating region Whole body heating

Local/regional heating

Hot water and blood flow

Heating techniques Ultrasound heating

Electromagnetic field heating

- Reduces the viability of cancer cells

- Increases their sensitivity to chemotherapy and

radiation

Disadvantage: the control of spatial extent of heating in tissue is still an unsolved challenging task

Targeting of a tumor with the help of magnetic nanoparticles in the presence of external alternating magnetic field that causes

production of heat through Néel-relaxation loss due to rapid changes in the direction of magnetic moments

http://technologytimes.pk/post.php?id=9852

What is magnetic hyperthermia?

42-43ºCMagnetic nanoparticles

Magnetic field

Catheter

Tissue/Organ

Arterial Feed

Magnet

Alternating

magnetic fieldAdvantages of using magnetic

nanoparticles

• Early cancer stages: localized

• Preservation of healthy tissues

• Control temperature from inside

• Possible frequent repeated treatments

• Increases their sensitivity to

chemotherapy and radiation

42ºC / 30 min Cancer is destroyed

Nearly complete regression of tumors via collective behavior of magnetic nanoparticles

in hyperthermia, C L Dennis et al., Nanotechnology 20 (2009)

Goya et al, Current Nanoscience 2008, 4, 1-16

Magnetic hyperthermia

Administration routes:

Arterial injection in which magnetic fluid is injected through artery supply of

tumor would be desirable.

Different AFM apparatus:

Field requirements: f x H = 6 x 106 Oe.Hz =Safety limit

Minimize eddy currents (smallest coil dimensions) and nerve stimulations.

Temperature control:

Temperature of tumor cells is increased within range of hyperthermia

temperature (41 – 46ºC).

Biological effect ?:

Less energy is lost, Energy transfer more effective, Rapid heating and

cooling. Biological processes in vivo reduce the heating.

CHALLENGES

Instituto de Nanociencias de AragonUnivertisy Hospital of Jena

100 - 900 kHz6- 35 kA/m

250 kHz- 10 kA/m400 kHz- 30 kA/m

119105 sAmfHDisconfort limit x 10

ApparatusNanoparticles RequirementsMagnetic hyperthermia

0 50 100 150 200 250 30010

initia

0 50 100 150 200 2500

(dT/dt)max

for SAR

What we actually

measure…

SAR= Cm f(DT/Dt)Cm = 4.185 Jg-1 K-1

Ø = mgFe/mL

ApparatusNanoparticles RequirementsMagnetic hyperthermia

Specific Absorption Rate = Specific Loss Power = Experimental

SAR= Cm f(DT/Dt) SLP = μ0 ⋅ π ⋅ f ⋅ H 2⋅ χ″(f )

where Cm is the specific

heat capacity of the sample

Specific hysteresis loss= SHL = Theoretical area

Intrinsic Loss Parameter = ILP= SAR/ H2.f

Important parameters

Frequency (77 kHz).

Physical

rotation for

sizes over

Ferrofluid Agar 1.2 mg/ml Agar 3 mg/ml0

Core size=22 nm / Hydrodynamic size=50 nm

435 kHz

VISCOSITY

CONCENTRATION

0 10 20 30 40 500

0 10 20 30 40 50 0 10 20 30 40 50

m0H (mT)

d0 = 14 nm 18 nm 22 nm

m0H (mT)

Effect of

dipolar

interactions

Salas et al., J. Phys. Chem. C 2014, 118, 19985−19994

ApparatusMagnetic hyperthermia

Biological effect

No perceptible change in temperature

MECHANISMS RESPONSABLE FOR CELL DEATH

• Inactivation of protein synthesis• Inhibition of DNA repair processes• Alteration of membrane permeability• ROS production= stress

Specific absorption rates (W/g).V

. 9 ’

Thermal damage

Heat generated is

limited to the immediate

proximity of the

nanoparticle surface.

Nano Lett. 2013, 13, 2399−2406Angewandte Chemie · December 2013 Hyperthermia could be used to locally modify tumor

stroma and thus improve drug penetration

ACS Nano 2013, 10.1021/nn405356r

Non-thermal damage

Mechanical damage

http://www.msiautomation.com/magnetichyperthermiafornanoparticleheating.html

Future

Combining Magnetic Hyperthermia and drug delivery

Combining Magnetic Hyperthermia and Photodynamic Therapy for Tumor Ablation with Photoresponsive Magnetic Liposomes.

Future

ACS Nano. 2015. DOI: 10.1021/nn506949t

Future

Huge potential of local heating or mechanicalstimulation with magnetic iron oxide nanoparticles

activated by remote magnetic field

Brain stimulation Locomotion controlManipulate

expresión of proteinsInsulin

Iron Oxides: From Nature to Applications, Damien Faivre, Richard B. FrankelISBN: 978-3-527-33882-5, June 2015, Pag 455

Facilitating Translational Nanomedicine via Predictive Safety Assessment

DOI: http://dx.doi.org/10.1016/j.ymthe.2017.03.011

Nanotoxicity

Interaction with cell, tissues

Biodistribution and degradation

CITOTOXICIDAD

0,5 mg Fe/mL- 24 horas

HeLa cells-DMSA

MTT TEST

NPs concentration

0 0,05 0,1 0,5mg/ml

Interaction with cells

Depending on the time and the dose

CONTROL

DMSA (-) , APS (+)

HEPARINE

Stained with a-tubulin

Microtubules (green)

DNA (blue)

Depending on the coating

Interaction with cells Cytoskeleton

Fluorescence and optical

microscopy show that

cytoskeleton is not affected

by the presence of the NPs.

Scale bar: 10 µm.

Interaction with cells Cytoskeleton

Depending on the cell type

Intracelular location of the NP

Lysotracker Red DND-99

Barra de escala: 10 mm

Nanoparticles-cells (Pan02) in vitro

Interaction with cells Location in lysosomes

Depending on the coating

Interaction with cells Uptake

Distribution of Iron in Adults

NANCY C. ANDREWS

The New England Journal of Medicine

Volume 341 Number 26, 1986, 1999

100 mg Fe => Endorem

(1-5 mg/Kg)

Biodistribution

Campo aplicado

Superparamagnético

Diamagnético

Paramagnético

Magnetisation curves

Biodistribution in vivo: Magnetic methods

All materials are magnetic

to some extent with their

magnetic response

depending on their atomic

structure and temperature

AC Suscepbility

AC MAGNETIC SUSCEPTIBILITY

Gutiérrez et al, Phys.Chem.Chem.Phys.,2014, 16, 4456.

Biodistribution in vivo: Magnetic methods

Biodistribution

Coating

L.Gutiérrez et al, J. Phys. D: Appl. Phys. 44 (2011)

In vivo

Long term particle transformations

Prussian blue staining

Long term biodistribution,

biotransformation and toxicity of

dimercaptosuccinic acid-coated

magnetic nanoparticles

R. Mejías, L. Gutiérrez, G. Salas,

S. Pérez-Yagüe, T. M. Zotes, Fr. J.

Lázaro, M. P. Morales, D.F. Barber

Journal of Controlled Release 171

(2013) 225–233

L. Lartigue, D. Alloyeau, J. Kolosnjaj-Tabi, Y. Javed,P. Guardia, A. Riedinger, C. Pechoux, T. Pellegrino,

C. Wilhelm and F. Gazeaut, ACS Nano, 2013, 7, 3939–3952.

Degradation in lysosome-like conditions

Instituto de Ciencia de Materiales de MadridChem Soc Rev. 2015 , DOI: 10.1039/c5cs00541h

How are Magnetic Nanoparticles Prepared?

IMPORTANT PARAMETERS

MAGNETIC CORE

Doping

Binding

region

to MNPs

Hydrophilic

armFunctional

group for

conjugation

COATING

Magnetic nanoparticle (MNP)

Different core size Different core

composition

Biocompatible polymers Colloidal stability Strong anchoring > MNPs blood life-time Core protection

Design a Nanoparticle for each application

Modelo Clásico

LaMer and Dinegar

IIIIII

Growth

Nucleation

Critical supersaturation

Synthesis and Characterization of Nanoparticles: Synthesis of Inorganic Nanoparticles,

Gorka Salas, Rocio Costo and María del Puerto Morales

Part I, Vol. 4 Nanobiotechnology, Inorganic Nanoparticles vs Organic Nanoparticles

edited by J.M. de la Fuente and V. Grazu, 2012 Elsevier Ltd, FRONTIERS OF

NANOSCIENCE, Series, Editor: R. E. Palmer, UK.

Nanoparticle synthesis routes

Synthesis and Characterization of Nanoparticles: Synthesis

of Inorganic Nanoparticles,

Gorka Salas, Rocio Costo and María del Puerto Morales

Part I, Vol. 4 Nanobiotechnology, Inorganic Nanoparticles

vs Organic Nanoparticles edited by J.M. de la Fuente and

V. Grazu, 2012 Elsevier Ltd, FRONTIERS OF

NANOSCIENCE, Series, Editor: R. E. Palmer, UK.

Nanoparticle synthesis routes

Design and Application of Magnetic-based Theranostic Nanoparticle Systems, Aniket S. Wadajkar, et al. Recent Pat Biomed Eng. Apr 1, 2013; 6(1): 47–57

Imaging agents

Therapeutic agents

Magnetic nanoparticles

advantages

Magnet assisted

Magnetic nanoparticles could help to improve clinical practice in the treatment of cancer, most probably in synergy with other conventional treatments.

Wrapping up

Modified from Sun, Q. H.; Radosz, M.; Shen, Y. Q. Challenges in Design ofTranslational Nanocarriers. J. Controlled Release 2012, 164, 156−169.

NanocarrierCapability

Process

Scale-up ability

Material excipientability

- Long circulation

-Non-toxic

SafeEffective

Producible

TN: Translational Nanomedicine

Wrapping up

Thank you for your

attention!

Helena Gavilán Rubiohelena_gr@icmm.csic.es

Helena Gavilán Rubio - Deutsche Physikalische … · Helena Gavilán Rubio M H Response to a...

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