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Instituto de Ciencia de Materiales de Madrid, ICMM/CSICDepartment of Energy, Environment and Health
Magnetism in Life Sciences
Helena Gavilán Rubio
M
H
Response to a magnetic field
M
H
Thermal
energyAlter NMR signal
Summer School "Magnetism: From Fundamentals to Spin based
Nanotechnology “, September 2017
Magnetism in Life Sciences
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.
Nanosystems in medicine
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
Nanosystems in medicine
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
Agentes de contraste para hígado y bazo
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
Agentes de contraste para hígado y bazo
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
M
H
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
p0
KAV
Tk
VK
B
aexp0
Relaxation time
Tk
VK
B
aexp10
Jump frequency
Small particle size
M
H
DE= KaV kBT
Basic principles in magnetism
Rotation of the moment within the NP
Mechanical rotation of the NP
Movement of domain walls in multidomain
Basic principles in magnetism
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
Basic principles in magnetism
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
Instituto de Ciencia de Materiales de Madrid
Size
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
Requirements for biomedical applications
Hydrodynamic size
Core + Molecules around
Requirements for biomedical applications
Instituto de Ciencia de Materiales de Madrid
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
Requirements for biomedical applications
Instituto de Ciencia de Materiales de Madrid
• 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
up.
Magnetic properties
M
H
Requirements for biomedical applications
Biomedical applications
Instituto de Ciencia de Materiales de Madrid
• 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
Instituto de Ciencia de Materiales de Madrid
Separation/selection
Biomedical applications
Instituto de Ciencia de Materiales de Madrid
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
M
time
"resonance" signal as the proton goes back
into alignment
NMR Imaging
Instituto de Ciencia de Materiales de MadridMRI made easy
T2T1
NMR imaging
NMR Imaging
Slow Fast Slow
T1
T2
Instituto de Ciencia de Materiales de Madrid
0 50 100 150 200 2500
100
200
300
400
500
Bibliog
4 nm
6 nm
9 nm
14 nm
r 2 (m
M F
e.
s)-1
Hydrodynamic size (nm)
EndoremSinerem
Resovit
Commercial
products = 5-10 nm
US
PIO
SP
IO
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
NMR Imaging
T1 Contrast Image agents
Multifunctional contrast agents
NMR Imaging
Biomedical applications
Instituto de Ciencia de Materiales de Madrid
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
Drug
Skin
Deep tissue
Driven
with a
magnet
Release drug by
photolysis, pH..
Reverse
field
Human prelimirary test
Drug delivery
IONP ionically orcovalently binding a
drug
Drug delivery
Drug carrier systems
IONP ionicallyor covalently
binding a drug
Polymer coatednanosystems
loaded with drugsand IONPs
Drug loadedmagneticmicelles
Lipid vesiclesloaded withdrugs and
IONPs
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
Instituto de Ciencia de Materiales de Madrid
IFN-
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
CNB
Cytokine
R. Mejías, Journal of Controlled Release 130,168, 2008
Drug delivery
Instituto de Ciencia de Materiales de Madrid
1 cm
Tumor size
Also for induced tumours
with 3-methylcholanthrene (MCA)
Drug delivery
Biomaterials 32, 2938, 2011.
Instituto de Ciencia de Materiales de Madrid
200 nm
Accumulation
in liver and spleen
<5.5 nm
Removable
through kidney
EXTERNAL
MAGNETIC FIELD
TUMOR
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
Instituto de Ciencia de Materiales de Madrid
Challenges
Drug delivery
Biomedical applications
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
M
H
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
Magnetic hyperthermia
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
Instituto de Ciencia de Materiales de Madrid
0 50 100 150 200 250 30010
20
30
40
50
60
T (
ºC
)
t (s)
B
initia
l slo
pe
0 50 100 150 200 2500
1
2
d(T
)/dt
t (s)
(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
Instituto de Ciencia de Materiales de Madrid
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
Magnetic hyperthermia
Frequency (77 kHz).
Physical
rotation for
sizes over
18 nm
Ferrofluid Agar 1.2 mg/ml Agar 3 mg/ml0
500
1000
1500
2000
2500
3000
SA
R (
W/g
Fe)
Core size=22 nm / Hydrodynamic size=50 nm
19 mT
40 mT
435 kHz
VISCOSITY
CONCENTRATION
0 10 20 30 40 500
100
200
300
400
0 10 20 30 40 50 0 10 20 30 40 50
SA
R (
W/g
Fe)
m0H (mT)
d0 = 14 nm 18 nm 22 nm
m0H (mT)
water
agar
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
OL.
5 ’
NO
. 9 ’
71
24
, 20
11
acs
nan
o
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
Instituto de Ciencia de Materiales de Madrid
http://www.msiautomation.com/magnetichyperthermiafornanoparticleheating.html
Future
Combining Magnetic Hyperthermia and drug delivery
Instituto de Ciencia de Materiales de Madrid
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
PAN02
Depending on the coating
Interaction with cells Uptake
Instituto de Ciencia de Materiales de Madrid
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
Mag
net
izac
ión
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
Long term particle transformations
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
Long term particle transformations
Instituto de Ciencia de Materiales de MadridChem Soc Rev. 2015 , DOI: 10.1039/c5cs00541h
Long term particle transformations
How are Magnetic Nanoparticles Prepared?
IMPORTANT PARAMETERS
MAGNETIC CORE
size
Doping
Binding
region
to MNPs
Hydrophilic
armFunctional
group for
bio-
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
Instituto de Ciencia de Materiales de Madrid
Modelo Clásico
LaMer and Dinegar
IIIIII
Growth
Nucleation
Critical supersaturation
Conce
ntr
atio
n
Time
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
TN: Translational Nanomedicine
Wrapping up
Thank you for your
attention!
Helena Gavilán Rubiohelena_gr@icmm.csic.es
Magnetism in Life Sciences
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