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Yunsuk Jo
Magnetic Nanoparticles for Biomedical Applications
Mamoun MuhammedRoyal Institute of Technology, (KTH)
Kista –Campus, Stockholm, [email protected]
Advanced Magnetic MaterialsPori, October 9-11, 2007
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Nano Medicine
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Biomedical Applications of Magnetic Nanoparticles
Hyperthermia
RF-Genarator410kHz3.5kW 2 loop
coil sample
Thermocouple
Ice water 0oCreference
Dataacquisition
Digital Voltmeter Tissue Engineering
Targeted Drug deliveryMR imaging
Diagnostics
Cell Separation
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Biomedical Applications of SPION
In-vivo Applications In-vitro Applications
250mlN S1ml
100ul
Pre-enrichment Immunocapture SeparationWashing &
Concentration Detection
Plating
ELISA
DNA/RNA
MP
N
S
N
S
Assay A :
biospecific surface analyte
1st reaction
magnetic conjugate
2nd reaction
Assay B :isolation of complexes by High GradientMagnetic Separation
Assay C :
magnet
Immunomagnetic assays (IMA)
Cell separation
Tissue Engineering MR imaging
Hyperthermia
RF-Genarator410kHz3.5kW 2 loop
coil sample
Thermocouple
Ice water 0oCreference
Dataacquisition
Digital Voltmeter
Drug delivery and release
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Antibody
++ Alexa Fluor
As a Nano-carriers
1. Design target specific tracers by using Fe3O4 as exogenous contrast media
2. Develop methods to monitor extracellular macromolecules both at a single cell level (genes and proteins) and at a network level (intercellular communication)
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Outline
• Magnetic nanoparticles– Superparamagnetic nanoparticles for MRI
– Magnetic relaxation of Thermally blocked nanoparticles
• Controlled Drug Release systems– Multifunctional PLA and PEG Nanoparticles
– Temperature sensitive polymeric nanospheres
• Summary
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Superparamagnetic and Thermally blockednanoparticles with strong magnetic response
Design of tailored Magnetic Nanoparticles
• Magnetite (Fe3O4)• Maghemite (γFe2O3)• Ferrites (CoFe2O4, ZnFe2O4, MnFe2O4, …) • Iron Platinum (FePt) & CoPt
Bio-compatibility and surface functionalisation
• Inorganic: Gold, Silica, hydroxyappatite, ...• Organic: Dextran, PVA, PEG, mPEG, …
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Synthesis Techniques
Magnetite by co-precipitation (90o)
Magnetite by sol-gel
Maghemite by oxidation (RT)
Cobalt Ferrite by co-precipitation (90o)
( ) 43C90,NO
22 OFeOHFeOH2Fe 3 ⎯⎯⎯ →⎯→+ °−+ −
[ ] 3243 OFe3OOFe2 γ→+
OH4OFeOH8Fe2Fe 24332 +→++ −++
−
−−++
++→
→+++
2242
322
NOOH3OCoFe
NOOH6Fe2Co
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A)
B)
2 3 4 5 6 7 8 90
10
20
30
40
50
60
<D> = 5.7 nm
Freq
uenc
y (%
)
Diameter (nm)
6 8 10 12 14 16 180
5
10
15
20
25
<D> = 12nm
Freq
uenc
y (%
)
Diameter (nm)
TEM images (left) and the corresponding particle size histograms (right) of magnetite nanoparticles prepared by controlled coprecipitation. (A) without heat treatment and (B) after heat treatment (80ºC for 1hrs)
Magnetite
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Magnetite by sol-gelLarge particle size
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Superparamagnetic iron oxide nanoparticles
• Average particle size=12 nm• XAS shows nonstochiometric phase Fe3O4-δ, the curve shifts to Fe2+.
After one year shelf storage
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Silica Coated Magnetic Nanoparticles
Control of thickness, porosity of coating layer
Silica layer
Magnetic core
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Magnetic characterisation
VSM measurement for SiO2 coated Fe3O4
by co-precipitation
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Magnetic characterisation
VSM measurement for SiO2 coated Fe3O4
by sol-gel
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Development of Superparamagnetic Nanoparticles
Fe48Pt52
*Monodispersed Fe-Pt nanoparticles for biomedical applications. D.K. Kim, et al. 2004, Nanotechnology
FePt and CoPtAdvatages
Narrow particle size distribution -60000 -40000 -20000 0 20000 40000 60000
-8
-6
-4
-2
0
2
4
6
8
x = 0.70 x = 0.52 x = 0.48
Mas
s M
agne
tizat
ion
(em
u/g)
Applied field (Oe)
Superparamagentic NP
Low toxicity- Fe48Pt52nanoparticles in brain endothelial cells*
Exosomes (biological vesicles exerted by dendritic cells) used a coating layer for the reduction of toxicity, recognition tumor cells and also as a cage for delivering drug to the inflammation site.
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Magnetic Nanoparticles• Oxide : magnetite, ferrite • Metal : Fe, Co, PtFe, CoPt
COATING• Gold• Silica• Hydroxyapatite• Dextran• Starch• Albumin• Sodium Oleate• Folic acid• L-aspartic acid• PVA • PEG• mPEG• PLLA (PDLLA)• PCL• PGA
Surface Functionalization of Magnetic Nanoparticles
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2 3 4 5 6 7 8 9 10 11-0.05
-0.04
-0.03
-0.02
-0.01
0.00
0.01
0.02
0.03
0.04
0.05
0.06
ESA
(mPa
*M/V
)
pH
Au@SPION SPION
ESA measurement of SPION and Au@SPION prepared by μE system
100 200 300 400 500 600
-0.5
0.0
0.5
1.0
1.5
2.0
2.5
(b)
(a)
Heat
(mW
/s)
Temp (oC)
DSC analysis of bare and coated nanoparticles. (a) Magnetite, and (b) Au coated SPION.
Effect of surface modificationAu Coating
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Nano Medicine
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Immunoassay formats for selective Multi-component detection
direct sandwich competition
γ-, , )
, )α ß ß
nanoparticles
antibodiesantigenes = analytes
Rutheniumchemiluminescentlabel
Magneto Diagnostics
Examples of assays:
Cytokines (IL-2, IL-4, IL-1ra, IL-1ß, IL-6, IL-10, γ-interferon)Hormones (FSH, LH, PTH, prolactin, TSH, insulin, testosterone, progesterone, estradiol)Peptides and Proteins (calcitonin, troponin, ICAM, IgG, IgE, Aß1-40, Aß1-42, APP)Growth Factors (NGF, TNF-α, TNF-ß, TGFß1, TGF-α)Signal transduction cAMPDrugsEnzymatic activity assays
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Néel relaxation
Brownian relaxation
Externalapplied field
Externalapplied field
kTKV
eN 0ττ =
τN = Nèel rel. timeτ0 = characteristic rel. timek = Boltzmann constantT = temperatureK = magnetic anisotropyV = single domain volume
kTVH
Bητ 3
=τB = Brownian rel. timeVH = Hydrodynamic particle
volumeη = viscosity
Relaxation of magnetic nanoparticles
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Brownian relaxation process can be detected in the frequency domain
M = magnetisationH = alternating external
magnetic fieldχ = complex magnetic
susceptibility
H)i(HM ''' χχχ −==
Bio-diagnostics based on Magnetic Relaxation
IMEGO AB
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Detect specific biomolecules by measuring changes in Brownian relaxation of thermally blocked magnetic nanoparticles.
Biosensor principleMagnetic relaxation
Kindly provided by IMEGO Institute (Göteborg - Sweden)IMEGO AB
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Detection of PSA by using magnetic nanoparticles
Kindly provided by IMEGO Institute (Göteborg - Sweden)
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Brownian relaxation frequency decreaseswhen PSA binds to the particles
1000100
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Nano Medicine
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• SPION: – mono-dispersed, Very narrow particle size distribution– highly crystalline high magnetization
• Synthesis in organic media and phase transfer to water phase
• High r2/r1 ratio good T2 contrast agent
Magnetic Nanoparticles for MRI
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Dose response of Fe3O4 nanoparticles in MRI
Kim, Do-Kyung, Thesis, KTH, 2001
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A)
B)
2 3 4 5 6 7 8 90
10
20
30
40
50
60
<D> = 5.7 nm
Freq
uenc
y (%
)
Diameter (nm)
6 8 10 12 14 16 180
5
10
15
20
25
<D> = 12nm
Freq
uenc
y (%
)
Diameter (nm)
TEM images (left) and the corresponding particle size histograms (right) of magnetite nanoparticles prepared by controlled coprecipitation. (A) without heat treatment and (B) after heat treatment (80ºC for 1hrs)
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Preparation of SuperparamagneticIron Oxide Nanoparticles (SPION)
Fe2+ + 2 Fe3+ + 8 OH-
Co-precipitation
Fe3O4 + 4 H2O
Pyrolysis of Fe salt of fatty acids
Fe oleate complex
Fe3O4 and/or γ-Fe2O3300 OC
Widely used to prepare currentcommercial T2 contrast agents
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Pros & Cons of Two Major Methods
Pros Cons
Co-precipitation 1. Neither organic solvents nor capping agents are used, water-based synthesis, “clean” for biomedical applications;
2. Low temperature (< 100 oC)
1. Broad size distribution;
2. Aggregation;
3. Formation of antiferromagnetic phase,
i.e. γ-FeOOH
Pyrolysis 1. Narrow size distribution;
2. Identical morphology;
3. Highly crystalline
Organic solvents (dioctyl ether) and capping agents (oleic acid) are used,
Not suitable for most biomedical applications
Phase transfer from organic to aqueous solution is required
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Hydrophobic-Hydrophilic Phase Transfer
Hydrophobic Hydrophilic
Organic coating molecules
Amphiphilic macromolecules with PEG section
Phase transfer
Water
Hexane
Water
Hexane
SPION
SPION: Suiperparamagnetic iron oxide nanoparticlesPEG: Poly(ethylene glycol)
Jian Qin et al, Advanced Material
(in press)
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Mechanism of phase transfer through Surface Coating
Hydrophobic poly(propylene oxide)
Hydrophilic poly(ethylene oxide)
ABA type triblock copolymer: Pluronic® F127 (PF127)
Amphiphilic coating layer
PF127/Oleic acid (POA)
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Superparamagnetism Retained
Magnetization curve of (a) as-synthesized SPION and (b) POA@SPION
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Cytotoxicity Tests
Viability of HeLa and MCF-12A cells exposed to POA@SPION at various iron concentrations.
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Compare with Conventional Iron OxideNanoparticle Based Contrast Agents
Particle name Surface polymer r2/r1 ratio
(0.47 T, 310 K)
Mean hydrodynamic
diameter (nm)
POA@SPION
AMI-25 (Feridex; Advanced Magnetics, Cambridge, Mass)
AMI-227 (Combidex; Advanced Magnetics, Cambridge, Mass)
MION-37 (R. Weissleder, Massachusetts General Hospital, Boston, Mass)
MION-37 (R. Weissleder, Massachusetts General Hospital, Boston, Mass)
NC100150 (Clariscan, Nycomed, Amersham, Oslo, Norway)
SH U 555 A (Schering AG, Berlin, Germany)
USPIO S (Schering AG, Berlin, Germany)
11641.5Pluronic F127 + Oleic acid
Dextran
Dextran
Dextran T10
Dextran T10
Oxidized Starch
72
Carboxydextran
4.0
2.2
2.2
2.2
1.6
7.1
19
16-28
18-24
11.9
Carboxydextran 2.3
65
21
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MRI Studies
Dextrane
MagneticCore
Blodkärl
fMRI
MagneticTargeting
Nanoparticles
Neuron
B. B. BjelkeBjelke
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Use of SPION in Brain MRI Study Use of SPION in Brain MRI Study
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T2 values as a function of unit pixel along the x-axis and y-axis. As indicated, a concentration gradient is observed with declining values towards the periphery of the injection.
100 120 140 160 180 2002x106
3x106
4x106
5x106
6x106
7x106
8x106
9x106
1x107
Inte
nsity
(T2)
Distance(pu)30 40 50 60 70 80
3x104
4x104
5x104
6x104
7x104
8x104
9x104
1x105
Inte
nsity
(T2)
D istance(pu)
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24h 0 ug Fe 24h 10 ug Fe
48h 10 ug Fe
Labelling stem cells from neonatal mouse cerebellum(C17-2 cell lines) with Au-SPION.
STEM CELLS
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1 month after transplantation
Neuronal stem cells labelled with Au-SPIONand transplanted into the rat spinal cord
2668 labelled cells, 4µl (4 x 667 cells/µl)
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Nano Medicine
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Design of MultifunctionalNanoparticles for DDS
• Magnetic: Imaging – markers – thermal• Carrier for a certain functional compound, e.g. drug, genes,
DNA, etc• Formation of stable suspension - physiologically
compatible• Controlled targeting of location, an organ or tissue, within
the living body• Keeping the particles localized in a given location for
desired period of time• Senstive to external stimulii, Temp, pH, bio-molecules, etc. • Controlled release of drugs through the pores of the shell
according to the pre-defined conditions • Bio-degradable and bio-resorable
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Fe2+ +Fe3+ + OH-
Etching
1 2
3
45
Fabrication of inorganic NP with loading capacity
SiO2
Au
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Core-shell Processing
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Core-shell ProcessingTemplated Gold-Magetite Nanoparticle
Filling sequence into gold hollow shell
Etched Filled Refilled Final coated
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Multifunctional NP for smart drug delivery system
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Biocompatible polymers
* O *
O
Poly ¥å-caprolactone
*O
*
O
Poly lactide
*O
*
O
Poly glycolide
*NH
*
O
CH2
CH2
CH2
CH2
NH2
Poly L-lysine
* CH2 *
N
O
O
Poly(ethyl-2-cyanoacrylate)
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Synthesis of PLA-mPEG amphiphilic diblock copolymer
hydrophilic hydrophobic
‘amphiphilic’ diblock copolymer
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Procedures for preparation of drug-loaded nanospheres
Drug and Fe3O4
loaded in the cavity
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TEM images of BSA-loaded nanospheresBSA-loaded PLA-mPEG nanospheres
BSA and Fe3O4-loaded PLA-mPEG nanospheres
Drug
Drug Fe3O4
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‘Smart’ polymeric nanomaterials
Poly(N-isoprorylacrylamide)
T<LCST T>LCST
Drug Drug
LCST : Lower critical solution temperature
Under the condition that temperature exceeds the LCST, amphiphlic micelles are collapsed so as to start to release the entrapped drug.
Thermosensitive polymer
Jo, Y. S., Muhammed, et al., Macromolecular Rapid Communications 2003, 24, 957.
Qin et al (2006)
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Schematic View of the “Shell-in-Shell” Structure
PNIPAAm: hydrophilic, stable PNIPAAm: hydrophobic, unstable
LCST: Lower critical solubility temperature
Below LCST
Drug release
Above LCST
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DSC curves
-2
-1.5
-1
-0.5
0
20 70 120 170 220 270 320
Temperature [˚C]
Hea
t flo
w [W
/g]
LL-SH DL-SH LL-FL
Endo
DL-SHTg: 43 C̊
LL-SHTc: 99 C̊
LL-SHTm: 162 C̊
DL-SHTd: 257 C̊
LL-SHTd: 293 C̊
LL-FLTc: 101 C̊
LL-FLTm: 171 C̊
LL-FLTd: 290 C̊
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TEM images
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Toxicity AssayAu@PLLA-PEG@PNIPAAm-PDLAand PLLA-PEG@PNIPAAm-PDLA
(a) (c)(b)
1000 μg/mL uncoated1000 μg/mL Au control
(a) (c)(b)
1000 μg/mL uncoated1000 μg/mL Au control
TCCV assay
MTS: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium
TCCV: Two-color cell fluorenscence viability
Green spots = living cellsRed spots = dead cells
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Mathematical modelingof controlled release rate
• Diffusion model • Dissolution model
⎟⎟⎠
⎞⎜⎜⎝
⎛∂∂
+∂∂
=∂∂
rc
rrcD
tc 2
2
2
⎟⎟⎠
⎞⎜⎜⎝
⎛∂∂
+∂∂
=∂∂
rc
rrcD
tc 2
2
2
( )∑∞
−
−
∞ +++
−=1
221
1 2
2
)39(161
n
DtRq
n
n
eqc
cαα
αα
)( 1cKckdtdcr pd −=−=
⎥⎦⎤
⎢⎣⎡ +
−−+
= )1exp(1)1(
01 kt
Kcc
p αα
α
Diffusion
Diffusion
Dissolution
Time
Jo. Y. S, Muhammed, M. et al, Nanotechnology 2004, 15 (9),1186-1194.
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Self-assembly of gold nanoparticleson the surface of PLA-mPEG nanospheresSilanization
Gold nanoparticle self-assembly
Y. S. Jo, M. Muhammed, et al., J. Materials Science: Materials in Medicine 2005,
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TEM images of ‘shell-in-shell’ structure nanoparticles
a) PLLA-PEG micelleb) ‘shell-in-shell’ structures covered with Au nanoparticles in partc) - d) ‘shell-in-shell’ structures fully covered with Au nanoparticles
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Releasing profile – DL1
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 5 10 15 20
Time [hrs]
c1∞
Vr/
c0
Diffusion modelDissolution modelDL1
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Releasing profile – LL2
0
0.1
0.2
0.3
0.4
0.5
0.6
0 5 10 15 20
Time [hrs]
c1∞
Vr/
c0
Diffusion modelDissolution modelLL2
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Application for controlled-release of estrogen
OH
HO
17β -estradiol
Hormone replacement therapy (HRP)
Estrogen or estrogen/progestin medication
Relieving menopausal symptoms
Reducing risk of osteoporosis, cardiovascular diseases, Alzheimer’s diseases, colon cancer, etc.
Target to evaluate estrogen effect
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in vivo test: estrogen release by PLA-PEO DDS
Group D
PLA-PEO DDS (loading 17¥â-estradiol) injected Dosage;(39.6 ¥ìg / 39.6 ¥ìg / 550 ¥ìL = 17¥â-estradiol / PLA-PEO DDS / PBS buffer solution)
D-IID-I
Group N
550 ¥ìL of PBS buffer solution injected
N-IIN-I
Group P
P-I; 550 ¥ìL of positive control solution (17¥â-estradiol dissolved in olive oil) injectedP-II; 17¥â-estradiol tablet implanted
P-IIP-I
Aromatase P450 (P450arom) Knocked-Out (ArKO) mice used in this work
Androgen precursor steroids
Estrogens
Aromatase P450
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Hearing ResearchHearing ResearchNanNanO O earear
Prof I. PykkProf I. Pykköö, Tampere Univ, Tampere Univ
B Bjelke
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Summary
• Magnetic relaxation using NP for multi-compound detection
• Magnetic nanoparticles useful for functional MRI studies• Construction of ‘smart’ materials responsive to external
stimuli (from surroundings) such as temperature, pressure, pH, etc– Use of Poly(N-isopropylacrylamide) (PNIPAAm) as Thermosensitive
polymeric materials. Tunable lower critical solution temperature(LCST)
• Applications– Can be cosntructed to sense changes in body temperture– Can be applied for external heating– Can be used in Nanosphere, Hydrogel, …
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Acknowledgement
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