O - KOCW

Synthesis, properties and perspectives
of hybrid nanocrystal structures
Pantaleo Davide Cozzoli, Teresa Pellegrino and Liberato Manna*
Chem. Soc. Rev., 2006, 35, 1195–1208
Kim, H.; Achermann, M.; Balet, L.; Hollingsworth, J. A.; Klimov, V. J. J. Am. Chem. Soc. 2005, 127, 544-546.
Kwon, K.-W.; Shim, M. J. Am. Chem. Soc. 2005, 127, 10269-10275.
(a) CdSe nanorods with PbSe tips at both ends; (b) with one PbSe tip
Mokari, T.; Sztrum, C. G.; Salant, A.; Rabani, E.; Banin, U. Nat. Mater. 2005, 4, 855-863.
Mokari, T.; Rothenberg, E.; Popov, I.; Costi, R.; Banin, U. Science 2004, 304, 1787-1790.
CdSe nanorods with two or one Au domain, respectively
Mokari, T.; Sztrum, C. G.; Salant, A.; Rabani, E.; Banin, U. Nat. Mater. 2005, 4, 855-863.
Mokari, T.; Rothenberg, E.; Popov, I.; Costi, R.; Banin, U. Science 2004, 304, 1787-1790.
Copper-Indium Sulfide Nanocrystal Heterostructures
S. H. Choi, et al., J. Am. Chem. Soc 2006, 128, 2520.
Dumbbell shaped Fe3O4-Au nanoparticles
S. Sun, Angew. Chem. Int. Ed., 2008, 47, 173.
• Fe3O4 nanoparticles were grown on the surface of the as-prepared
Au nanoparticles.
• PEG conjugated with dopamine and thiol groups was attached to
the surface of Fe3O4 and Au moieties via the surfactant-exchange
reaction, respectively, and an antibody was conjugated at the
terminal group of PEG on Fe3O4.
• Cancer targeted MRI images were obtained using these antibody
conjugated Fe3O4-Au nanoparticles.
• In addition, the cancer cells could be visualized with a scanning
confocal microscope using the surface plasmon resonance of the
Au nanostructure.
TEM images of the 8–20-nm Au–Fe3O4 particles
before (b) and after (c) surface modification.
S. Sun, Angew. Chem. Int. Ed., 2008, 47, 173.
a) T2-weighted MRI images of i) 20-nm Fe3O4, ii) 3–20-nm
Au–Fe3O4, iii) 8–20-nm Au–Fe3O4 nanoparticles, and iv) A431 cells
labeled with 8–20-nm Au–Fe3O4 nanoparticles.
b) Reflection images of
the A431 cells labeled with 8–20-nm Au–Fe3O4 nanoparticles.
S. Sun, Angew. Chem. Int. Ed., 2008, 47, 173.
a) Reflection image of the labeled cells
b) Detection-limit examination of the 8–20-nm Au–Fe3O4–EGFRA label
ed A431 cells.
c) Reflection image of Fe3O4-labeled A431 cells.
d) Reflection image of Au–Fe3O4 labeling without EGFR antibody.
S. Sun, Angew. Chem. Int. Ed., 2008, 47, 173.
Heterostructured nanoparticles composed
of metals of Au, Ag, Pt, or Ni and oxides of Fe3O4 or MnO
50 nm
50 nm
Thermal
decomposition of
mixtures of
metal-oleate
complexes and
metal-oleylamine
complexes
S. Choi et al., J. Am. Chem. Soc.
2008, 130, 15573.
50 nm
50 nm
Multifunctional Nanomedical Platforms
Multimodal Imaging and Simultaneous Diagnosis & Therapy
J. Kim et al. Chem. Soc. Rev. 2009, 38, 372.
Multifunctional Nanostructured Materials for Multimodal
Imaging, and Simultaneous Imaging and Therapy
• Due to their unique characteristics including
superparamagnetic or fluorescent properties, and small
size comparable to biomolecules, nanostructured
materials have emerged as novel bioimaging, diagnostic,
and therapeutic agents in future medical field.
• combinations of various nanostructured materials with
different modalities can offer synergetic advantages
compared to the use of single modality.
• Multimodal imaging and simultaneous diagnosis &
therapy.
Imaging and therapeutic modalities using nanomaterials
Modality
Imaging
Component
optical imaging
organic dye
dye-doped silica
quantum dots
lanthanide atom
carbon nanotube
MRI
paramagnetic ion (Gd3+, Mn2+)
nanoparticles of paramagnetic ion (Gd2O3, MnO)
superparamagnetic nanoparticle (Fe3O4, MnFe2O4, FeCo)
OCT
gold nanostructure (nanoparticle, nanorod, nanoshell, nanocage)
PET, SPECT
radioisotope (18F, 124I,
CT
Iodine
gadolinium
gold nanoparticle
bismuth sulfide nanoplate
ultrasound
microbubble
perfluorocarbon nanoparticle
chemotherapy
anticancer drug (doxorubicin, camptothesin, paclitaxel, etc.)
photodynamic therapy
photosensitizer
quantum dots
photothermal therapy
gold nanostructure (nanoparticle, nanorod, nanoshell, nanocage)
carbon nanotube
graphitic carbon shell
neutron-capture therapy
boron
gadolinium
Therapy
64Cu, 99mTc, 111In)
Part I: Multimodal imaging probes
• Most popular nanostructured multimodal imaging probes are
combinations of magnetic resonance imaging (MRI) and
optical imaging modalities
• MR imaging can offer high spatial resolution and the capacity
to simultaneously obtain physiological and anatomical
information, whereas optical imaging allows for rapid
screening.
• multimodal imaging probes into (1) superparamagnetic iron
oxide nanoparticle (SPIO) based and (2) paramagnetic
gadolinium (Gd) complex based multifunctional nanoplatforms.
Magnetic Fluorescent Drug Delivery Vehicle
using Uniform Mesoporous Silica Spheres
Embedded with
Monodisperse Magnetic and
Semiconductor Nanocrystals
(Quantum dots)
J. Kim et al., J. Am. Chem. Soc. 2006, 128, 688.
Synthetic procedure of monodisperse magnetite nanocrystals
embedded in mesoporous silica spheres (M-MSS).
• Hydrophobic magnetic and fluorescent nanoparticles were transferred
into the aqueous phase using CTAB as a secondary surfactant.
• Because CTAB also acted as a structure directing agent of the
mesostructures, the subsequent silica sol-gel reaction resulted in the
formation of mesoporous silica spheres embedded with magnetic and
fluorescent nanoparticles.
150 nm Silica spheres with uniform 3 nm pores containing Magnetic nanoparticles
150 nm Silica spheres with uniform 3 nm pores
Containing both Magnetic nanoparticles and Semiconductor nanoprticles
Magnetite
nanoparticles
Quantum
dots
Uniform
3 nm Pores
Green
Emitting
Quantum
Dots
SuperPara
magnetic
Demonstration of Magnetic Separation
Magnetic Separation and
Release of ibuprofen from M-MSS and M-MSS-NH2.
Demonstration of
Magnetic Guiding
Demonstration of
Controlled Release
Fe3O4-CdSe heterodimer nanoparticles
J. Y. Ying, Angew. Chem. Int. Ed., 2007, 46, 2448.
• Growing CdSe on the surface of the as-synthesized
Fe3O4 nanoparticles
• The resulting Fe3O4-CdSe nanoparticles were coated
with silica shells via the silica sol-gel reaction in a
reverse microemulsion system.
• The silica surface was functionalized with the oleylPEG group and the optical imaging of live cells was
demonstrated using these probes.
Self-Assembled Hybrid Nanoparticles
for Cancer-Specific Multimodal Imaging
W. Lin, J. Am. Chem. Soc., 2007, 129, 8962.
• Synthesized dye-doped mesoporous silica nanoparticles with an
average size of 75 nm and modified their surface via postfunctionalization with Gd-Si-DTTA
• The relaxivities per particle of the mesoporous silica nanoparticles
loaded with Gd3+ were even higher than those of non-porous silica
nanoparticles loaded with Gd3+ via the LbL method.
• The enhanced MR relaxivity was attributed to the ready access of
water molecules through the mesopores of the Gd3+-loaded
mesoporous silica particles.
• In vivo MR contrast enhancing efficiency was demonstrated.
TEM images of nanoparticles
Part II: Simultaneous imaging
and therapeutic agent
• Multifunctional nanostructured materials for simultaneous imaging
and therapy
• The nanomaterials investigated in cancer therapy can be
categorized into two classes according to their role.
1) Carriers of therapeutic molecules including anticancer drugs,
photosensitizers, and therapeutic oligonucleotides. The loaded
molecules have the capability to destroy the cancer cells, while
the nanomaterials are used as vehicles to carry the therapeutic
molecules into them.
2) Therapeutic nanomaterials that have intrinsic properties
related to therapy, for example, iron oxide or gold nanoparticles
that have the ability to induce hyperthermia.
Multifunctional Polymer Nanoparticles:
Magnetic Guided Diagnostic and
Therapeutic Nanomedicine
J. Kim et al. Adv. Mater. 2008, 20, 478.
Scheme
Multifunctional Polymer Nanoparticles
for Cancer Imaging and Therapy
CdSe/ZnS
NPs
Fe3O4
NPs
Doxorubicin
F127 in water
O/W emulsion
by sonication
PLGA
evaporation
of organic
solvent
+ + + +
+ + +
PLL-PEG-FOL
PLGA (MNP/DOXO) Nanoparticles
► 7 nm Fe3O4 nanoparticles
in PLGA nanoparticles
► 100 ~ 200 nm sized PLGA
nanoparticles
► 15 nm Fe3O4 nanoparticles
► 100 ~ 200 nm sized PLGA
nanoparticles
Folate Conjugation
+ + + +
+ + +
PLL-PEG-FOL
PEG Groups for
Biocompatibility
Positively Charged
PLL groups
Folate Groups to Target
the Folate Receptors
on Cancer Cells
In Vitro Targeted MRI and Drug Delivery
(1) Folate Targeting
(2) Magnetic Attraction
(High Magnetic Moment)
KB cell : a human epidermal carcinoma cell line
folate receptor-overexpressing cell line
► Imaging of Cancer Cells Using T2 MRI
► Cell Growth Inhibition by Doxorubicin
In Vitro T2 MRI
KB cells were mixed with 1% agarose solution for MRI scan
T2-weighted
image
Control
Naked PLGA(MNP/DOXO)
Darker
PLGA(MNP/DOXO)-PLL-PEG-FOL
PLGA(MNP/DOXO)-PLL-PEG-FOL
+ Magnetic Field
PLGA(MNP/DOXO) nanoparticles can be used as a T2
contrast agent in targeted MRI for the detection of cancer cells
Cellular Uptake (CLSM)
Naked
PLL-PEG
PLL-PEG-FOL
PLL-PEG-FOL
+ Magnetic Field
Confocal
Optical
Merged
MAGNET
Magnetic Guiding Effect
MAGNET
The Magnetic Field Enhanced the Uptake of PLGA(MNP/DOXO) Nanoparticles
Cytotoxicity Assay
0.4 μM DOXO, 4h incubation at 37 oC,
After further incubation for 5 days, CCK-8 assay
120
Trivial toxicity
of (PLGA/MNP)
80
60
40
PL
G
-P A(M
LL N
-P P/D
EG O
-FO XO
L )
PL
-P G A
+ MLL-P (MN
ag EG P/D
ne -F OX
tic OL O
)
Fie
ld
PL
GA
(M
NP
)
Fr
ee
0
DO
XO
20
Co
ntr
ol
Cell Viability (%)
100
Multifunctional Uniform Nanoparticles
Composed of Magnetite Nanocrystal Core
and Mesoporous Silica Shell
for Simultaneous Magnetic Resonance and
Fluorescence Imaging, and Drug Delivery
Inside Cover Article
J. Kim et al., Angew. Chem. Int. Ed. 2008, 47, 8438.
Magnetite nanocrystal/mesoporous silica core/shell nanoparticles
TEM images of core/shell and hollow mesoporous silica NPs
45 nm
60 nm
90 nm
Field dependent magnetization at 300 K.
0.08
0.04
0.02
0.00
-0.02
1000
3
-0.06
-0.08
-10
-8
-6
-4
-2
0
2
Field (kOe)
4
800
6 6008
1.8
1.6
1.4
1.2
1.0
0.8
10 0.6
0.4
0.2
0.0
dV/dlogD
-1
-0.04
Volume Adsorbed (cm g )
-1
Moment (emu g )
0.06
400
2
3
4
5
6
7
8
9
10
Pore Size (nm)
200
Adsorption
Desorption
0
N2 adsorption/desorption isotherms
0.0
(inset: pore size distribution)
0.2
0.4
0.6
Relative Pressure (P/P0)
0.8
1.0
Photoluminescence spectra of Fe3O4@mSiO2
1.2
Intensity (normalized)
Fe3O4@mSiO2(F)
1.0
Fe3O4@mSiO2(R)
0.8
0.6
0.4
0.2
0.0
450
500
550
600
Wavelength (nm)
650
700
In vivo multimodal imaging using Fe3O4@mSiO2 nanoparticles
a. In vivo T2-weighted MR image and b, fluorescent image
c, In vivo T2-weighted MR images
a
Label
unlabel
b
Label
Pre
2h
unlabel
24 h
c
High
Low
In vitro cytotoxicity of
DOX-loaded Fe3O4@mSiO2(R)-PEG against SK-BR-3 cells
Nano-Alchemical (?) Fabrication of
Hollow Iron Oxide Nanocapsules
for Simultaneous MRI
and Drug Delivery
Y. Piao et al., Nature Mater. 2008, 7, 242.
Wrap/Bake/Peel Process for Nanostructural Transformation
from FeOOH Nanorods to Biocompatible Iron Oxide Nanocapsules
Hollow Hematite (-Fe2O3) Nanocapsules
Hollow Magnetite (Fe3O4) Nanocapsules
T2-weighted MR images of the magnetite nanocapsules
Uptake of free DOX and PEG-MNC-DOX in cancer cells
PEG-MNC-DOX was accumulated mostly in the cytoplasm,
whereas free DOX was mostly found in the cell nuclei
Multifunctional Magneto-Polymeric Nanohybrids for Targeted
Detection and Synergistic Therapeutic Effects on Breast Cancer
Y.-M. Huh & S. Haam, Angew. Chem. Int. Ed., 2007, 46, 8836.
• Superparamagnetic MnFe2O4 nanoparticles and DOX were
embedded in carboxyl-terminated poly-(ethylene glycol)-blockpoly(D,L-lactic-co-glicolic acid) (PEG-PLGA) micelles and the
HER2 antibody was conjugated at the terminal carboxyl groups.
• The nude mice with the tumor model of the NIH3T6.7 cell lines
were injected intravenously with the HER2-conjugated
multifunctional polymer micelles to confirm the efficacy of T2 MRI
and drug delivery.
• a signal decrease in T2 MRI was observed at the tumor site
• therapeutic efficacy was also increased remarkably, owing to the
targeted release of DOX at the tumor site.
Synthesis of Magnetic Gold Nanoshells
and their Application to
Immuno-targeted MRI
and NIR Photothermal Therapy
J. Kim et al., Angew. Chem. Int. Ed. 2006, 45, 7754.
Gold Nanoshells for NIR detection and Therapy
Naomi J. Halas
Dielectric silica core/metal shell (gold or silver shell)
Chem. Phy. Lett. 1998, 288, 243-247
Unique optical property dependent on core/shell ratio
Absorption at Near Infra-red (NIR) region
Water window region: 700 ~ 1300 nm
(High physiological transmissivity)
Nanoshell
Strong Absorber for photothermal therapy
Halas, N. J. and West, J. L. Proc. Natl. Acad. Sci. USA 2003, 100, 13549.
Synthesis of Magnetic Gold Nanoshell
Magnetic Nanoparticle (Fe3O4) + Au Nanoshell
MR Imaging
NIR therapy
J. Kim et al., Angew. Chem. Int. Ed. 2006, 45, 7754.
NIR absorption of Magnetic Nanoshell
Extinction (a.u.)
Absorption at NIR region
400
600
800
1000
Wavelength (nm)
1200
Conjugation with Antibody (anti-HER2)
For Targeted Diagnosis/Theraphy
Ab
Ab
SS-
Thiol-PEG-Antibody
Thiol-PEG
S-
SS-
S-
MNS
S-
S-
Ab
S-
HER2 : over-expressed on cancer cell
SKBR3 : Breast cancer cell line, HER2-positive
H520 : Lung cancer cell line, HER2-negative
S-
S-
S-
Ab
Ab
Ab
Targeted MR imaging using Magnetic Gold Nanoshell
SKBR3
(positive)
Control
H520
(negative)
H520
(negative)
SKBR3
(positive)
T2-weighted
image
T2 (ms)
115
76.9
54.8
Targeted NIR therapy using Magnetic Gold Nanoshell
H520
(negative)
SKBR3
(positive)
Killed cells were stained blue by trypsin blue for 10 min.
Cancer cells targeted with magnetic gold nanoshells were rapidly
destroyed by exposing them to femtosecond NIR laser at a low power.
J. Kim et al., Angew. Chem. Int. Ed. 2006, 45, 7754.