Multifunctional nanoparticles for photothermally controlled drug delivery and magnetic resonance imaging enhancement.
- SourceAvailable from: washington.edu[show abstract] [hide abstract]
ABSTRACT: The biological application of nanoparticles is a rapidly developing area of nanotechnology that raises new possibilities in the diagnosis and treatment of human cancers. In cancer diagnostics, fluorescent nanoparticles can be used for multiplex simultaneous profiling of tumour biomarkers and for detection of multiple genes and matrix RNA with fluorescent in-situ hybridisation. In breast cancer, three crucial biomarkers can be detected and accurately quantified in single tumour sections by use of nanoparticles conjugated to antibodies. In the near future, the use of conjugated nanoparticles will allow at least ten cancer-related proteins to be detected on tiny tumour sections, providing a new method of analysing the proteome of an individual tumour. Supermagnetic nanoparticles have exciting possibilities as contrast agents for cancer detection in vivo, and for monitoring the response to treatment. Several chemotherapy agents are available as nanoparticle formulations, and have at least equivalent efficacy and fewer toxic effects compared with conventional formulations. Ultimately, the use of nanoparticles will allow simultaneous tumour targeting and drug delivery in a unique manner. In this review, we give an overview of the use of clinically applicable nanoparticles in oncology, with particular focus on the diagnosis and treatment of breast cancer.The Lancet Oncology 09/2006; 7(8):657-67. · 25.12 Impact Factor
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ABSTRACT: Due to strong electric fields at the surface, the absorption and scattering of electromagnetic radiation by noble metal nanoparticles are strongly enhanced. These unique properties provide the potential of designing novel optically active reagents for simultaneous molecular imaging and photothermal cancer therapy. It is desirable to use agents that are active in the near-infrared (NIR) region of the radiation spectrum to minimize the light extinction by intrinsic chromophores in native tissue. Gold nanorods with suitable aspect ratios (length divided by width) can absorb and scatter strongly in the NIR region (650-900 nm). In the present work, we provide an in vitro demonstration of gold nanorods as novel contrast agents for both molecular imaging and photothermal cancer therapy. Nanorods are synthesized and conjugated to anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies and incubated in cell cultures with a nonmalignant epithelial cell line (HaCat) and two malignant oral epithelial cell lines (HOC 313 clone 8 and HSC 3). The anti-EGFR antibody-conjugated nanorods bind specifically to the surface of the malignant-type cells with a much higher affinity due to the overexpressed EGFR on the cytoplasmic membrane of the malignant cells. As a result of the strongly scattered red light from gold nanorods in dark field, observed using a laboratory microscope, the malignant cells are clearly visualized and diagnosed from the nonmalignant cells. It is found that, after exposure to continuous red laser at 800 nm, malignant cells require about half the laser energy to be photothermally destroyed than the nonmalignant cells. Thus, both efficient cancer cell diagnostics and selective photothermal therapy are realized at the same time.Journal of the American Chemical Society 03/2006; 128(6):2115-20. · 10.68 Impact Factor
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ABSTRACT: Nanoshells are a novel class of optically tunable nanoparticles that consist of a dielectric core surrounded by a thin gold shell. Based on the relative dimensions of the shell thickness and core radius, nanoshells may be designed to scatter and/or absorb light over a broad spectral range including the near-infrared (NIR), a wavelength region that provides maximal penetration of light through tissue. The ability to control both wavelength-dependent scattering and absorption of nanoshells offers the opportunity to design nanoshells which provide, in a single nanoparticle, both diagnostic and therapeutic capabilities. Here, we demonstrate a novel nanoshell-based all-optical platform technology for integrating cancer imaging and therapy applications. Immunotargeted nanoshells are engineered to both scatter light in the NIR enabling optical molecular cancer imaging and to absorb light, allowing selective destruction of targeted carcinoma cells through photothermal therapy. In a proof of principle experiment, dual imaging/therapy immunotargeted nanoshells are used to detect and destroy breast carcinoma cells that overexpress HER2, a clinically relevant cancer biomarker.Nano Letters 05/2005; 5(4):709-11. · 13.03 Impact Factor
Multifunctional Nanoparticles for
Photothermally Controlled Drug Delivery and
Magnetic Resonance Imaging Enhancement**
Huiyul Park, Jaemoon Yang, Sungbaek Seo,
Kyujung Kim, Jinsuk Suh, Donghyun Kim,
Seungjoo Haam, and Kyung-Hwa Yoo*
Recently, near-infrared (NIR) resonant nanomaterials such
as gold nanoshell particles,[1–6]hollow Au nanoshells,[7,8]and
Au nanorods[9,10]have been extensively studied for promis-
ing applications in biomed-
icine, because optical trans-
mission through tissues is op-
(800–1200 nm). These nano-
NIR light and convert it into
heat; thus, they can be utiliz-
ed for photothermal therapy.
Indeed, Hirsh et al.demon-
strated that silica/Au nano-
shell particles could be used
to deliver a therapeutic dose
of heat to kill targeted cells
cellsbecause of excessive
local heating. Furthermore,
nanoparticles and cancer-cell-specific antibodies to develop
a multifunctional platform for simultaneous diagnosis via
magnetic resonance imaging (MRI) and NIR photothermal
Photothermal conversion in Au nanoshells increases the
temperature locally; elevated temperature can sensitize tar-
geted cells to cytotoxic agents by increasing membrane per-
meability and blood vessel dilation.Therefore, if the pho-
tothermal therapy is combined with chemotherapy, a much
higher therapeutic efficacy is expected. In a previous
(NIPAAm-co-AAm))–Au/Au2S nanoshell composites con-
taining methylene blue, ovalbumin, or bovine serum albu-
min (BSA) were synthesized, and the drug release from
these composites was reported to be enhanced upon NIR ir-
radiation. However, NIPAAm-co-AAm hydrogels, which
undergo a reversible phase transition in response to NIR ir-
radiation, are not appropriate for drug delivery because of
Thus, we herein propose biodegradable polymer–metal
multilayer half-shell nanoparticles (H-S NPs) for drug deliv-
ery, as shown in Figure 1. The drug is encapsulated within
biocompatible and biodegradable polymer nanoparticles,
and metal multilayers are deposited on these nanoparticles.
Since the physical deposition method yields half-shells, the
drug is released through the open half of the shell, the inte-
rior of which is now exposed. Moreover, since these nano-
particles are NIR resonant and the drug release from poly-
mer nanoparticles is accelerated by increasing the tempera-
ture,it would be possible to modulate the rate of drug re-
lease in response to NIR irradiation. In this study, we have
fabricated poly(lactic-co-glycolic acid) (PLGA)–Au H-S
NPs and PLGA–Mn/Au H-S NPs containing rhodamine as a
model drug and demonstrated their use for photothermally
controlled drug delivery and MRI enhancement.
Figure 2a shows the absorption spectra measured by
using a UV-visible/NIR spectrometer for PLGA–Au H-S
NPs having different Au shell thickness. In spite of the
asymmetric geometry, these absorption peaks are located in
the NIR region, in agreement with the results reported for
Figure 1. Schematic diagram of drug-loaded polymer–metal multilayer H-S NPs. The drug is loaded into
biocompatible and biodegradable polymer nanoparticles, and magnetic and Au layers are deposited on
the polymer nanoparticles. These nanoparticles provide multiple functions, such as photothermal thera-
py, photothermally controlled drug delivery, and MRI contrast enhancement.
[*] H. Park, Prof. K.-H. Yoo
Department of Physics
Seoul 120-742 (Korea)
Fax: (+82) 231-270-90
J. Yang, S. Seo, S. Haam
Department of Chemical Engineering
Seoul 120-742 (Korea)
K. Kim, Prof. D. Kim
Department of Electrical and Electronic Engineering
Seoul 120-742 (Korea)
Prof. J. Suh
Department of Radiology, College of Medicine
Seoul 120-752 (Korea)
[**] This work has been financially supported by the Korea Science
and Engineering Foundation through the National Core Research
Center for Nanomedical Technology (Grant No. R15-20040924-
Supporting Information is available on the WWW under http://
www.small-journal.com or from the author.
? 2008 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim
small 2008, 4, No.2, 192–196
silica–Au nanoshell particles.However, the peak positions
are barely affected by altering the Au shell thickness, proba-
bly because of the nonhomogenous size distribution of the
PLGA nanoparticles (see below, Figure 4).
The NIR absorption peak indicates that NIR light is ab-
sorbed by PLGA–Au H-S NPs and converted into thermal
energy via electron–phonon and phonon–phonon interac-
tions.[3,4]In order to investigate this photothermal conver-
sion property, the temperature of the PLGA–Au H-S NP
solution was measured using a thermocouple while the solu-
tion was irradiated with NIR light, with a laser diode of
wavelength l = 808 nm and a power density of 7 W cm?2.
The sample was exposed from 0 to 120 s but not from 120 to
240 s. As shown in Figure 2b, the temperature of the
PLGA–Au H-S NP solution (concentration of 145 mg mL?1)
increases linearly from 26.3 to 33.18C (~T?78C) under NIR
irradiation. However, when the Au nanoparticle solution
(2.7 mg mL?1), thePLGA
(3.3 mg mL?1), and the deionized water are irradiated by
NIR light, the temperature increases much less than that of
the PLGA–Au H-S NP solution. These results confirm the
photothermal conversion property of PLGA–Au H-S NPs.
We have also studied the dependence of this property on
the laser power density and the PLGA–Au H-S NP solution
concentration. Higher power densities and nanoparticle con-
centrations are seen to result in larger increases in tempera-
ture (see the Supporting Information, Figure S1). It implies
that ~T can be controlled by adjusting NIR power density
and nanoparticle concentration.
In in vitroreleaseexperiments,
PLGA–Au (25 nm) H-S NPs were prepared and the amount
of released rhodamine was measured by using a UV spec-
trophotometer. The release profiles obtained with and with-
out NIR irradiation are presented in Figure 3a. Drug release
from PLGA particles generally shows a triphasic profile; an
initial burst release, a lag
phase, and a secondary burst
Since rhodamine used as the
model drug is a fluorescent
dye, we also monitored rhod-
amine release from PLGA
nanoparticles by using total
cence microscopy (TIRFM).
mine-loaded PLGA–Au H-S
NPs with and without NIR
irradiation, respectively, for
different times. The red cir-
nanoparticles. The diameter
of these red circles signifi-
cantly decreases with increas-
ing NIR irradiation time, and
the peak emission intensity
of a rhodamine-loaded PLGA nanoparticle is reduced ap-
proximately by an order of magnitude for 50 min (see the
Supporting Information, Figure S2). On the other hand, the
background intensity increases until 15 min and then de-
creases because of the diffusion of released rhodamine.
However, when not exposed to NIR light, very little rhod-
amine seems to be released from PLGA nanoparticles
within 50 min. These TIRFM data support photothermally
controlled drug delivery.
Figure 4a–c shows field-emission scanning electron mi-
croscopy (FESEM) and transmission electron microscopy
(TEM) images of rhodamine-loaded PLGA–Au H-S NPs
before NIR irradiation, and after 2-, and 3-day exposure, re-
spectively. After a 3-day irradiation, the PLGA uncovered
with Au is rapidly degraded and only Au H-S NPs are left,
whereas rhodamine-loaded PLGA–Au H-S NPs without ir-
radiation maintain their shapes even after three days. These
results are consistent with the in vitro release experiments
in Figure 3a.
Besides morphology studies, we have further investigat-
ed the optical and photothermal conversion properties of
rhodamine-loaded PLGA–Au H-S NPs with PLGA nano-
particles partially degraded by NIR irradiation. As shown in
Figure 5a, the absorption peak is around 823 nm before
NIR irradiation. However, the peak is shifted to shorter
wavelengths with increasing NIR irradiation time and re-
mains nearly unchanged after a 3-day irradiation. This find-
ing indicates that the surface plasmon resonance peak of Au
half-shells is about 783 nm because PLGA nanoparticles are
completely degraded within 3 days under NIR irradiation.
Figure 5b shows the time dependence of the temperature
for the PLGA–Au H-S NP solution irradiated by NIR light
from a laser diode at 808 nm. During the experiments, one-
minute irradiation periods were repeated with a power den-
sity of 7 W cm?2. At first, the temperature increases rapidly
Figure 2. a) Visible/NIR spectra for PLGA–Au H-S NPs with different Au shell thickness. The inset is a
field-emission scanning electron microscopy (FESEM) image of the PLGA–Au H-S NPs. b) Temperature
versus time for the PLGA–Au H-S NP solution (145 mg mL–1), the Au nanopraticle solution (2.7 mg mL–1),
the PLGA nanoparticle solution (3.3 mg mL–1), and the deionized water irradiated by the 808-nm laser
diode with a power density of 7 W cm–2from 0 to 120 s, but turned off from 120 to 240 s.
small 2008, 4, No.2, 192–196 ? 2008 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim
up to nearly 578C with oscillations in response to the peri-
odic NIR exposure. Then, the temperature remains constant
for 3 days, although it decreases slightly because of the shift
of the absorption peak.
Figure 6a shows the absorption spectra of PLGA–Mn/
Au H-S NPs. For Mn (10 nm)/Au (0 nm), a surface plasmon
resonance peak is not observed in the range 400–1100 nm.
For Mn (10 nm)/Au (25 nm), however, the absorption peak
is found at about 845 nm. The surface plasmon resonance
peak of PLGA–Mn/Au H-S NPs is still in the NIR range in
spite of the Mn layer, so that NIR light can be converted to
thermal energy, as shown in the inset of Figure 5b. In Fig-
ure 6b and c, the spin–spin relaxation time (T2)-weighted
spin-echo MR images and 1/T2measured at 1.5 T are shown
as a function of nanoparticle concentration for PLGA–Mn
(10 nm)/Au (25 nm) H-S NPs
and PLGA–Au (25 nm) H-S
NPs without a Mn layer. For
the former, 1/T2increases lin-
early with increasing nano-
whereas 1/T2of nanoparticles
without a Mn layer has the
same value as that of water,
independent of the concen-
tration. These results suggest
that PLGA–Mn/Au H-S NPs
can be used as MRI contrast
agents because of the Mn
layer. In addition, we have
also investigated the mobility
of rhodamine-loaded PLGA–
Mn/Au H-S NPs in an exter-
nal magnetic field by a fluo-
nanoparticles were observed
to move in the direction of
the magnetic field (see the
Movie S1). It indicates that
H-S NPs could possibly be
used as magnetic drug carri-
ers for targeted delivery.
For targeted drug delivery
and MRI, the potential toxic-
should be evaluated. Howev-
er, since PLGA, Au, and Mn,
which comprise these nano-
particles, appear biocompat-
supported by recent experi-
ments on human cells,[15,16]
their toxicity is expected to
be within a tolerable range.
In summary, we have de-
veloped NIR-resonant rhod-
amine-encapsulated PLGA–Mn/Au H-S NPs by depositing
metal multilayers on PLGA nanoparticles and we have
shown that these nanoparticles can be used for photother-
mally controlled drug delivery and MR imaging. The photo-
thermal conversion in the Au layer has been investigated by
measuring the temperature of the nanoparticle solution, and
the temperature increase ~T is observed to be dependent
on NIR irradiation time, power density, and nanoparticle
concentration. Upon NIR irradiation, the release rate of
rhodamine from the PLGA nanoparticles is found to be
about twice as great as the one without NIR irradiation;
this photothermally controlled drug delivery has been con-
firmed through FESEM/TEM and TIRFM images and ab-
sorption spectra. Furthermore, if these nanoparticles are
conjugated with targeting ligands, as reported by other
Figure 3. a) Rhodamine release profiles from PLGA nanoparticles (molecular weight, Mw= 20 000) with
and without NIR irradiation. One-minute irradiation periods were repeated during the experiments with a
power density of 7 W cm–2. b,c) Evolution of TIRFM images as rhodamine is released from PLGA–Au H-S
NPs during NIR irradiation using a 808-nm laser diode with a power density of 20 W cm–2(b) and with-
out NIR irradiation (c).
? 2008 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim
small 2008, 4, No.2, 192–196
selectivecelltargeting mightpossibly be
Preparation and characterization of rhodamine-loaded PLGA
nanoparticles: PLGA (100 mg, Mw= 20 000, Wako Chemicals)
and rhodamine B (4 mg, Mw= 443, Sigma–Aldrich) were dis-
solved in a 50:50 ratio in 10 mL of chloroform. The organic solu-
tion was mixed with 20 mL of
poly(vinyl alcohol) (2%, Mw=
15 000–20 000, Aldrich Chemi-
cal Co.) as a stabilizer. After
the mutual saturation of organ-
ic and continuous phases, the
10 min by ultrasonication at
250 W. The organic solvent was
evaporated and the rhodamine-
were purified by centrifugation
at 20 000 rpm for 30 min. The
size of the nanoparticles, deter-
mined by dynamic light scatter-
ing (DLS), was approximately
(75?12) nm in diameter, and
their glass transition tempera-
ture, measured by a differential
scanning calorimetry (TA Instru-
The amount of encapsulat-
ed rhodamine was measured
as follows: The dried PLGA
nanoparticles were mixed in
(pH 7.4). This suspension was
then stirred and sonicated to
nanoparticles. After centrifuga-
tion, the amount of rhodamine
loaded in the PLGA nanoparti-
cles was measured using a UV
spectrometer (Optizen 2120UV,
MECASYS Co.). The encapsula-
tion efficiency, which is defined
as the percentage of the actual
mass of drug encapsulated in
the PLGA polymer relative to
loaded, was estimated to be
Fabrication of PLGA–metal
metal multilayer H-S NPs are
fabricated by depositing thin
metal layers onto monolayers
of PLGA nanoparticles, which were prepared by spin-casting
aqueous suspensions of nanoparticles onto a silicon sub-
strate.[18,19]After the deposition of the metal films, metal-depos-
ited polymer nanoparticles were released into water from the
substrate surface by sonication and collected by centrifugation.
Measurements of photothermal conversion properties: 4 mL
of PLGA–Au (25 nm) H-S NP solution was prepared in a transpar-
ent vial. The temperature of the solution was measured using a
thermocouple, while it was irradiated with a 808-nm coherent
diode laser (Unique mode 30k/400/20 (808 ?3) nm, Jenoptik
Figure 4. FESEM images of PLGA–Au H-S NPs right after fabrication (a), after 2-day NIR irradiation (b),
after 3-day NIR irradiation (c), and in the water for three days without NIR irradiation (d). The insets are
Figure 5. a) Absorption spectra for PLGA–Au H-S NPs irradiated for different time intervals. b) Tempera-
ture versus time for PLGA–Au H-S nanoparticle solution irradiated at 808 nm with a power density of
7 W cm–2. The inset is temperature versus time during the first 20 min for PLGA–Au H-S NPs with a con-
centration of 200 mg mL–1and PLGA–Mn/Au H-S NPs with a concentration of 100 mg mL–1. During the
experiments, one-minute irradiation periods were repeated.
small 2008, 4, No.2, 192–196? 2008 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim
Co.) for 2 min. In order to investigate the dependence of laser
power density and nanoparticle concentration on photothermal
conversion properties, the laser power density was varied from 7
to 25 W cm?2and the nanoparticle concentration was varied
from 36.25 to 145 mg mL?1.
In vitro release experiments: 5 mL of rhodamine-encapsulat-
ed PLGA–Au (25 nm) H-S NP solution with a concentration of
about 200 mg mL?1was loaded into a 10 000 Dalton molecular-
weight cut-off membrane dialysis tube. The tube was immersed
in a transparent vial filled with 4 mL of phosphate buffer solu-
tion (pH 7.4, 10 mm) during release experiments. The release ex-
periments were performed with and without NIR irradiation at
room temperature. During the experiments, one-minute irradia-
tion periods were repeated with a power density of 7 W cm?2.
The amount of released rhodamine was measured through UV
absorbance. All measurements were conducted in triplicate.
Total internal reflection fluorescence microscopy experiments:
TIRF microscopy was performed with a Nikon Eclipse TE2000 in-
verted fluorescence microscope (Nikon, Melville, NY, USA)
equipped with a 532 nm laser (CrystaLaser, Reno, NV, USA) and
a digital camera C9100 EM-CCD (Hamamatsu, Bridgewater, NJ,
USA). The output power of the laser was 200 mW. The micro-
scope uses a CFI Apochromat oil-immersion objective (100?, nu-
merical aperture, NA = 1.49) and detects with a filter set (EX:
510–560 nm, DM: 570 nm, and BA: 590 nm). The sample stage
index-matched custom-made glass bottom well dishes were
from MaTek cultureware (Ashland, MA, USA). The filter set and
the camera were controlled by Metamorph software (Universal
Imaging, Downingtown, PA, USA). Release images were captured
every five minutes for an hour with an exposure time of 1 ms.
The NIR irradiation was maintained during the experiments with
the power density of 20 W cm?2.
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Figure 6. a) Absorption spectra for PLGA–Mn (10 nm)/Au (0, 25 nm) H-S NPs. b) T2-weighted images of
PLGA–Mn (10 nm)/Au (25 nm) H-S NPs for different nanoparticle concentrations. c) 1/T2versus relative
nanoparticle concentration for PLGA–Mn (10 nm)/Au (25 nm) and PLGA–Mn (0 nm)/Au (25 nm) H-S NPs.
? 2008 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim
small 2008, 4, No.2, 192–196