A drug-delivery vehicle combining the targeting and thermal ablation of HER2+ breast-cancer cells with triggered drug release

Article abstract of DOI:10.1002/anie.201209804

Covering all three bases: Drug-delivery vehicles that encapsulate doxorubicin (Dox) within a pH-sensitive matrix embedded with gold nanoparticles were synthesized with Herceptin-poly(ethylene glycol) conjugates on the surface for the specific binding of c

Full text of DOI:10.1002/anie.201209804

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DOI: 10.1002/anie.201209804
Cancer Nanotechnology
A Drug-Delivery Vehicle Combining the Targeting and Thermal
Ablation of HER2 + Breast-Cancer Cells with Triggered Drug
Release**
Jin-Oh You, Peng Guo, and Debra T. Auguste*
Breast cancer is the second leading cause of cancer-related
deaths in women, surpassed only by lung cancer.[1] Current
clinical therapies target the estrogen receptor (ER) and
human epidermal growth factor receptor-2 (HER2) to reduce
cancer-cell proliferation. These methods are often used in
conjunction with surgery, chemotherapy, and/or radiation in
efforts to eradicate the disease. However, 25% of patients
face tumor recurrence and resistance within 5 years after
treatment.[2] Ideally, the initial treatment would supply
a robust, broad-spectrum therapy to eliminate all cancer
cells while minimizing damage to healthy tissue.
to direct delivery to the tumor site through activation by
a physiological change or an external source; in this way, off-
target effects were minimized. We previously synthesized
a pH-sensitive drug-delivery vehicle that triggered the release
of paclitaxel in acidic tumor environments.[6] The thermal
ablation of tumors as a result of the localized heating of
carbon nanotubes[7] or gold particles[8] activated with near-
infrared (NIR) light was effective in the treatment of skin,[9]
breast,[10] liver,[11] and ovarian cancers.[12] Individually, each
targeted therapy provided a substantial advantage over
nontargeted methods.
Tumor-targeting strategies have the potential to improve
the therapeutic efficacy of chemotherapeutic agents relative
to systemic approaches. To date, targeted therapeutics have
been engineered by the use of receptor-mediated or stimuli-
responsive methods. Molecules that recognize and/or inhibit
receptor function—alone, pegylated, or tethered to a cargo—
have been shown to improve targeting and reduce cancer-cell
proliferation and/or migration (e.g., folate,[3] anti-CXCR4,[4]
anti-HER2).[5] Stimuli-sensitive therapeutics have been used
The integration of two targeting methods in one vehicle
has improved tumoricidal efficacy relative to the use of each
approach independently. A drawback associated with the
merging of two targeting approaches is the introduction of
additional synthesis and purification steps, which often lead to
low encapsulation of the drug. Doxorubicin (Dox) encapsu-
lation can reduce the overall efficacy of the chemotherapeutic
agent relative to systemic administration.[13] Dox, an effective
and widely used chemotherapeutic agent owing to its hydro-
philicity and high toxicity, suffers from low drug loading and
fast release rates when encapsulated within polymeric nano-
particles. Furthermore, the simultaneous or stepwise delivery
of heat and the drug may drastically affect the therapeutic
result.[14] A tunable drug-delivery strategy engineered to
provide the greatest therapeutic impact would be desirable.
In this study, we synthesized a single drug carrier that
targets HER2, triggers Dox release, and thermally ablates
breast-cancer cells. The particles encapsulate Dox within
a pH-sensitive matrix that is embedded with Au nanoparticles
and decorated with poly(ethylene glycol)–HER2 conjugates
within five steps (Figure 1; PEG = poly(ethylene glycol)).
[*] Prof. Dr. J.-O. You, Dr. P. Guo, Prof. Dr. D. T. Auguste
School of Engineering and Applied Sciences, Harvard University,
Cambridge, MA 02138 (USA)
Prof. Dr. J.-O. You
Department of Engineering Chemistry, Chungbuk National Univer-
sity, Cheongju, 361-763 (Republic of Korea)
Dr. P. Guo, Prof. Dr. D. T. Auguste
Department of Surgery, Harvard Medical School
Boston, MA 02115 (USA)
and
Vascular Biology Program, Children’s Hospital Boston
Boston, MA 02115 (USA)
and
Dithiolated
dimethylaminoethyl
methacrylate
(dT-
DMAEMA), the pH-responsive monomer, was synthesized
by reversible addition–fragmentation chain-transfer (RAFT)
polymerization and characterized by NMR spectroscopy (see
Figure S1 in the Supporting Information). Particles encapsu-
lating Dox were prepared by oil-in-water emulsification.
Tuning of the dT-DMAEMA/HEMA ratio and the pH value
of the buffer regulated the swelling properties of the matrix.
We have previously shown that DMAEMA/HEMA matrices
are sensitive to incremental changes in the pH value (> 0.2
pH units).[6,15] The pH-responsive matrix effectively acts as
a logic gate: Dox is entrapped within the matrix until the
network is opened.
Department of Biomedical Engineering, The City College of New
York, New York, NY 10031 (USA)
E-mail: dauguste@ccny.cuny.edu
[**] We thank Prof. David Mooney and Dr. Praveen Arany for use of the
NIR laser device and Dariela Almeda for FACS analysis. We
gratefully acknowledge financial support from the Kavli Institute for
Bionano Science and Technology at Harvard University. This
research was supported by NIH (1DP2A174495) and NSF (DMR-
0820484). This research was performed in part at the Center for
Nanoscale Systems (CNS), a member of the National Nano-
technology Infrastructure Network (NNIN), which is supported by
the National Science Foundation under NSF award no. ECS-
0335765. CNS is part of the Faculty of Arts and Sciences at Harvard
University.
Subsequently, gold nanoparticles were formed homoge-
neously throughout the pH-responsive matrix. Thiol groups in
dT-DMAEMA show affinity for colloidal Au and Au ions. dT-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209804.
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(mol/mol) nanoparticles (HPG-Dox-30D70H) were designed
to target HER2 + breast-cancer cells, trigger the release of
Dox, and induce hyperthermia upon activation by irradiation
with a near-infrared (NIR) laser.
The size and morphology of all nanoparticles were
examined by transmission electron microscopy (TEM; Fig-
ure 2a) and dynamic light scattering (see Table S1 in the
Supporting Information). Examination of the nanoparticles
revealed a uniform and smooth surface morphology (see
Figure S2a). The average diameter of HPG-Dox-30D70H
nanoparticles was (186.4 Æ 18.6) nm (see Figure S2b) with
a negative surface charge of À7.3 Æ 2.1 mV. The size and
charge of HPG-Dox-30D70H are suitable for systemic
delivery; these nanocarrier traits have resulted in enhanced
permeability and retention (EPR).[19] The negative charge of
HPG-Dox-30D70H is caused by unreacted PEG-COOH. The
amine groups in DMAEMA become protonated as the
pH value decreases. As the dT-DMAEMA content increased
from 10 to 30%, the z potential rose from À18.9 to À7.3 mV
in parallel. Nanoparticle aggregation in a serum-free medium
was not observed during cell-viability and targeting experi-
ments.
The Au content of HPG-Dox-10D90H (10 dT-
DMAEMA/90 HEMA (mol/mol)) and HPG-Dox-30D70H
was characterized by thermogravimetric analysis (TGA) by
heating from 20 to 6008C under a continuous flow of argon
(Figure 2b). TGA analysis of the Au-embedded, pH-sensitive
nanoparticles revealed an Au-nanoparticle content of (1.45 Æ
0.10) and (2.71 Æ 0.22)% (w/w) for HPG-Dox-10D90H and
HPG-Dox-30D70H, respectively. The Au density increased
with the Au content of the dT-DMAEMA particles. In
a previous study, we demonstrated that under similar reaction
conditions the in situ synthesis of Au colloids was dictated by
the initial thiol content.[16b] The encapsulation of Dox had no
effect on the ability to synthesize Au colloids within dT-
DMAEMA/HEMA matrices. The UV/Vis spectrum of HPG-
Dox-30D70H nanoparticles indicated absorption in the near-
infrared range with a peak at 795 nm (Figure 2c).
To demonstrate the potential of HPG-Dox-30D70H for
photothermal cancer therapy, we exposed HPG-Dox-
30D70H nanoparticles to NIR laser irradiation at 810 nm
with a power density of 5 WcmÀ2 for 10 min. Changes in
temperature were measured and imaged by a thermal camera
over the duration of the experiment (Figure 2di,ii). Repre-
sentative thermal images taken at different time points during
the exposure of HPG-Dox-30D70H (5 mgmLÀ1) to NIR
irradiation show the temperature distribution within each
well (see Figure S3). The temperature of HPG-Dox-30D70H
aqueous solution increased by 15.38C during this experiment;
under the same conditions, the temperature of nanoparticle-
free distilled water increased by almost 18C. During NIR
laser irradiation, the particle size was not affected by changes
in temperature.
Figure 1. Schematic diagrams of a) the synthesis of Herceptin-conju-
gated, Dox-encapsulating, and pH-sensitive dT-DMAEMA/HEMA
(HPG-Dox-30D70H) nanoparticles and b) cancer therapy. SIPN=semi-
interpenetrating polymer network.
DMAEMA/HEMA nanoparticles were immersed in an
aqueous solution of potassium tetrachloroaurate (KAuCl4)
and reduced with
a solution of sodium borohydride
(NaBH4).[16] Au nanoparticles were distributed homogene-
ously within the Dox-encapsulating dT-DMAEMA/HEMA
nanoparticles (30:70 (mol/mol); Figure 2a). This transforma-
tion was also observed visually; the white particles became
brown after Au synthesis (Figure 2ai,ii).
The particles were functionalized on the exterior with
difunctional poly(ethylene glycol) molecules (SH-PEG-
COOH, 10 mmol/10 mg particles) substituted with a thiol
group at one end and a carboxylic acid group at the other. The
introduction of a thiol group enabled the noncovalent attach-
ment of PEG to Au and dT-DMAEMA. Thiol-functionalized
PEGs are useful for triggering the release of PEG within the
glutathione-rich cytoplasmic environment.[17] After the sepa-
ration of anchored PEG from free PEG in solution by dialysis,
Herceptin was conjugated through a carbodiimide reaction
(9 nmol/10 mg particles). Herceptin has been shown clinically
to target and reduce proliferation in HER2 + breast
tumors.[18] Herceptin–PEG-labeled, gold-embedded, Dox-
encapsulating, pH-responsive 30 dT-DMAEMA/70 HEMA
In addition to local heating, the nanocarriers were
designed to swell in response to changes in the pH value,
and thus to trigger the release of Dox. Volumetric swelling
was measured as a function of the molar ratio of dT-
DMAEMA to HEMA and of the pH value of the swelling
medium (Figure 2e,f, respectively). The volume swelling ratio
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Figure 2. Characterization of multitargeted nanoparticles. a) TEM
image of an HPG-Dox-30D70H nanoparticle. Au nanoparticles
were homogeneously distributed in the nanoparticles. Images were
taken of the nanoparticle pellets after the centrifugation of Dox-
30D70H (white, i) and HPG-Dox-30D70H (dark brown, ii). Scale
bar: 50 nm. b) TGA curves of HPG-Dox-10D90H (light blue) and
HPG-Dox-30D70H (dark blue). c) UV/Vis spectrum of HPG-Dox-
30D70H nanoparticles (peak at 795 nm). d) Temperature change of
HPG-Dox-30D70H in distilled water (5 mgmLÀ1; dark blue) and
nanoparticle-free distilled water (light blue) during NIR laser
irradiation for 10 min. Images were taken with an NIR thermal
camera for i) HPG-Dox-30D70H in distilled water and ii) only
distilled water after NIR laser irradiation for 10 min. e) Volume
swelling ratios of HPG-Dox-10D90H (light blue), HPG-Dox-
20D80H (blue), and HPG-Dox-30D70H (dark blue) in 20 mm
phosphate buffer (pH 5.5) at 0, 2, 4, 6, and 8 h. f) Volume swelling
ratios of HPG-Dox-30D70H in 20 mm phosphate buffer at pH 5.5
(light blue), 6.5 (blue), and 7.4 (dark blue) at 0, 2, 4, 6, and 8 h.
g) Cumulative Dox release from HPG-Dox-30D70H (5 mgmLÀ1) in
20 mm phosphate buffer at pH 5.5 (squares, dark-blue curve) and
7.4 (diamonds, light-blue curve) over 12 h. To evaluate the photo-
thermal effect induced by NIR irradiation, HPG-Dox-30D70H was
incubated at pH 5.5 (circles) and 7.4 (triangles) in 20 mm phos-
phate buffer and then irradiated with an NIR laser for 6 h. The
error is the standard deviation from the mean (n=3, * is
P<0.05).
Dox was encapsulated during particle synthesis. The
efficiencies of Dox encapsulation in HP-Dox-30D70H
(without gold) and HPG-Dox-30D70H nanoparticles were
(95.2 Æ 3.1) and (72.3 Æ 6.7)%. The reduction in Dox
loading was a result of multiple washing steps after Au
synthesis and antibody conjugation. Dox encapsulation is
high within liposome formulation (greater than 90%);[21]
polymeric nanoparticles have failed to show similar
results.[22]
To confirm that pH-induced swelling triggered the
release of Dox, Dox release was measured as a function of
time at pH 5.5 and 7.4 (Figure 2g). The release of Dox was
significantly enhanced under acidic conditions. After 8 h,
(44.05 Æ 5.79)% of the encapsulated Dox had been
released at pH 5.5, whereas (15.01 Æ 3.80)% had been
released at pH 7.4. In comparison, for other pH-sensitive
nanocarriers, 25% Dox release after 24 h at pH 5.5 was
reported,[23] or a significant burst release (50% of the
loaded Dox) was observed.[13b] Our pH-sensitive nanocarriers
exhibited a slow, controlled release of Dox at pH 7.4 and then
a rapid release upon a decrease in the pH value.
We also investigated the ability of HPG-Dox-30D70H
nanoparticles to release Dox under NIR laser irradiation.
HPG-Dox-30D70H nanoparticles were allowed to release
Dox in a buffer at pH 5.5 for 6 h and then heated (810 nm,
5 WcmÀ2, 6 h). Dox release was enhanced at pH 5.5 after laser
irradiation relative to that observed for the nonirradiated
control (Figure 2g). The temperature of the well increased
from 37.7 to 48.98C after NIR irradiation for 5 min, which
significantly increased Dox release (see Figure S3). Approx-
imately 30% of the initial dose was delivered when the
pH value changed; subsequent irradiation delivered an addi-
tional 50% of the entrapped drug. At pH 7.4, only 10% of the
is defined as the nanoparticle diameter after swelling divided
by the original diameter.[20] Figure 2e depicts the swelling
ratio for dT-DMAEMA/HEMA molar ratios of 10:90, 20:80,
and 30:70 as a function of time. The swelling ratio of dT-
DMAEMA/HEMA nanoparticles increased with the dT-
DMAEMA content owing to the greater number of proton-
ated amine groups. After 4 h at pH 5.5, the swelling ratio of
HPG-Dox-10D90H and HPG-Dox-30D70H had increased to
1.29 Æ 0.04 and 1.56 Æ 0.09, respectively. To investigate the pH
sensitivity of the nanoparticles, we measured the swelling
ratio of HPG-Dox-30D70H as a function of the pH value
(Figure 2 f). The swelling ratios (measured after 8 h)
increased from 1.13 Æ 0.07 at pH 7.4 to 1.61 Æ 0.14 at pH 5.5.
The nanoparticle formulation may be tuned to control pH-
induced swelling.
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initial dose was available after 6 h; this amount increased to
30% of the entrapped drug after laser irradiation. The
coupling of pH-triggered release and localized heating in one
carrier yielded enhanced Dox delivery. This synergistic
delivery approach enables the tunable release of Dox within
the tumor microenvironment.
The HPG-Dox-30D70H nanoparticles were conjugated
with Herceptin for the targeting of HER2 + breast-cancer
cells. The number of Herceptin molecules on the nanoparticle
surface was determined by a DC (detergent-compatible)
protein assay (see Table S2). Approximately 116 and 117
Herceptin molecules were conjugated on HPG-30D70H and
HPG-Dox-30D70H nanoparticles, respectively. The binding
affinity of HPG-Dox-30D70H for a breast-cancer cell line
with low HER2 expression, MCF-7, and a breast-cancer cell
line that overexpresses HER2, SK-BR-3, was measured by
flow cytometry (Figure 3). As a control, IgG–PEG-labeled
Dox-30D70H with and without laser irradiation (at a concen-
tration equivalent to 0.26 mm Dox). This dose was 10-fold
lower than the half maximal inhibitory concentration (IC50)
for free Dox (see Figure S4). Nontargeting IPG-Dox-30D70H
was used as a control. Cell viability was measured quantita-
tively by a fluorescence plate reader and qualitatively by
microscopy. SK-BR-3 cells treated with HPG-30D70H (with-
out Dox) and HPG-Dox-30D70H without laser irradiation at
pH 7.4 exhibited (77.31 Æ 4.13) and (51.81 Æ 5.39)% cell
viability, respectively. After NIR laser irradiation, SK-BR-3
cell viability significantly decreased to (31.23 Æ 7.68) and
(14.49 Æ 3.60)% for HPG-30D70H and HPG-Dox-30D70H,
respectively. HPG-Dox-30D70H (Figure 4c,d) showed an
enhanced tumoricidal effect relative to the antibody-labeled
nanoparticle without Dox, HPG-30D70H (Figure 4a,b).
When laser irradiation was added, the tumoricidal effect
was enhanced by both the increased temperature and Dox
release. The treatment of SK-BR-3 cells with nanoparticles
that coupled receptor targeting, chemotherapy, and thermal
ablation resulted in a maximal cell survival of 14%. Given the
low Dox concentration and mild irradiation conditions, this
level of toxicity is significantly more efficacious than the use
of systemic Dox or combinations of Herceptin/Dox, Hercep-
tin/NIR, or Dox/NIR.
Conversely, no significant difference was observed
between HPG-30D70H and HPG-Dox-30D70H in their
effect on MCF-7 cells in the absence of NIR laser irradiation.
After exposure to NIR laser irradiation, the cell viability of
MCF-7 cells treated with HPG-30D70H (Figure 4e,f) and
HPG-Dox-30D70H (Figure 4g,h) was not significantly differ-
ent. This result is attributed to lack of targeting, the low dose,
and reduced Dox release.
IPG-30D70H and IPG-Dox-30D70H were used as con-
trols for the cell-toxicity experiments. With these nano-
particles, the tumoricidal effect was hindered as a result of
nonspecific targeting (Figure 4i,j; see also the fluorescence
images in Figure S5). The nanocarriers without Dox were not
cytotoxic (approximately 91–93% cell viability for both cell
lines with and without Au synthesis). The viability results
were similar to those found with poly(lactic-co-glyoclide)
(PLGA) nanoparticles (nearly 93% for both cell lines), which
are widely used for systemic drug delivery (see Figure S6).
Other “multifunctional” vehicles have incorporated two
modalities, either Dox/NIR,[25] Dox/targeting,[26] or targeting/
NIR.[22] Significantly better results were reported for these
systems than for the unidimensional control with either Dox,
NIR irradiation, or the targeting moiety alone. Ideally, Dox
delivery would be localized to avoid off-target effects, and
Dox would be released quickly. Dox-encapsulating PLGA
nanoparticles exhibit slow release.[27] Stimuli-triggered deliv-
ery could be beneficial. However, previous examples of pH
sensitivity exhibited either slow release or an uncontrolled
burst release.[28] The vehicles presented herein are different:
they have a high encapsulation efficiency and can trigger Dox
release within hours in response to a small change in the
pH value.
Figure 3. a,b)Flow cytometry analysis of SK-BR-3 (a) and MCF-7 (b)
cells treated with HPG-Dox-30D70H or IPG-Dox-30D70H. The blue,
green, and red curves correspond to nontreated, IPG-Dox-30D70H-
treated, and HPG-Dox-30D70H-treated samples, respectively. c) Nor-
malized fluorescence intensities determined by flow cytometry. The
error is the standard deviation from the mean (n=3, ** is P<0.001).
(IgG = immunoglobulin G), gold-embedded, Dox-encapsu-
lating, pH-responsive, 30 dT-DMAEMA/70 HEMA nanopar-
ticles (IPG-Dox-30D70H) were prepared. As expected,
HPG-Dox-30D70H nanoparticles exhibited a 5.4-fold en-
hancement in the binding of SK-BR-3 cells relative to the
binding of MCF-7 cells. These results confirmed claims in
previous reports that Herceptin may be used to distinguish
between cell lines with low and high HER2 expression.[24] Our
HPG-Dox-30D70H nanocarriers exhibited similar behavior
to that described in prior reports of HER2 targeting.[22]
To investigate the therapeutic efficacy of HPG-Dox-
30D70H, we treated SK-BR-3 and MCF-7 cells with HPG-
The functionalization of particles with an antibody or
peptide is a conventional approach for targeting. Nano-
carriers that couple both a targeting moiety and either Au
4
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irradiation, gold surface coatings are
used.[22] Instead, in our method, we
employed polymers as a template for
Au colloids. We have demonstrated
that the NIR thermal effect on Au
nanoparticles is similar to that
observed with Au coatings (Fig-
ure 2d). Additionally, our templat-
ing method is suitable for manufac-
turing and scale-up.
The fusion of three targeting
modalities led to a significant benefit
relative to the use of each method
alone. The multitargeted drug-deliv-
ery platform resulted in 14% cell
viability, whereas the equivalent
dosage of free Dox resulted in 81%
cell viability. The addition of Her-
ceptin in conjunction with pH-trig-
gered Dox release or NIR ablation
increased toxicity relative to that of
free Dox but did not cause a decrease
in cell viability at the levels reached
when all three methods were com-
bined.
In conclusion, we have synthe-
sized a unique multitargeted vehicle
that couples three modalities: target-
ing, triggered release, and thermal
ablation. HPG-Dox-30D70H nano-
particles had a high loading effi-
ciency and exhibited pH-responsive
Dox release, which was enhanced by
laser irradiation. Enhanced targeting
relative to that of IgG-labeled nano-
carriers was achieved by conjugating
Figure 4. a–h) Fluorescence microscopy images of SK-BR-3 (a–d) and MCF-7 (e–h) cells treated
with HPG-30D70H and HPG-Dox-30D70H with or without NIR laser illumination. Multitargeted
nanocarriers were conjugated with Herceptin (a–h) or IgG (see Figure S3c-l in the Supporting
Information). Yellow and red arrows indicate the areas treated and not treated with the NIR laser,
respectively. i,j) The cell viability of SK-BR-3 (i) and MCF-7 (j) cells was determined by a resazurin-
based toxicology assay. Cells were treated with nanocarriers conjugated with either Herceptin or
IgG. The error is the standard deviation from the mean (n=3, * is p<0.05, ** is P<0.01).
nanoparticles[22] or Dox[26] on the surface show a significant
decline in targeting ability. We chose Herceptin because it was
currently used in the clinic. Herceptin-functionalized nano-
particles (HPG-30D/70H) without Dox or laser irradiation
resulted in 77% cell viability. The presence of Herceptin
alone did not result in a significant tumoricidal effect.
Targeting with the addition of encapsulated Dox has been
shown to be useful; however, we have demonstrated that
some cancer-cell types are resistant to this type of therapy and
require the use of alternative methods.[29]
Herceptin–PEG conjugates to the surface. Critical to trans-
lation, these particles are relatively simple to prepare with
high reproducibility. The observed toxicity suggests that
multitargeted delivery has great potential as a cancer therapy.
HPG-Dox-30D70H is the first carrier to integrate targeting,
stimuli-responsive drug delivery, and thermal ablation for use
in breast-cancer research.
Received: December 7, 2012
Revised: February 5, 2013
Published online: && &&, &&&&
Laser irradiation is a powerful technique that can achieve
penetration depths of up to 50 mm.[30] HPG-30D/70H nano-
particles exhibited 30% cell viability after laser irradiation.
Cancer cells were reported to be most vulnerable to hyper-
thermia and chemotherapeutic agents above 438C.[14] In this
study, we used mild irradiation conditions (810 nm, 10 min,
5 WcmÀ2) to cause a temperature increase of 158C, whereas
an increased laser power was required in other studies for
Keywords: cancer nanotechnology · drug delivery ·
gold nanoparticles · photothermal therapy ·
pH-sensitive nanoparticles
.
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6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
Communications
Cancer Nanotechnology
Covering all three bases: Drug-delivery
vehicles that encapsulate doxorubicin
(Dox) within a pH-sensitive matrix
embedded with gold nanoparticles were
synthesized with Herceptin–poly(ethy-
lene glycol) conjugates on the surface for
the specific binding of cancer cells (see
picture; NIR=near infrared). Cell target-
ing was combined with enhanced cyto-
toxicity through triggered drug release (at
pH 5–6) and thermal ablation (a photo-
thermal effect).
J.-O. You, P. Guo,
D. T. Auguste*
&&&& — &&&&
A Drug-Delivery Vehicle Combining the
Targeting and Thermal Ablation of
HER2+ Breast-Cancer Cells with
Triggered Drug Release
Angew. Chem. Int. Ed. 2013, 52, 1 – 7
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!