REVIEW

BIOENGINEERING

Cancer Nanomedicine: From Drug Delivery to Imaging

Edward Kai-Hua Chow1,2* and Dean Ho3,4,5,6,7*

Nanotechnology-based chemotherapeutics and imaging agents represent a new era of “cancer nanomedicine”
working to deliver versatile payloads with favorable pharmacokinetics and capitalize on molecular and cellular
targeting for enhanced specificity, efficacy, and safety. Despite the versatility of many nanomedicine-based
platforms, translating new drug or imaging agents to the clinic is costly and often hampered by regulatory
hurdles. Therefore, translating cancer nanomedicine may largely be application-defined, where materials are
adapted only toward specific indications where their properties confer unique advantages. This strategy may
also realize therapies that can optimize clinical impact through combinatorial nanomedicine. In this review, we
discuss how particular materials lend themselves to specific applications, the progress to date in clinical
translation of nanomedicine, and promising approaches that may catalyze clinical acceptance of nano.

ALL ABOUT THE APPLICATION
Nanomaterials come in many flavors. They include lipid-based vehicles
(liposomes, solid lipid nanoparticles, and micelles) (1–3); polymer
carriers, such as hydrogels, polymersomes, dendrimers, and nanofibers
(4–16); metallic nanoparticles (gold, silver, and titanium) (17–20);
carbon structures [nanotubes, nanohorns, nanodiamonds (NDs), and
graphene] (21–30); and inorganic particles, such as silica (31–34). These
nanomaterials have been envisioned as drug and imaging agent de-
livery vehicles (or even as drugs and imaging agents themselves). Nano-
medicine applications range from cancer to inflammation and regenerative
medicine—in essence, the gamut that is clinical medicine. It is becoming
clear, however, that different classes of materials are optimal for spe-
cific applications. For example, albumin is an effective solubilization
platform for hard-to-deliver chemotherapeutics, such as paclitaxel
(ClinicalTrials.gov: NCT00733408). Metallic particles are promising
photothermal therapeutic agents (35). Nanocarbons have mediated un-
precedented increases in magnetic resonance (MR) efficiency for im-
proving imaging-based diagnosis (36). In addition, the rational and
scalable design of targeted polymeric nanoparticles because of the abil-
ity to tailor their chemical makeup and properties have enabled the
stabilization of small interfering RNA (siRNA) therapies without
the need for toxic polycationic agents, as well as small-molecule thera-
pies. These attributes have catalyzed their translation into the clinic
with improved efficacy over current standards. Recent studies have
also examined how combining the innate attributes of varying classes
of nanomaterials to both induce biological responses and respond to
biological signals can be used to shrink tumors (32, 37, 38).
More than 7 million people died of cancer in 2008 worldwide, and
it continues to be the second leading cause of death in the United States
(39, 40). Successful treatment and imaging of cancer relies on several
capabilities that can be uniquely addressed via nanomedicine. Nano-
material sizes match the length scales of tumor interendothelial junc-
1
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599,
Singapore. 2Department of Pharmacology, Yong Loo Lin School of Medicine, National
University of Singapore, Singapore 117599, Singapore. 3Division of Oral Biology and
Medicine and Division of Advanced Prosthodontics, University of California, Los Angeles
(UCLA) School of Dentistry, Los Angeles, CA 90095, USA. 4The Jane and Jerry Weintraub
Center for Reconstructive Biotechnology, UCLA, Los Angeles, CA 90095, USA. 5California
NanoSystems Institute, UCLA, Los Angeles, CA 90095, USA. 6Jonsson Comprehensive Cancer
Center, UCLA, Los Angeles, CA 90095, USA. 7Department of Bioengineering, The Henry
Samueli School of Engineering and Applied Science, UCLA, Los Angeles, CA 90095, USA.
*Corresponding author. E-mail: csikce@nus.edu.sg (E.K.-H.C.); dean.ho@ucla.edu (D.H.)
tions, allowing for efficient penetration and retention (EPR) for improved
localization (Fig. 1). Versatile surface chemistry and surface area–to–
volume ratios of nanoparticles mediate potent drug binding or high
drug-loading capacities to improve retention, efficacy, and safety. The
ability to cofunctionalize nanoparticles with targeting moieties, im-
aging agents, and drug payloads enables the synthesis of multimodal
complexes that may simultaneously provide patients with improved
treatment specificity and highly sensitive imaging capabilities to mon-
itor treatment progress and outcomes. Highlighting these attributes,
and discussing remaining challenges, which, when addressed, may lead
to the fruition of these approaches in the clinic, serves as the foundation
for a focused look at how nanotechnology can uniquely affect cancer.
Currently, most nanomedicine studies focus on a single drug to treat
cancer, lower toxicity, etc., which can benefit the patient to an extent.
Nanomedicine, however, will have the greatest impact when admin-
istered in combination with traditional clinical therapies, like radiation,
cell therapy, and small-molecule and biological drugs. Current combi-
nation therapy using unmodified drug compounds is often based on ex-
isting additive guidelines for single therapy treatment, which precludes
optimization of combinatorial therapy treatment for maximal efficacy
and safety. For example, docetaxel in combination with doxorubicin,
followed by cyclophosphamide-methotrexate-fluorouracil (CMF) ther-
apy, has been compared to other variations to this combination for
operable breast cancer treatment (NCT00174655). With regard to the
potential of nanomedicine and combination therapy, a recent study in
animals suggests that timed combination therapy—where an siRNA
and a drug are released sequentially from liposomal nanoparticles—
might even be the key to overcoming chemoresistance (38).
This review will examine cancer nanomedicine progress toward the
clinic with the theme of application-dependent selection of nanoparticle
agents. One important way to rationally select nano platforms is struc-
ture. For example, cyclodextrins can greatly improve nucleic acid stabil-
ity to improve transfection efficacy. Gold nanoparticles are particularly
effective at crossing the blood-brain barrier (BBB), which can open new
avenues for glioblastoma treatment. Photoactive nanoparticles can
modulate changes in their own temperature for spatially controlled
therapy. Furthermore, faceted properties of materials such as NDs
can mediate marked enhancements in MR imaging (MRI) contrast.
This review will also examine how algorithm-defined strategies can
simultaneously optimize for efficacy, safety, and pharmacokinetics
(PK), among other parameters. Ultimately, the rationally designed therapy

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Leaky vasculature
Tumor
Drug-loaded NP
Normal
epithelia
Lymphatic
drainage
Fig. 1. Passive versus targeted nanomedicine delivery and reten-
tion. Nanoparticles larger than 8 nm in size can passively target tumors
through preferential passage through larger interendothelial junctions (40 nm
to 1 µm) compared to those of healthy tissue (≤8 nm). Large junctions are a key
characteristic of the irregular tumor vasculature. Nanoparticles can also be
conjugated with targeting agents, such as antibodies specific to proteins more
or imaging method could save time and energy in making sure nano-
CREDIT: C. BICKEL/SCIENCE TRANSLATIONAL MEDICINE
medicine will translate to those who need it most: the patients.
CONQUERING CANCER
The use of nanomaterials to treat and image cancer is arguably the
most active area of nanomedicine research. Intrinsic properties like
surface charge, structure, and biocompatibility can be harnessed for
cancer therapy. Size, which can be controlled during synthesis, has been
shown to play a major role in nanomedicine efficacy. In particular,
extensive work with liposomal and polymer drug delivery vehicles
has revealed that complexes greater than 8 nm in diameter preferen-
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Tumor- or vasculature-targeting
Tumor
Tumor
Tumor-targeting NP
Impaired lymphatic drainage
highly expressed in tumors than healthy tissue, to actively target tumors. These
proteins include epidermal growth factor receptor (EGFR/Her1), human epider-
mal growth factor receptor 2 (Her2), folate receptor, endoglin (CD105), prostate-
specific membrane antigen (PSMA), epithelial cell adhesion molecule (EpCAM),
CD20, CD44, CD90, and CD133. Once nanoparticles enter tumors, defective lym-
phatic drainage of nanoparticles results in enhanced retention.
tially home to tumor tissue versus healthy tissue (Fig. 1) (1). This is due
to tumor interendothelial junctions ranging from 40 to 80 nm, on av-
erage, and as large as 1 mm, whereas interendothelial junctions of
healthy tissues are ≤8 nm wide (41). This preferential uptake combines
with defective lymphatic drainage of nanoparticle complexes to pro-
mote EPR in tumor tissue (Fig. 1) (1). With this particular approach,
efficient intratumoral localization of nanoparticles, and resulting im-
provements in treatment specificity, can be mediated without function-
alizing the vehicle with a targeting moiety. However, harnessing the EPR
effect in drug development may be dependent on characteristics that in-
fluence tumor vasculature such as tumor type, size, and organ location
(42). Therefore, EPR-mediated drug delivery may likely be indication-
dependent or reliant on combination therapy.
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Although EPR mediates enhanced delivery of larger nano-drug com-
plexes to tumors compared with free small-molecule drugs, increased
size can adversely affect nano-drug circulation half-life. Larger particles
are more easily recognized and cleared by the liver and phagocytic cells
of the reticuloendothelial system (43). Rapid clearance can be partially
alleviated by adding polymer coatings, like poly(ethylene glycol) (PEG).
PEGylated liposomes 200 nm in diameter, however, are still cleared
faster than 100-nm PEGylated liposomes (44). When these studies are
taken together, optimal drug delivery complex size for cancer therapy
likely ranges from 8 to 100 nm, when relying on the EPR effect. These size
requirements are likely to extend from conventional liposomal and poly-
meric complexes to other nanomedicine platforms, such as metal- or
carbon-based ones (45, 46). Targeted drug delivery complexes likely
have a wider range of optimal size. Further studies, however, are needed
to determine how large these complexes can be and still maintain ac-
ceptable body retention rates.
CREDIT: C. BICKEL/SCIENCE TRANSLATIONAL MEDICINE
Fig. 2. Designer nanomedicine. Nanomedicine platforms can take on any number of properties to tailor therapy or imaging, and improve chances of
translation.
www.ScienceTranslationalMedicine.org
Passive tumor targeting by nanoparticles has proven successful in
humans, with liposomal doxorubicin (Doxil) already being clinically
used for breast cancer (47). Yet, there are other exciting developments
in the field of cancer nanomedicine that capitalize on the unique and
intrinsic properties of certain materials for targeted delivery of thera-
peutics (Fig. 2), including those that are difficult to solubilize, chal-
lenging to deliver, or unstable (that is, easily degraded) in vivo (48–52).
Although the field is vast, some promising examples for translation are
described herein.
Aiming at a target
Drug-loaded nanoparticles can be targeted to surface molecules over-
expressed in cancer cells or tumor vasculature. By adding a targeting com-
ponent, nanoparticles can further improve their efficacy of tumor-specific
drug delivery beyond EPR-mediated tumor homing (Fig. 1). Recently, a
poly(lactic-co-glycolic acid) (PLGA)/PEG–based nanoparticle, named
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BIND-014, was designed to target prostate cancer. The polymeric par-
ticle, with a PSMA-targeting moiety on the surface and a docetaxel
payload, has been tested in preclinical studies and in humans in early-
phase clinical trials for metastatic lung cancer and tonsillar cancer (53).
The first studies showed the importance of targeted drug delivery and
prolonged circulation toward improved therapeutic efficacy and safety
via an optimized multimodal polymer nanoparticle where BIND-014
effective concentrations were only 20% of those needed with free
docetaxel, which is an important consideration for reducing toxicity
of chemotherapeutics. BIND-014 administration to prostate, breast,
and lung xenografted tumors that normally (in humans) show little to
no response to unmodified docetaxel treatment resulted in a significant
therapeutic effect in animals (53). To date, clinical trials pertaining to
examining the efficacy of BIND-014-001 in advanced and metastatic
cancers are active (NCT01300533), and another clinical trial pertaining
to the application of BIND-014-005 has been approved for non–small
cell lung cancer (NCT01792479).
Transferrin receptor targeting using nanoparticles has also been
explored clinically in pancreatic cancer, which overexpresses the trans-
ferrin receptor in as much as 93% of the tumor cells, whereas normal
tissue did not stain positively for the transferrin receptor (54). This in-
cludes recent developments in the clinical evaluation of transferrin
receptor–targeted liposomal gene therapy that may improve standard
drug efficacy through restoration of tumor suppressor genes such as
p53 (NCT00470613) and Rb94 (NCT01517464) (Table 1). This was
particularly well demonstrated with SGT-53 (SynerGene Therapeutics
Inc.), a transferrin receptor–targeting liposomal nanoparticle that delivers
p53-containing plasmids to tumors that overexpress the transferrin re-
ceptor. Preclinical data demonstrated enhanced gene therapy to murine
metastatic pancreatic tumors, improving gemcitabine response (55).
Clinical trials demonstrated that single-agent SGT-53 delivery is well toler-
ated and the p53 transgene can be seen specifically in metastatic tumor spec-
imens and not in normal tissue. The trials have since been modified to
include combinatorial therapy with docetaxel, as originally intended (56).
In addition to targeting cancer cells, targeting the tumor vasculature
has also demonstrated to be a viable method for targeted drug delivery
(Fig. 2 and Table 1). This is best exemplified by RGD-containing pep-
tides that target av integrins overexpressed in tumor vasculature (57).
Conjugation and coadministration of nanoparticles with internalizing
RGD (iRGD), a peptide that combines RGD with a tumor-penetrating
CendR motif, exhibited enhanced tumor targeting, penetration, and
efficacy compared to nontargeted nanoparticles (58, 59). Clinical trials
are currently under way to evaluate the effect of iRGD on tumor vascu-
lature and should pave the way to translation of iRGD-targeted delivery
of drugs and nanoparticles (NCT01741597).
Capitalizing on carbon
Carbon nanomaterials, including nanotubes, nanohorns, fullerenols,
graphene, and NDs, have been the subject of several promising preclinical
studies owing to their versatile surface properties. Carbon materials can
deliver a wide spectrum of therapeutic compounds, often with little to no
modification to the drug or nanomaterial, owing to the ability to me-
diate p-p stacking with nanocarbon surfaces for noncovalent delivery
(21, 24, 26, 27, 60–63). A major concern surrounding these materials is their
safety because of potential cardiopulmonary toxicity. However, multiple
reports show no apparent toxicity after nanocarbon administration
in mouse models (24, 26, 45, 60, 62). Carbon nanomaterials have yet
to be tested in humans, as continued safety assessments are ongoing
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prior to U.S. Food and Drug Administration (FDA) approval for clin-
ical studies.
A major hurdle of cancer therapy is intrinsic or acquired chemo-
resistance, which contributes to treatment failure in more than 90% of
metastatic cancers (64). A common mechanism of chemoresistance is
the overexpression of adenosine triphosphate–binding cassette (ABC)
transporter proteins that can efflux a wide range of small molecules, includ-
ing chemotherapeutics (65). Conventional methods of overcoming ABC
transporter protein chemoresistance have involved the development of in-
hibitors of these proteins. Clinical trials for such drugs have met little suc-
cess as potent inhibitors of multiple transporter proteins and have been
associated with trial-ending toxic side effects (66). More specific inhibi-
tors struggle to find a balance between efficacy and tolerability (67).
Moreover, administering a single inhibitor is unlikely to succeed because
chemoresistant tumors often express different ABC transporter proteins.
Delivery of anthracyclines—a class of DNA-damaging chemotherapeutics—
by NDs has been shown to overcome ABC transporter drug efflux without
targeting the transporter itself or another overexpressed cancer protein
(26, 68). In mouse models of anthracycline-resistant cancer, delivery of the
anthracycline doxorubicin by NDs (Fig. 2) resulted in increased tumor-
killing efficacy as well as lower systemic toxicity, including less myelo-
suppression, compared with free doxorubicin (26). The combination of
safety and efficacy observed with the ND-doxorubicin agents was mediated
by potent drug binding, without the need for chemical modification of the
drug or the ND surface. A targeting moiety was also not present, suggest-
ing that the efficacy of NDs was likely related to EPR.
Although anthracycline delivery by NDs improved therapeutic efficacy
compared to traditional chemotherapy—at least in mouse models—even
more impressive therapeutic gains can be achieved using a targeting com-
ponent. Hybrid drug delivery complexes containing epirubicin (a chemo-
therapeutic) and an EGFR antibody (Fig. 2) were delivered to mice bearing
triple-negative breast cancer (TNBC) human breast cancer (MDA-MB-231)
xenografts (Table 1) (45). Drug-loaded EGFR-targeted complexes main-
tained the enhanced safety profile of their untargeted counterparts while
increasing homing to EGFR-positive mammary tumors. This resulted in
increased tumor response and, in some cases, complete regression of these
highly aggressive tumors.
These studies demonstrate a clear clinical potential for untargeted and
targeted carbon nanomedicine. However, judging by the lack of nano-
carbon clinical trials being conducted, continued toxicity and clearance as-
sessment in rodent and large animal models remains a critical precursor to
translation.
Silencing genes
One area where the intrinsic properties of nanoparticles can improve
drug delivery is RNA interference (RNAi). RNAi is a promising method
for silencing cancer-causing genes, but is hampered by enzymatic deg-
radation of small RNAs in vivo. As the most clinically developed example,
cyclodextrin-based polymers (CDPs) are well tolerated and can self-
assemble to protect and deliver siRNA to cancer cells (Fig. 2) (69–71).
Following successful preclinical studies, these CDPs were used in the
first siRNA-based cancer therapy clinical trial targeting patients with
recurrent or metastatic solid malignancies (NCT00689065) (69, 71).
Calando Pharmaceuticals developed CALAA-01, a CDP-siRNA com-
plex functionalized with a transferrin-targeting ligand for the treatment
of metastatic melanoma, PEG to promote stability and biocompatibility
in vivo, and an siRNA to silence the gene RRM2 (ribonucleotide reductase
M2 subunit) (Table 1). A striking element of this approach is the ability
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Table 1. Example nanoparticle applications in cancer drug delivery. Table is organized by stage of translation.

Agent delivered Material(s) Translational status Key details of study References

Doxorubicin Pluronic block Phase 2 P-glycoprotein–targeted chemotherapeutic delivery used against (48, 49)
copolymers clinical trials human gastroesophageal adenocarcinoma
Acceptable safety profile and enhanced efficacy compared to
free doxorubicin in phase 2 clinical trials (SP1049C-202-UK)
Docetaxel PEG-PLGA Phase 1 PSMA-targeted small-molecule–treated mouse xenografts (53)
clinical trials of human prostate tumors
Ongoing clinical trials demonstrate favorable PK and initial efficacy
in human lung and tonsillar cancers (NCT01300533, NCT01792479)
p53 or Rb94 plasmid Lipid Phase 1 Transferrin receptor–targeted liposomes enhanced delivery and (55, 56)
clinical trials transgene expression in metastatic tumors in mouse metastatic
pancreatic cancer
Ongoing clinical trials in patients with advanced solid tumors
demonstrate favorable dose response and successful overexpression
of transgene in tumors compared to normal tissue (NCT00470613,
NCT01517464)
Paclitaxel Albumin Phase 1 Tumor vasculature–targeting and tumor-penetrating iRGD-coated Abraxane (59)
clinical trials (nanoparticle albumin–bound paclitaxel) exhibited enhanced tumor
uptake and tumor growth inhibition of mouse xenografts of human
breast cancer compared to Abraxane treatment
Ongoing clinical trials are investigating the ability of iRGD to
modify human metastatic breast cancer permeability as
measured by MRI (NCT01741597)
RRM2 siRNA Cyclodextrin-containing Phase 1 Transferrin-mediated tumor targeting allowed knockdown of (69–71)
polymers clinical trial RRM2, which inhibited growth of syngeneic graft murine
neuroblastoma tumors
Phase 1 clinical trials in humans are ongoing as of 2008 and
show evidence of RRM2 knockdown in metastatic human
melanoma tumors (NCT00689065)
Cisplatin Carbon Preclinical Drug-loaded carbon nanohorns enhanced efficacy in human (21)
lung cancer mouse xenograft tumors in vivo compared to
unmodified cisplatin
Paclitaxel Carbon Preclinical Drug-loaded single-walled carbon nanotubes enhanced circulation (24)
half-life, tumor killing, and overall survival in 4T1 murine breast
cancer model compared to unmodified paclitaxel
Doxorubicin Carbon Preclinical Drug-loaded NDs enhanced blood circulation, tumor killing, and (26)
animal survival in chemoresistant mouse breast and liver
tumors compared to unmodified doxorubicin
Epirubicin Carbon, lipid Preclinical EGFR-targeted, drug-loaded ND-lipid hybrid particle enhanced (45)
tumor homing and tumor regression in a mouse model of
human TNBC compared to free drug
ID4 siRNA Peptides Preclinical Tumor-penetrating peptide nanocomplexes loaded with (51)
siRNA-treated human ovarian tumors in mice
Proprietary siRNA Carbon Preclinical Multiwalled carbon nanotubes loaded with siRNA inhibited tumor growth (62)
and prolonged overall survival in human lung cancer xenografted mice
compared to siRNA alone or liposomal delivery of siRNA
Melittin peptide Carbon Preclinical Drug-loaded perfluorocarbon nanoparticles improved circulation (63)
and therapeutic efficacy against human breast cancer mouse
xenograft tumors and syngeneic graft mouse melanoma tumors
compared to free drug
Bcl2L12 siRNA Gold Preclinical Gold-based spherical nucleic acid (SNA) delivery crossed BBB and (73)
accumulated in human glioma tumors in mice to silence target
gene and reduce tumor burden

for self-assembly of the nanoparticles through the interaction of the pos- siRNA complex included stabilizing RNA therapeutics, manufacturing
itively charged cyclodextrin chains around the negatively charged siRNA scale-up [for example, chemistry, manufacturing, and controls (CMC)
to improve nucleic acid stability. The process of translating the CDP- compliance], and ensuring delivery specificity to melanoma solid tumors.

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Although the clinical trials are still ongoing, there is evidence of siRNA
activity in tumor biopsies from treated patients (69).
In addition to CDP-based siRNA delivery, a previous clinical study
used liposomal bcr-abl siRNA for imatinib-resistant chronic myeloid
leukemia (CML) treatment that resulted in reduced bcr-abl gene expres-
sion in peripheral blood samples and reduced extramedullar CML node
size (72). However, transfection efficiency decreased by the third round
of administration, in turn reducing the ability to affect bcr-abl mRNA
levels. A stable and rationally designed delivery system could perhaps
resist serum ribonuclease activity that limits transfection efficiency. To
improve delivery and increase the circulatory half-life of siRNA, lipid-
based carriers with tumor-targeting and tumor-penetrating moieties
have been developed (51) (Table 1). These “siRNA nanocomplexes” were
designed to display a cyclic nonapeptide on its surface, LyP-1. LyP-1 tar-
gets p32—a mitochondrial protein overexpressed on stressed tumor
and tumor-associated cells—and is also able to penetrate cells after being
proteolytically processed by endogenous proteases. This ensured that
the particle was more toxic to tumors than to healthy tissue, because
the payload was only released once inside the cancer cell. The nano-
complexes were loaded with siRNA against the oncogene inhibitor of
DNA binding 4 (ID4) and tested in mouse models of human ovarian
cancer. Tumor-penetrating nanoparticles functionalized with ID4-
silencing siRNA suppressed tumor growth by 82%, whereas control
injections (saline and untargeted control nanoparticles) did not sup-
press tumor growth.
As another example of how nanoparticles deliver siRNA—except
with the nucleic acids displayed on the outside rather than encapsulated—
Jensen et al. created gold nanoparticle–based SNAs (73). These SNAs
were recently used for RNAi against the Bcl2L12 oncogene in a mouse
glioblastoma model. SNAs exhibited no apparent toxicity, and owing
to their resistance to nuclease-triggered degradation, they mediated sta-
ble and persistent gene transfection without the need for polycationic
polymers. SNAs exhibited substantial accumulation in the brain tissue
of healthy mice with an intact BBB after systemic injection, providing
a strong basis for applications in brain cancer therapy, given the fact
that the presence of the BBB has blocked many candidate therapies
(Fig. 2).
Pulling the trigger
Photothermal therapy involves the use of heat to kill cancer cells, which has
gained interest because the inducible and noninvasive nature of this trig-
gered therapy can be applied to a wide range of solid tumors (Table 2). A
novel class of materials based on a gold nanoshell encapsulating a silica
core (Fig. 2) has been shown to be effective in near-infrared laser-induced
cancer therapy in multiple cancer models, including lung, head and
neck, prostate, and gliomas (46, 74–76). Unique properties that make
these nanoshells clinically promising include biocompatibility of the par-
ticles as well as the tunability of the surface plasmon resonance of the
gold metal shell based on the modulation of the ratio of the dielectric
core radius to shell thickness. This architecture allows for highly effi-
cient and localized conversion of light to heat. These two properties
are critical to developing a safe product that can be used for heat therapy
in a targeted area (as wide as 2 mm) with minimal laser power require-
ments (10 to 100 mJ/cm2) (77, 78). In a recent mouse study, these gold-
coated silica particles were labeled with VEGF to target the blood vessels
of intracerebral tumors (35). Following administration and photo-
thermal ablation, the vasculature of diseased tissue was ruptured,
whereas healthy tissue was not damaged. This nanoshell technology has
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been commercialized by Nanospectra Biosciences as AuroLase, with clin-
ical trials in head and neck cancer (NCT00848042) and primary and meta-
static lung tumors (NCT01679470) already under way.
In addition to photothermal therapy, several other triggered modal-
ities based on radio- or magneto-stimulus are being explored, including
magnetic and radio-based methods for enhancing drug delivery and ef-
ficacy (Table 2) (79, 80). These methods may be more easily translated
because MRI and radiotherapy are already commonly used in cancer
treatment. Radiotherapy is a standard method of tumor treatment that
relies on greater absorption of x-rays in tumor tissue compared to nearby
normal tissue. Radio-induced nanomedicine, specifically using hafnium
oxide nanoparticles, has demonstrated enhanced energy deposit in
nanoparticle-containing subcellular structures of cells, which results in
enhanced energy release and subsequent localized cellular destruction
from nanoparticle clusters. Multiple xenograft tumor models demon-
strated greater sensitivity to ionizing radiation treatment when pretreated
with hafnium oxide nanoparticles compared to radiation treatment alone.
This approach is currently being evaluated clinically in patients with soft
tissue sarcoma of the extremity or advanced squamous cell carcinoma
of the oral cavity (NCT01946867 and NCT01433068) (80).
Immune system plays defense
Immunotherapy involves the activation or suppression of immune re-
sponses for disease treatment. In essence, immunotherapy capitalizes
on our natural defense system to prevent the growth (or occurrence) of
cancer. Emerging immunotherapeutic strategies for cancer involve the de-
livery of agents, such as tumor-specific antigens (Fig. 2), that can prime or
stimulate one’s own immune system to actively seek out and destroy cancer
cells that have these antigens (Table 2). As a new area of research, nano-
particles may be used to modulate the immune response to tumors (81).
Nanotechnology has made the passive and targeted delivery of antigens
and adjuvants possible. In addition, nanomaterials have helped overcome
biological barriers that have stunted the development of more conventional
approaches to adjuvant delivery such as oral delivery. This is particularly
evident when delivering adjuvants and antigens orally through enhanced
uptake by mucosal immune cells, as well as delivering easily degradable
adjuvants, such as RNA (82, 83). Because of the preclinical successes of
nano-based immunotherapy, several clinical trials (NCT00291473 and
NCT00651703) are currently underway to translate these approaches to a
variety of human diseases ranging from cancer to allergies (84, 85) (Table 2).
Nanoparticles have been recently used in cancer immunotherapy
vaccines because they can co-deliver multiple agents, such as an antigen
and adjuvant, in a single, biocompatible platform with enhanced uptake
and efficiency compared to conventional treatment [for example, standard
vaccines and dendritic cell (DC) therapy]. Cancer vaccines impair cancer
progression or prevent occurrence by delivering specific tumor antigens
that induce the generation of antigen-specific cytotoxic T lymphocytes
(CTLs). Strong CTL response often requires the coadministration of
adjuvants. Nanoparticles are well suited for this application because they
can ensure delivery of both an adjuvant and an antigen to the same im-
mune cell, whereas standard vaccine formulations are more inefficient and
require concentration-dependent levels of both adjuvant and antigen to
achieve similar effects. One of the first nanoparticle cancer vaccine de-
livery vehicles was based on a truncated Her2 protein complexed with
hydrophobic polysaccharides into nanoparticles that enhanced the
uptake of Her2. Delivery of both an antigen and an adjuvant in a single
nanoparticle in mice resulted in the stronger production of anti-Her2
antibodies compared to vaccination with Her2 protein alone as well as
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Table 2. Example nanoparticle applications in cancer therapy. Table is organized by stage of translation.

Type of therapy Material(s) Translational status Key details of study References

Immunotherapy, vaccine
Photothermal
Radiotherapy
Immunotherapy, vaccine
Immunotherapy, vaccine
Magneto-responsive
Immunotherapy, vaccine
Immunotherapy, RNA adjuvant
Protein Phase 2 clinical trial Viral-like protein shell delivery of CpG-rich oligodeoxynucleotide (85)
(CpG-ODN) and melanocyte differentiation antigen resulted
in enhanced CD8+ T cell response in melanoma patients
compared to antigen alone (NCT00651703)
Silica, gold Phase 1 clinical trials Vascular endothelial growth factor (VEGF)–targeted nanoshells (35)
for thermal ablation and vessel disruption in mouse
glioma model
Currently in clinical trials for head and neck cancer
(NCT00848042) and primary and/or metastatic lung
tumors (NCT01679470)
Hafnium oxide Phase 1 clinical trials Nanoparticles for radio-induced tumor cell killing in (80)
crystals mesenchymal and epithelial tumor xenograft
mouse models
Phase 1 clinical trials are ongoing as of 2011
(NCT01946867, NCT01433068)
Polysaccharide Phase 1 clinical trial Her2 antigen cholesteryl mannan and cholesteryl pullulan (84, 86–88)
nanoparticle vaccines previously tested in Her2-expressing
murine sarcomas
Currently being evaluated in patients with advanced cancer
with Her2-expressing tumor cells (NCT00291473)
PLG Phase 1 clinical trial PLG matrices that co-deliver granulocyte-macrophage (90)
colony-stimulating factor (GM-CSF), CpG-ODN, and tumor
lysate antigen for recruitment of DCs to PLG matrices,
potent local and systemic antitumor CD8+ T cell response
in mouse melanoma model
Starting phase 1 study of implantable vaccine to treat
melanoma (NCT01753089)
Iron/cobalt, PLGA Preclinical Magnetically guided polymer carriers loaded with Fe-Co (79)
nanoparticle and doxorubicin for drug-nanoparticle
deposition in right or left liver lobe of rabbits
PEG-PLGA Preclinical Ovalbumin-loaded PEG-PLGA nanoparticles displaying (82)
RGD peptide for targeted M cell uptake and vaccination
in mice
Lipid Preclinical Lipidoid delivery of immunostimulatory RNA for antiviral (83)
and adjuvant activity in vivo in mice

CTL-mediated repression of Her2-expressing murine tumors in vivo
(86). This work is currently in clinical trials (NCT00291473) where it
has been relatively well tolerated and elicits similar immune responses
in humans (84, 87). Immune response was seen in 93% of patients, which is
compelling when compared to clinical trials with E75, an immunogenic
peptide from Her2/neu protein, that saw postvaccine delayed-type hyper-
sensitivity response in 74% of treated patients (88).
Antigen-presenting cells (APCs) are required for CTL response to
an antigen. DCs have been identified as the most potent APCs and have
subsequently been used for vaccines. Conventional DC-based vaccines
involve the isolation and expansion of antigen-exposed DCs in vitro,
followed by reintroduction of activated DCs into cancer patients. Al-
though DC vaccines are a promising strategy that has seen some success
in clinical trials, this procedure remains costly and inefficient. Several
studies suggest that, owing to their versatile surface chemistry and func-
tionalization, nanoparticles can be used as modular platforms to ef-
ficiently deliver antigens and prime DCs for an anticancer immune
response (89, 90). These studies often incorporate antigen exposure
with DC chemoattractants and DC activators, such as Toll-like receptor
(TLR) ligands. For instance, polylactide-co-glycolide (PLG) was used to
form matrices that expressed the TLR9 ligand CpG-ODN and also re-
leased the cytokine GM-CSF as well as melanoma tumor antigens (90).
This work demonstrated that GM-CSF was capable of recruiting DCs to
the PLG matrices in vivo in mice, whereas CpG-ODN activated the re-
cruited DCs. Exposure of these activated DCs to melanoma tumor anti-
gens by PLG matrices resulted in a potent CD8+ CTL response and an
enhanced impairment of melanoma tumor progression. Translation of
this work into the clinic should lead to a cheaper and faster DC-based
vaccine approach compared to current methods that require the re-
moval, ex vivo activation, and reimplantation of a patient’s DCs. Indeed,
phase 1 trials are underway (NCT01753089).
NANO GETS A BETTER VIEW
Many of the advantages that are offered by nanotechnology for drug
delivery, such as improved circulation half-life, EPR, and reducing tox-
icity, are also beneficial to imaging. However, for nanomedicine to

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REVIEW
benefit the imaging community in a translational setting, it is important
that properties unique to the nano-imaging agents be harnessed. Con-
ventional approaches to making nano-imaging agents include high-
density encapsulation of contrast agents such as gadolinium (Gd) or
manganese oxide into liposomes and PLGA, or loading the contrast
agents onto the surface of nanoparticles, such as carbon nanotubes,
gold, or NDs. These strategies can improve circulation time and mediate
tumor localization through EPR, thus improving imaging capabilities
(Table 3). Perhaps one of the most promising nano-imaging approaches
is the use of superparamagnetic iron oxide nanoparticles, which are
currently in clinical trials for lymph node imaging and pancreatic can-
cer staging (NCT00920023) (91). Iron oxide nanoparticles are para-
magnetic, which can be imaged after the application of an external
magnetic field. Coating iron oxide nanoparticles with lipid-like mate-
rials has resulted in improved control of particle size, dispersal, and, im-
portantly, biocompatibility (92). Iron oxide degradation in vivo is
also possible, which provides clear pathways for clearance after ad-
ministration (93).
Although established imaging platforms, such as iron oxide, have
transitioned into clinical studies, emerging approaches using novel ma-
terials that can uniquely enhance imaging safety and efficacy are being
developed. With regard to cancer nanomedicine (94, 95), nano-enhanced
imaging can be used to track therapy or diagnose disease. In particular,
nanoparticles have been designed to enhance contrast agent efficiency
(96). Some nanoparticles, such as self-assembling protein cages, can
be used to increase packaging of paramagnetic ions (97). Such systems
have demonstrated enhanced localized relaxivity over free paramagnetic
ions. ND-based MRI is a revolutionary approach to MRI because the
ND surface mediates a per-Gd relaxivity (contrast efficiency) increase of
Table 3. Example nanoparticle applications in cancer imaging. Table is organized by translational status.
Imaging method Material Translational status
MR Iron oxide, dextran Phase 4 clinical trial
Fluorescence Quantum dots (Qdots) Clinical samples
Fluorescence Polystyrene Preclinical
Fluorescence Gelatin, PEG, Qdots Preclinical
Fluorescence Gold, PEG Preclinical
MR, photoacoustic, Raman Gold, silica Preclinical
MR Lipid Preclinical
www.ScienceTranslationalMedicine.org
12-fold (36). This is among the highest reported per-Gd relaxivity values
owing to the faceted ND surface, which potently attracts water. The abil-
ity of the NDs to facilitate water molecule interaction with Gd enables
higher MR signal, and in turn, a lower Gd concentration is needed to
achieve the clinically required brightness and contrast. Clinically
speaking, one order of magnitude reduction in the amount of Gd
needed would represent a game-changing advance in medicine because
this would allow for simultaneous high-contrast imaging while also
markedly reducing the amount of contrast agent needed to achieve this.
Furthermore, this may increase the population of Gd-amenable patients
who were previously precluded from Gd-based MRI because of renal
toxicity. In addition to ND-Gd, gadofullerenes, gadonanotubes, and
silica-based imaging agents have demonstrated per-Gd relaxivity increases
over the delivery of Gd alone (98, 99).
MRI is a standard of care for preoperative diagnostic imaging of
tumors, yet intraoperative MRI has proven to be difficult and not very
accurate. Kircher et al. developed a trimodal MRI-photoacoustic-
Raman (MPR) nanoparticle imaging complex. This multimodal particle
used both photoacoustic and Raman imaging for imaging during tumor
resection combined with accurate MRI preoperative evaluation of
tumors (100). MPRs accumulated preferentially in tumors via EPR and
successfully delineated brain tumor margins preoperatively and intra-
operatively with a single injection in a human glioblastoma mouse model.
A particularly promising approach being developed for MRI is
CEST, which uses polypeptides as biocompatible and biodegradable
MRI agents. Amide, amine, and hydroxyl protons and their unique
exchange rates can be assigned specific colors to produce multicolor
MR probes (101, 102). Recent studies have also demonstrated the ap-
plicability of CEST compounds as pH sensors to monitor cell transplan-
Key details of study References
Iron oxide (superparamagnetic) core within densely (91)
packed dextran nanoparticle allows for imaging of
lymph nodes in a clinical trial (NCT00920023)
Qdot conjugated to different antibodies allowed for (95)
multiplexed molecular mapping of benign and
metastatic prostate tumor cells in human prostatectomy
or needle biopsy prostate cancer specimens
CD47 or “self”-peptide conjugation impaired macrophage (52)
clearance of nanobeads, thus enhancing tumor
near-infrared imaging compared to nontargeted
nanobeads in mice with human lung cancer
xenografts
Gelatin core conjugated to PEG-Qdots increased blood (94)
circulation half-life and deeper tumor penetration
in vivo in human fibrosarcoma mouse xenograft
tumor models compared to silica Qdots
In vivo assembly of molecular contrast agent and gold (96)
nanoparticle for near-infrared imaging of human
breast cancer mouse xenografts in vivo
Gold core–silica shell nanoparticle for trimodal imaging (100)
before, during, and after surgery after single intravenous
injection into human glioblastoma xenografts in mice
Diamagnetic chemical exchange saturation transfer (102)
(CEST) liposomes for “multicolor” imaging of lymph
nodes in mice
18 December 2013 Vol 5 Issue 216 216rv4 8
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tation and viability (103). Here, mouse hepatocytes and liposomes
loaded with L-arginine, a pH-sensitive CEST agent, were injected into
mice. Reductions in pH after cell death resulted in decreased MR signal
from the L-arginine–loaded liposomes, which served as a modality to
monitor murine hepatocyte viability after transplantation. Additional
studies demonstrated the use of CEST functional liposomes that carry
color signatures unique to the polypeptides being carried, which result
in spatially defined, multicolor imaging of popliteal lymph nodes (102).
These studies exemplify how well-designed nanoparticle systems can
address clinical problems that more conventional approaches are unable
to achieve.
THE RIGHT COMBINATION
Safety is of paramount importance in any drug’s translational roadmap.
Although the highlighted approaches in this Review have demonstrated
remarkable potential toward clinical translation, continued clinical trials
of promising platforms and development of pathways toward approval
of nanomaterials will continue to shape the landscape of how nano-
medicine can affect clinical practice. The cancer applications described
here, where nanomedicine is poised to improve the safety and efficacy
of treatment in a clinical setting—and is already doing so in clinical
trials—are by no means exhaustive, because enhanced drug delivery
and imaging can also benefit the fields of ophthalmology, regenerative
medicine, neurodegenerative diseases, sexually transmitted diseases,
infectious diseases, and global health.
The issue that follows now is the evaluation of the role nanomedicine
will play, if any, in truly transforming the way that medicine is practiced.
Nanoparticles can affect a wide range of diseases by improving efficacy
and safety, prolonging circulation time, and enhancing delivery speci-
ficity. For cancer, whether or not a single drug can truly lead to sustained
remission is a major question moving forward in nanomedicine design.
The concept of combinatorial treatment is gaining traction as a required
method of treatment, particularly in the field of cancer therapy (Fig. 2).
Furthermore, as cancer therapy begins to marry diagnostics and thera-
peutics into a more personalized approach, optimal combinatorial ther-
apy will likely differ for subsets of patients within a single type of cancer.
With regard to clinical evaluation of the best methods of combina-
torial treatment, these studies are often based on the therapeutic guidance
and additive combination of singular treatment with these drugs, re-
sulting in only marginal improvements to efficacy and safety. As med-
ical research begins to become more multidisciplinary, emerging methods,
such as feedback system control (FSC) and combinatorial drug design
(CDD), can be used to bring engineering approaches to rational CDD
and optimization using nanomedicine. Real-time drug monitoring and
personalized PK will enable more tailored nano-based therapies (104).
In addition, emerging strategies including live cell interferometry can
quantify changes in cellular mass and resulting fitness from populations
of cells in response to drug dosing. This information can serve as a vital
readout to monitor tissue response to combinatorial nanomedicine (105).
One of the emerging methods that may transform the way that
nanotherapy is administered and remove its barriers to acceptance is
the concept of FSC, a top-down approach that directs a cell or popula-
tion of cells toward a desired phenotype through control strategies that
were conventionally reserved for nonbiological scenarios (106, 107).
When drug compounds with arbitrarily decided concentrations are
applied to cells, their signaling pathways respond unpredictably. If a
www.ScienceTranslationalMedicine.org
specific outcome is not met (for example, optimal apoptosis and op-
timal safety), FSC is a broad approach that draws from a set of math-
ematical search algorithms. These include Differential Evolution and
the Gur Game, which select the next group of iterative drug adminis-
tration conditions to rapidly achieve desired phenotypes, even among
a prohibitively large testing parameter space. Although six drugs with
10 selected concentrations would each require 1,000,000 potential trials,
FSC “self-guides” a cellular population toward desired phenotypic out-
comes that rapidly converge with only tens of iterations. In addition,
because FSC can take PK/PD (pharmacodynamics) into account during
the search process, it is easily adaptable toward the implementation of
nanotherapeutic combinations that are comprehensively optimized for
both efficacy and safety.
In addition to FSC, additional large-scale, high-throughput methods
and databases can be unified to analyze interactions at the gene, sig-
naling pathway, and whole systems level after the coadministration of
candidate drugs. CDD assesses these interactions to converge upon a
directed dosage of multiple compounds that result in a targeted pheno-
typic outcome and simultaneously reduces off-target effects. Effective
CDD uses publicly available databases in parallel with computational/
mathematic resources to evaluate varying types of drug interactions and
test entire parameter spaces to arrive at a combinatorial dose that sat-
isfies designated criteria including optimized efficacy and safety (108).
These include DrugBank (http://drugbank.ca) and Therapeutic Targets
Database (http://bidd.nus.edu.sg/group/cjttd/), which provide informa-
tion on thousands of drug compounds and targets. The National Insti-
tutes of Health Clinical Collection (www.nihclinicalcollection.com)
provides information on more than 400 small molecules that are widely
used in clinical trials. STRING (http://string-db.org) is a database of more
than 5 million proteins that provides insight into protein-protein interac-
tions. These libraries can be paired with computational and modeling
tools such as flux balance analysis, which has been used to design drug
combinations for cancer and other disorders by accounting for both drug
activity and toxicity. Petri nets can assess drug-mediated effects upon
gene expression and subsequently use this information to formulate
synergistic approaches to enhance treatment potency.
FSC and CDD serve as optimal dosing principles that can guide the
packaging of directed drug combinations into nanomedicine delivery
vehicles to maximize their clinical efficacy. This is particularly applicable
for drugs, such as chemotherapeutics, that require improved circulatory
stability, intratumoral retention in the cases of innate and acquired
chemoresistance, and half-life. To address these challenges, promising
strategies are on the horizon. These include the aforementioned use of
layer-by-layer co-delivery of siRNA and small molecules for TNBC treat-
ment (38) to overcome chemoresistance. A recent study (109) combined
liposomal and silica nanoparticle delivery to treat pancreatic ductal
adenocarcinoma by interfering with the formation of pericytes, which
are cells that not only protect vascular endothelial cells but also typically
block nanoparticle access to the vasculature. These studies demonstrate
that combinatorial drug delivery through single or multinanoparticle
platforms serves as a feasible and promising route toward translating
rationally developed drug combinations into the clinic.
FUTURE STEPS FOR NANO
Although a nanomaterial-modified therapeutic may be a stand-alone
solution for cancer owing to improved safety and efficacy over an un-
18 December 2013 Vol 5 Issue 216 216rv4 9
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modified compound, the issue of whether or not a single nanoparticle
agent can effectively cure a patient of cancer should be raised. The need
for an effective combination of small-molecule drugs, biologics, nu-
cleic acids, and/or other compounds may be necessary to mediate
comprehensive cancer management, or potentially a cure. The diverse
properties of nanomaterials should be able to facilitate combinatorial
treatment, and optimization methods such as FSC and CDD can improve
the likelihood of such combinatorial therapies ending up in the clinic. Fur-
thermore, if nanoparticles are needed as carriers, a determination of which
nanoparticle would be best suited for each compound or imaging agent is
required. As reviewed here, nanoparticles can have varying properties, such
as aspect ratios, surface properties, and capacity for and interaction with
external and biological stimuli, that will determine the best nanoparticle
for a particular application (Fig. 2).
Bringing nanomedicine to market is a multidisciplinary effort, and
brings unique challenges and opportunities at the intersection of manu-
facturing, regulation, and funding. Regulatory bodies from all over the
world, including the FDA, Pharmaceuticals and Medical Devices Agency
of Japan, and European Medicines Agency, have been actively developing
procedures for the consideration of new drugs or imaging agents that
are delivered via nanotechnology, and the general requirements for trans-
lation into clinical studies have been established (Fig. 2) (110–112). Be-
fore the filing of an Investigative New Drug (IND) application, which is
important for both the commencement of clinical trials and any sub-
sequent product development, these requirements include compliance
with quality control guidelines [for example, good laboratory practice
(GLP) and good manufacturing practice (GMP)] to ensure material uni-
formity and reproducibility. Absorption, distribution, metabolism, and
excretion (ADME) and toxicity studies account for acute and chronic
material safety. CMC guidelines, which include analytical testing and
process controls, serve as the foundation for synthesis at the kilogram
and larger quantity scales, as well as achieving the selected formulation
required for administration (for example, intramuscular, intravenous,
and oral).
The completion of these and other requirements for FDA IND
filings and subsequent clinical trials represents an ambitious threshold.
Key barriers in completing these requirements include the significant
costs of manufacturing scale-up, completing GLP-compliant preclinical
safety, and toxicity and efficacy studies that are adequately designed so
that findings can be accepted by the FDA. Despite these important chal-
lenges that must be addressed, the cancer nanomedicine field is starting
to experience success in navigating the complex roadmap needed to
realize its impact in the clinic. As previously mentioned, funding is a
necessary part of this roadmap, and support from government agencies,
venture firms, and pharmaceutical companies has served as a catalyst
for the translation of nanomedicines described in this Review. This is
exemplified by partnerships between BIND Therapeutics [for example,
BIND-014 (53)] and AstraZeneca, Amgen, and Pfizer. With these
requirements in mind, success in achieving accelerated drug approval
through the FDA 505(b)(2) pathway remains to be seen for cancer
nanomedicines in the pipeline. The 505(b)(2) approval of Abraxane,
a paclitaxel-albumin nanoparticle for the treatment of non–small cell
lung cancer in combination with carboplatin, represents a positive step
forward for fast-track approvals of nanotherapeutics. This, coupled with
the existing approvals for imaging drugs such as iron oxide (Feridex)
and Gd-diethylenetriamine pentaacetic acid (Gd-DTPA/Magnevist),
may further support the translation of nanotechnology-modified im-
aging compounds (Table 3).
www.ScienceTranslationalMedicine.org
In summary, a clearer roadmap toward solidifying how nano-
medicine can move from enhancing treatment efficacy to eliminating
the major diseases of our generation is coming to fruition. To this end,
harnessing the highlighted unique features of nanomaterial platforms
will inspire the rational design of combinatorial nanotherapeutics,
which, combined with powerful new imaging agents, will underscore
the true catalysis of nanomedicine translation.
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Acknowledgments: We would like to acknowledge the studies that we were unable to in-
clude in this Review. Competing interests: D.H. is listed as an inventor on pending patents
pertaining to ND drug delivery and imaging.
Submitted 5 February 2013
Accepted 27 November 2013
Published 18 December 2013
10.1126/scitranslmed.3005872
Citation: E. K.-H. Chow, D. Ho, Cancer nanomedicine: From drug delivery to imaging. Sci.
Transl. Med. 5, 216rv4 (2013).
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