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ANNUAL
REVIEWS Further Nanoparticle Delivery
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1
Lineberger Comprehensive Cancer Center, University of North Carolina School of
Medicine, Chapel Hill, North Carolina 27599; 2 Carolina Center for Nanotechnology
Excellence, Chapel Hill, North Carolina, 27599; email: zawang@med.unc.edu
3
Departments of Chemistry, Chemical Engineering, and Mechanical Engineering, and
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139; email: rlanger@mit.edu
4
Massachusetts Institute of Technology–Harvard Center for Cancer Nanotechnology
Excellence, Cambridge, Massachusetts 02139
5
Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham
and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115;
email: ofarokhzad@zeus.bwh.harvard.edu

Annu. Rev. Med. 2012. 63:185–98 Keywords

First published online as a Review in Advance on
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nanomedicine, nanotherapeutics, nanocarriers, molecular targeted
nanoparticles, nano-oncology
Abstract
Nanomedicine, the application of nanotechnology to medicine, en-
abled the development of nanoparticle therapeutic carriers. These drug
carriers are passively targeted to tumors through the enhanced per-
meability and retention effect, so they are ideally suited for the de-
livery of chemotherapeutics in cancer treatment. Indeed, advances in
nanomedicine have rapidly translated into clinical practice. To date,
there are five clinically approved nanoparticle chemotherapeutics for
cancer and many more under clinical investigation. In this review, we
discuss the various nanoparticle drug delivery platforms and the impor-
tant concepts involved in nanoparticle drug delivery. We also review
the clinical data on the approved nanoparticle therapeutics as well as
the nanotherapeutics under clinical investigation.

185
 ME63CH12-Wang ARI 12 December 2011 12:26
INTRODUCTION
Nanotechnology is the science of engineering
EPR: enhanced materials and systems on a molecular scale.
permeability and Its application to medicine, nanomedicine, has
retention enabled the development of nanoparticle
PEG: polyethylene drug-delivery vehicles. These nanocarriers are
glycol generally <100 nm in size and have the ability
to carry and deliver therapeutics to disease sites.
One of the main applications for the nanoparti-
cle drug carriers has been the delivery of cancer
drugs. Conventional chemotherapeutics dis-
tribute throughout the body, where they affect
both cancer cells and normal cells. Nanopar-
ticles, through the enhanced permeability
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and retention (EPR) effect, preferentially
accumulate in tumors (1). This differential
in biodistribution allows nanoparticle-based
chemotherapeutics to achieve higher intratu-
moral drug concentration and lower normal-
tissue concentrations than their small-molecule
counterparts. It can also translate into higher
therapeutic efficacy and lower toxicity for
nanoparticle therapeutics. Indeed, pegylated
liposomal doxorubicin, a nanoparticle formu-
lation of doxorubicin, has lower dose-limiting
toxicity than doxorubicin, and nab-paclitaxel,
a nanoparticle formulation of paclitaxel, has
demonstrated higher therapeutic efficacy
against breast cancer than paclitaxel (2). An-
other unique property of nanoparticle carriers
is their ability to encapsulate and deliver poorly
soluble cancer therapeutics, such as the tax-
anes. Because of these favorable characteristics,
there has been intense interest in developing
nanoparticle-based cancer drugs. Today,
there are five clinically approved nanoparticle
cancer drugs, with many more in clinical and
preclinical development. These nanoparticle
drugs are poised to have significant impact on
the treatment of oncologic diseases.
In this review, we first discuss the various
nanoparticle platforms used to deliver cancer
therapeutics; second, the clinical data on cur-
rently approved nanoparticle cancer therapeu-
tics; and third, clinical and preclinical data on
the nanoparticle cancer drugs in development
and the future of nanomedicine for oncology.
186 Wang · Langer · Farokhzad
NANOPARTICLE DRUG
DELIVERY PLATFORMS
Even though nanomedicine is a relatively new
branch of science, many novel nanoparticle
drug delivery platforms have been developed
over the past three decades. These platforms
generally fall into the following categories:
liposomes, nanoparticle albumin-bound (nab)
technology, polymeric nanoparticles, den-
drimers, metal nanoparticles, and molecular
targeted nanoparticles.
Liposomes
First described in 1965, liposomes are one of
the first nanoparticle platforms to be applied
in medicine (3). Today, there are more than
11 formulations approved for clinical use, with
many more in clinical and preclinical develop-
ment. Liposomes are spherical vesicles with an
aqueous core and a vesicle shell. They contain
a single or multiple bilayered membrane struc-
ture composed of natural or synthetic lipids (4).
Depending on design, they can range in size
from tens of nanometers up to micrometers in
size. Their biocompatible and biodegradable
composition, as well as their unique ability to
encapsulate hydrophilic agents in their aque-
ous core and hydrophobic agents within their
lamellae, make liposomes excellent therapeutic
carriers. To improve their stability and circula-
tion half-life, liposomes can also be coated with
polymers such as polyethylene glycol (PEG)
(4). Liposomal drug formulations typically im-
prove the pharmacokinetics and biodistribution
of a drug. For example, pegylated liposomal
doxorubicin reduces the volume of distribution
of doxorubicin from ∼1,000 liters/m2 in the
free drug form to 2.8 liters/m2 by restricting the
distribution within the plasma. Furthermore, it
can achieve higher drug concentrations within
tumor while reducing drug concentration
in normal tissues, such as heart (6). Clinical
data on nanoparticle chemotherapeutics are
discussed in detail in a later section of this
review.
 ME63CH12-Wang ARI 12 December 2011 12:26
Nanoparticle Albumin-bound (nab)
Technology
The nanoparticle albumin-bound (nab) plat-
form utilizes albumin as a therapeutic carrier for
the delivery of hydrophobic chemotherapeu-
tics. Albumin is a natural carrier of hydropho-
bic molecules through reversible noncovalent
binding (7). In addition, albumin can bind to the
glycoprotein (gp60) receptor and mediate the
transcytosis of albumin-bound molecules (8).
These favorable characteristics led to the devel-
opment of the nab technology, a nanoparticle
composed of albumin and bound hydrophobic
therapeutics. The first commercial product
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based on the nab platform was the 130-nm
nab-paclitaxel (Abraxane R
), which has been
approved for the treatment of breast cancer.
Several other nab-based chemotherapeutics
are currently under clinical investigation (7).
Polymeric Nanoparticles
Many of the nanoparticle therapeutics in clini-
cal and preclinical investigations are polymeric
nanoparticles, which have been extensively in-
vestigated as therapeutic carriers (9). Polymeric
nanoparticles are engineered from biocom-
patible and biodegradable polymers. Most of
these nanoparticles are formulated through a
self-assembly process using block-copolymers
consisting of two or more polymer chains with
different hydrophilicity. These copolymers
spontaneously assemble into a core-shell struc-
ture in an aqueous environment (10). Specifi-
cally, the hydrophobic blocks form the core to
minimize their exposure to aqueous surround-
ings while the hydrophilic blocks form the shell
to stabilize the core (11). This results in a struc-
ture that is well suited for drug delivery. The
hydrophobic core is capable of carrying ther-
apeutics with high loading capacity while the
hydrophilic shell provides a steric protection
for the nanoparticle. Polymeric nanoparticles
have been formulated to encapsulate either hy-
drophilic or hydrophobic small drug molecules,
as well as macromolecules such as proteins and
nucleic acids (12). It is important to note that
self-assembly is not the only method of formu-
lating polymeric nanoparticles. For example,
particle replication in nonwetting templates
(PRINT) is a technique in which particles can
be formulated with precise size, shape, and
composition using films of tiny molds (13).
Dendrimers
Dendrimers are well defined, regularly
branched macromolecules (14). They are
generally synthesized from either synthetic or
natural elements such as amino acids, sugars,
and nucleotides. These nanoparticles can be
easily modified and conjugated to therapeutics.
Alternatively, dendrimers can be loaded with
drugs using the cavities in their cores through
hydrophobic interactions, hydrogen bonds, or
chemical linkages. The preclinical develop-
ment of dendrimers has been focused largely
on forming dendrimer-drug conjugates.
Metal Nanoparticles
Other nanoparticle drug-delivery vehicles that
have been extensively studied include metal
nanoparticles. Metallic nanoshells, generally
composed of inert metals such as gold or tita-
nium, have been used for controlled release of
chemotherapy (15). Each of these platforms has
unique properties. Although these metal parti-
cles are inert and biocompatible, a significant
fraction of the particles is retained in the body
after administration, and accumulation of metal
particles after repeated administration can lead
to toxicity. Therefore, most of the work on
metal nanoparticle drug delivery has been in
the preclinical stage.
Molecular Targeted Nanoparticles
One of the major breakthroughs in cancer
treatment over the past two decades has been
the development of targeted cancer therapeu-
tics. They have achieved impressive clinical
results that have eluded conventional therapeu-
tics (16–20). Examples include imatinib for the
treatment of chronic myelogenous leukemia
www.annualreviews.org • Nanoparticle Chemotherapeutics 187
 ME63CH12-Wang
MPS: mononuclear
phagocyte system
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ARI 12 December 2011 12:26
(CML) and trastuzumab for the treatment
of human epidermal growth factor receptor
type 2 (HER-2)–positive breast cancer. The
success of molecular targeted agents has led
to increasing interest in combining molecular
targeting and nanoparticle delivery.
Molecular targeted nanoparticles have been
formulated by functionalizing the nanoparti-
cles’ surfaces with targeting ligands. These
targeting ligands can bind to tumor-specific
surface markers and mediate the uptake of
nanoparticles. This in turn results in higher
intratumoral drug concentrations and lower
systemic toxicities. Actively targeted nanopar-
ticles have several important advantages: the
ability to partition more of the nanoparticles
within target tissue, increased uptake into tar-
get cells, higher therapeutic efficacy, and lower
toxicity. These targeting ligands include mon-
oclonal antibodies (such as trastuzumab), ap-
tamers, peptides, antibody fragments, and small
molecules (such as folate), all of which have
been conjugated to nanoparticles (21). Preclin-
ical data on these targeted nanoparticles thus
far have supported the advantages of targeted
nanoparticles (21). Currently, several molecu-
lar targeted nanoparticle therapeutics are un-
der clinical investigation. BIND-014 is a poly-
meric nanoparticle formulation of docetaxel
with controlled-release property that just en-
tered phase I clinical investigation (22).
IMPORTANT CONCEPTS IN
NANOPARTICLE DRUG
DELIVERY FOR CANCER
There are several general concepts that are im-
portant in nanoparticle drug delivery. These
include the enhanced permeability and reten-
tion (EPR) effect, nanoparticle clearance by the
mononuclear phagocyte system (MPS), and de-
sirable nanoparticle characteristics for cancer
applications.
Enhanced Permeability
and Retention Effect
Tumor vasculatures are generally abnormal,
with aberrant branching and leaky walls (23).
188 Wang · Langer · Farokhzad
This leakiness is due to the rapid proliferation
of endothelial cells and decreased number of
pericytes. These characteristics result in large
pores in the tumor vasculatures, ranging from
100 nm to several hundred nanometers in di-
ameter, as compared to normal vessel junctions
of 5–10 nm (24). These large pores allow higher
vascular permeability and hydraulic conductiv-
ity in tumors, enabling macromolecules such
as nanoparticles to pass into tumors (23, 25).
In normal tissue, macromolecules are cleared
by the lymphatic system. However, solid tu-
mors are generally characterized by impaired
lymphatics (26). Proliferating tumor cells com-
press lymphatic vessels and collapse most of
the vessels, especially at the center of tumors.
The impaired lymphatic system coupled with
increased permeability of tumor vasculature re-
sults in the EPR effect. Nanoparticles, like
other macromolecules, have extended retention
times in tumor, which results in higher concen-
trations than in plasma or in other tissues. Thus,
nanoparticles can achieve passive targeting to
tumors through the EPR effect.
Nanoparticle Clearance by the
Mononuclear Phagocyte System
To fully take advantage of the EPR effect,
nanoparticles must remain in circulation long
enough for tumor accumulation. However,
nanoparticles are prone to clearance by the
mononuclear phagocyte system, previously
called the reticuloendothelial system. The MPS
is part of the immune system that is mainly
responsible for clearing macromolecules from
circulation (27). The MPS comprises bone
marrow progenitors, blood monocytes, and
tissue macrophages. It also includes the Kupffer
cells of the liver and macrophages of the spleen,
which are responsible for clearance of macro-
molecules from circulation. Nanoparticles
can interact with MPS cells and lead to their
opsonization. Since premature elimination
from circulation will prevent nanoparticles
from accumulating in tumors, much effort has
been devoted to creating “stealth” nanopar-
ticles. The most common strategy has been
 ME63CH12-Wang ARI 12 December 2011 12:26

grafting PEG or other macromolecules such as
polysaccharides onto the nanoparticle surface
(28). The presence of PEG or other molecules
enables steric stabilization, preventing protein
adsorption, interactions among particles, and
interactions with immune cells.
are six clinically approved nanoparticle-based
cancer therapeutics. These include liposomal
formulations of anthracyclines, the liposomal
formulation of cytarabine, the nab formulation
of paclitaxel, and the polymeric nanoparticle
formulation of paclitaxel (Genexol-PM).

Optimal Nanoparticle Characteristics

Liposomal Anthracyclines
for Cancer Treatment
Anthracyclines are a class of antibiotic
There has been intense interest in identify-
chemotherapy derived from Streptomyces
ing nanoparticle characteristics that are best
bacteria (36). The anthracyclines are highly
suited for oncology applications. Many studies
effective against a wide range of cancers,
have demonstrated that nanoparticle size is a
including leukemias and lymphomas as well as
major factor affecting nanoparticle distribution
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breast, ovarian, and lung cancers. Members of

into tumors (29–31). In general, nanoparticles
this class include doxorubicin, daunorubicin,
smaller than 100 nm are considered excellent
epirubicin, and idarubicin. Doxorubicin is the
for tumor targeting. Recently, Perrault et al.
most commonly used anthracycline (37). It
studied the effect of nanoparticle size on tumor
is part of the standard treatment for many
accumulation in a murine cancer model. Their
cancers, including acute myeloid leukemia,
data suggested sub-20-nm particles have rapid
Hodgkin’s lymphoma, breast cancer, and
permeation into tumors but have poor reten-
soft tissue sarcomas. Doxorubicin’s main side
tion/accumulation (32). Particles that are larger
effect, which is also its dose-limiting toxicity,
than 100 nm tend to have low permeation into
is cardiac toxicity. Risk of cardiac toxicity
tumors. In this study, the optimal nanoparti-
increases at doses above 550 mg/m2 , and the
cle sizes were approximately 60 nm to 80 nm.
toxicity tends to be irreversible (38).
Nanoparticle sizes also affect the intracellu-
Liposomal anthracyclines were the first
lar trafficking, which in turn can affect tumor
nanoparticle therapeutics approved for clinical
accumulation (33, 34).
use. Today, there are three clinically approved
In addition to size, nanoparticle surface
liposomal formulations of anthracyclines: pegy-
charge is also a major factor affecting tumor
lated liposomal doxorubicin (PLD; DOXIL in
uptake. Although positive-charged nanoparti-
the United States, Caelyx elsewhere), nonpegy-
cles are rapidly taken up by tumor cells, they
lated liposomal doxorubicin (NPLD; Myocet)
also lead to significant immune reactions. Thus,
and liposomal daunorubicin (DaunoXome) (6).
neutral and negatively charged nanoparticles
These liposomal formulations differ in their
are preferable for clinical applications (35).
size, lipid composition, rate of drug release,
Shape is also beginning to emerge as a key
and biodistribution. Thus, their clinical results
variable in macrophage clearance, cell uptake,
cannot be extrapolated from one to another.
and biodistribution (35). Although there is
Pegylated liposomal doxorubicin has a vesi-
currently no clear consensus on optimal char-
cle diameter of ∼105 nm with a surface coating
acteristics for nanoparticles, more studies are
of PEG. As mentioned above, PEG prevents
addressing these issues in a systematic fashion.
opsonization by plasma proteins and decreases
the uptake by the MPS. This results in a
CLINICALLY APPROVED circulation half-life of 2–3 days versus <5 min
NANOPARTICLE for doxorubicin (37). PLD’s main clinical indi-
CHEMOTHERAPEUTICS cations are treatment for breast cancer, ovarian
Advances in nanomedicine have been rapidly cancer, and Kaposi’s sarcoma. Two phase III
translated into clinical practice. Today, there studies established PLD’s role in the treatment

www.annualreviews.org • Nanoparticle Chemotherapeutics 189

 ME63CH12-Wang
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ARI 12 December 2011 12:26
of advanced breast cancer. Keller et al. random-
ized 301 patients with taxane-resistant breast
cancer between PLD 50 mg/m2 and either
weekly vinorelbine or vinblastine in combi-
nation with mitomycin C (39). Although the
progression-free survival (PFS) rates and the
overall survival rates were comparable between
the arms, subgroup analysis demonstrated that
anthracycline-naı̈ve patients did better with the
PLD regimen (5.8 versus 2.1 months in PFS).
In a second phase III clinical trial, O’Brien et al.
randomized 509 patients with metastatic breast
cancer to PLD 50 mg/m2 every 4 weeks or dox-
orubicin 60 mg/m2 every 3 weeks as first-line
therapy (40). Although progression-free sur-
vival and overall survival were again comparable
between the arms, risk of cardiotoxicity was sig-
nificantly higher with doxorubicin than PLD
(hazard ratio = 3.1; p < 0.001). In addition,
PLD is associated with less myelosuppression,
alopecia, and nausea/vomiting. Palmar-plantar
skin reactions and mucositis, on the other hand,
are more frequent with PLD than doxorubicin.
It is important to note that in both of these
trials, the total dose of doxorubicin was lower in
the arm receiving PLD than the arm receiving
doxorubicin, and thus it is difficult to defini-
tively conclude that PLD has a lower toxicity
profile than doxorubicin. Randomized phase
III trials were also conducted in ovarian cancer
and Kaposi’s sarcoma. The results established
the use of PLD in both of these diseases
(41, 42).
NPLD vesicles have diameters of ∼150 nm.
They have circulation half-lives of 2–3 hours.
NPLD’s main indication is treatment of
breast cancer. It is approved in Europe for
first-line treatment with cyclophosphamide.
Randomized clinical trials comparing NPLD
and doxorubicin demonstrated similar survival
and response rates but less grade-4 cardiac
toxicity and neutropenia in NPLD arms
(43, 44).
Liposomal daunorubicin vesicles are
∼45 nm in size and have been approved for
the treatment of AIDS-associated Kaposi’s
sarcoma. In a randomized phase III trial com-
paring liposomal daunorubicin to a regimen of
190 Wang · Langer · Farokhzad
doxorubicin, bleomycin, and vincristine, both
treatments were similar in efficacy (45).
Nab-Paclitaxel
Paclitaxel is a mitotic inhibitor chemotherapeu-
tic that was first extracted from the Pacific yew
tree, Taxus brevifolia (46). Like doxorubicin, it is
effective against a wide range of cancers, includ-
ing breast, lung, ovarian, head and neck, and
Kaposi’s sarcoma. Paclitaxel is poorly soluble in
water and requires a solvent for clinical appli-
cations. Taxol, the commercial formulation of
paclitaxel, utilizes cremophor as a solvent. Cre-
mophor is toxic and can cause life-threatening
hypersensitivity reactions (47). Although pre-
medication and slow infusions have improved
the rates of hypersensitivity, it remains a signif-
icant toxicity. There has been intense interest
in identifying alternative formulations of pacli-
taxel that are less toxic.
Nab-paclitaxel (Abraxane) is an albumin-
bound, 130-nm nanoparticle formulation of
paclitaxel (48). It has been approved for the
treatment of breast cancer and is undergoing
clinical investigation for other clinical indica-
tions. The pharmacokinetics of nab-paclitaxel
have been compared to those of cremophor-
paclitaxel (49). Nab-paclitaxel was found to
have a higher plasma clearance and a larger
volume of distribution. The efficacy of nab-
paclitaxel was compared directly to cremophor-
paclitaxel in a phase III randomized trial (2).
Patients were randomized to 3-week cycles
of 260 mg/m2 nab-paclitaxel or 175 mg/m2
cremophor-paclitaxel. A total of 454 patients
with metastatic breast cancer were accrued with
229 patients randomized to the nab-paclitaxel
arm. The study found that the nab-paclitaxel
arm had significantly higher response rates
compared with cremophor-paclitaxel (33%
versus 19%, p = 0.001) and significantly
longer time to disease progression (23.0 versus
16.9 weeks, p = 0.006). In addition, the inci-
dence of grade 4 neutropenia was lower in the
nab-paclitaxel arm. On the other hand, grade 3
neuropathy rates were higher in patients who
received nab-paclitaxel. No hypersensitivity
 ME63CH12-Wang ARI 12 December 2011 12:26
reaction occurred in patients who received
nab-paclitaxel. This trial established the basis
for the FDA approval of Abraxane for the
treatment of breast cancer. It is also the
first large randomized trial demonstrating a
higher therapeutic efficacy for a nanoparticle
therapeutic than for the normal formulation of
that therapeutic.
Polymeric Nanoparticle Formulation
of Taxane
Since the development of nab-paclitaxel, an-
other nanoparticle formulation of paclitaxel
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has been developed using biodegradable poly-
mers. The polymeric micelle formulation of
paclitaxel (Genexol-PM) is composed of block
copolymers of PEG and poly-(D,L-lactic acid)
(50). These nanoparticles have diameters of 20–
50 nm and are completely soluble in aqueous
environments. In a phase I clinical trial, poly-
meric micelle paclitaxel was found to have a
maximum tolerated dosage of 390 mg/m2 (50).
The dose-limiting toxicities were neuropathy,
myalgia, and neutropenia. In subsequent clini-
cal trials, polymeric micelle paclitaxel was found
to have good response rates (51, 52). Currently,
Genexol-PM is approved for the treatment of
breast and lung cancers in Korea.
Nanoparticle Pyrimidine Antagonists
Pyrimidine antagonists are also hydrophilic
drugs, and most of the nanoparticle for-
mulations have been focused on liposomes.
Liposomal cytarabine has been developed for
the treatment of disseminated lymphomatous
meningitis (6). Liposome is used to slow the
clearance of cytarabine from the cerebral spinal
fluid. DepoCyte, the commercial formulation
of liposomal cytarabine, has diameters of 3
to 30 μm. These are large particles and not
nanoparticle formulations per se. In random-
ized clinical trials, liposomal cytarabine has
been at least as effective as methotrexate or
conventional cytarabine for neoplastic menin-
gitis (58). It has been approved for use in the
United States and Europe for this indication.
NANOPARTICLE
THERAPEUTICS UNDER
CLINICAL AND PRECLINICAL
INVESTIGATION
In addition to the above-mentioned clini-
cally approved nanoparticle therapeutics, many
other therapeutics are undergoing preclini-
cal and clinical investigation. A 2006 global
survey conducted by the European Science
and Technology Observatory (ESTO) revealed
that >150 companies are developing nanoscale
therapeutics (10). Most of the nanoparticle
therapeutics undergoing clinical investigation
are listed in Table 1. Because it is not feasible
to discuss all the research efforts in preclini-
cal and clinical development, we focus on the
trends of development for each type of cancer
therapeutic.
Nanoparticle Platinum Therapeutics
Most of the interest in developing nanoparticle
therapeutics from the alkylators class has been
focused on the platinum drugs. Platinums
including cisplatin, carboplatin, and oxaliplatin
have a wide range of applications in cancer.
Because the platinum drugs are water soluble,
the most common strategy to develop nanopar-
ticle formulations has been the utilization of
liposomes. Lipoplatin, LiPlaCis, and SPI-077
are all pegylated liposomal formulations of cis-
platin. These drugs also demonstrated excellent
preclinical data prior to entering clinical trials.
Although Lipoplatin has demonstrated lower
renal toxicity than cisplatin, the therapeutic
efficacy has been mixed in phase II clinical trials
(53, 54). SPI-077 also showed lower toxicity in
clinical trials but failed to demonstrate efficacy
in most of these trials (6). One of the key limita-
tions was the poor release of cisplatin from the
liposomes. LiPlaCis is a more recent liposomal
formulation with a built-in drug release trigger.
Unfortunately, LiPlaCis led to significant renal
toxicities and infusion reactions in a recent
phase I clinical trial (55). Cessation of further
clinical investigation was recommended. In
addition to cisplatin, nanoparticle formulations
www.annualreviews.org • Nanoparticle Chemotherapeutics 191
 ME63CH12-Wang ARI 12 December 2011 12:26

Table 1 Nanoparticle therapeutics undergoing clinical investigation

Agent Formulation Company Indication Status
Nontargeted nanoparticle therapeutics
S-CKD602 Pegylated liposomal CKD602 Alza Corporation Various cancers Phase I/II
(topoisomerase inhibitor)
CRLX101 Polymeric nanoparticle Cerulean Pharma Various cancers Phase II
(cyclodextrin) formulation of
camptothecin
CPX-1 Liposomal irinotecan Celator Pharmaceuticals Colorectal cancer Phase II
LE-SN38 Liposomal SN38 NeoPharm Colorectal cancer Phase II
NC-6004 Polymeric nanoparticle NanoCarrier Co. Various cancers Phase I
(PEG-poly amino acid)
formulation of cisplatin
NK105 Polymeric nanoparticle Nippon Kayaku Co., Ltd. Various cancers Phase II
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(PEG-poly aspartate)
formulation of paclitaxel
NK911 Polymeric nanoparticle Nippon Kayaku Co., Ltd. Various cancers Phase I
(PEG-poly aspartate)
formulation of doxorubicin
SP1049C Glycoprotein micelle of Supratek Pharma Inc. Various cancers Phase II
doxorubicin
SPI-077 Pegylated liposomal cisplatin Alza Corporation Head and neck cancer, Phase II
lung cancer
NK012 Polymeric micelle SN-38 Nippon Kayaku Co., Ltd. Various cancers Phase II
ALN-VSP Lipid nanoparticle formulation Alnylam Pharmaceuticals Liver cancer Phase I
of siRNA against vascular
endothelial growth factor and
kinesin spindle protein
CPX-351 Liposomal cytarabine and Celator Pharmaceuticals Acute myeloid Phase I
daunorubicin (5:1) leukemia
OSI-7904L Liposomal thymidylate synthase OSI Pharmaceuticals Various cancers Phase II
inhibitor
OSI-211 Liposomal lurtotecan OSI Pharmaceuticals Various cancers Phase II
Molecular targeted nanoparticle therapeutics
BIND-014 Polymeric nanoparticle BIND Bioscience Various cancers Phase I
(PEG-PLGA)a formulation of
docetaxel
MCC-465 Human antibody fragment National Cancer Center, Gastric cancer Phase I
(GAH) targeted liposomal Japan (not continued)
doxorubicin
MBP-426 Transferrin targeted liposomal Mebiopharm Co., Ltd. Various cancers Phase II
oxaliplatin
CALAA-01 Transferrin targeted polymeric Calando Pharmaceuticals Solid tumors Phase I
nanoparticle (cyclodextrin)
formulation of siRNA
SGT53-01 Transferrin targeted liposome SynerGene Therapeutics Solid tumors Phase I
with p53 gene

a
PLGA: poly(lactic-co-glycolic acid).

192 Wang · Langer · Farokhzad

 ME63CH12-Wang ARI 12 December 2011 12:26
of oxaliplatin have been developed. MBP-426
is a liposomal formulation of oxaliplatin that
is currently undergoing early-phase clinical
investigation.
Polymeric nanoparticle formulations of
platinum drugs have also been developed. NC-
6004 is a polymeric micelle formulation of cis-
platin (56). Phase I clinical trial data showed low
but significant renal toxicities and hypersensi-
tivity reactions. Another strategy to incorporate
platinum drugs into polymeric nanoparticles is
to modify the platinum drugs into hydropho-
bic molecules. In a preclinical study demon-
strating proof of principle, Dhar et al. en-
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capsulated a hydrophobic prodrug of cisplatin
into biodegradable polymers and targeted them
against prostate cancer cells (57).
Nanoparticle Alkaloids
The plant alkaloid class of chemotherapeutics
contains many commonly used chemothera-
pies. These include vincristine, camptothecin
derivatives, and the taxanes. All of these
chemotherapeutics have been engineered into
nanoparticle formulations.
Liposomal vincristine (OncoTCS,
Marqibo) is a 120-nm vesicle. It was de-
veloped to prolong the plasma half-life of
vincristine (6). A phase II single-agent trial in
patients with chemoresistant non-Hodgkin’s
lymphoma demonstrated significant activity
with overall response rates of 41%. In a sep-
arate clinical trial using liposomal vincristine
as part of combination chemotherapy for
aggressive B cell lymphoma, 17/23 patients
had a complete response to treatment. There
has been no report on randomized phase III
studies with this therapeutic, and it has not
been approved for clinical use.
Camptothecin is a cytotoxic alkaloid that
inhibits DNA enzyme topoisomerase I. Al-
though it showed great promise in preclinical
evaluations, its poor solubility and high toxicity
prevented its clinical translation. Water-
soluble analogues of camptothecin, irinotecan
and topotecan, have been approved for clinical
use. With the development of nanoparticle
drug carriers, there is renewed interest in
camptothecin. CRLX101 is a polymeric
nanoparticle composed of cyclodextrin-PEG
copolymer conjugated to camptothecin (59).
It increases the solubility of camptothecin
>1,000-fold. Preclinical studies have also
demonstrated improved efficacy. The results
of its phase Ib/IIa trial are pending.
Various liposomal formulations of irinote-
can have been studied in preclinical research.
CPX-1, the most advanced liposomal formu-
lation of irinotecan, recently entered clinical
investigation. The phase I data showed an
acceptable toxicity profile and a good response
rate. It is important to note that response was
not a primary end point (60).
SN-38 is the active metabolite of irinotecan.
Even though SN-38 is 200-fold more potent
than irinotecan, its poor water solubility
prevented its clinical application. Several
nanoparticle formulations of SN-38 have been
developed. LE-SN38 is a liposomal formu-
lation of SN-38, which is in phase II clinical
investigation. Another SN-38 therapeutic,
NK-012, is a polymeric micelle formulation
of SN-38 (61). Its phase I data were recently
reported and showed an acceptable toxicity
profile. Phase II clinical trials are under way to
evaluate its efficacy.
In addition to Abraxane and Genexol-PM,
many other nanoparticle formulations of tax-
anes are in preclinical and clinical development.
The taxanes are poorly soluble in water and
generally require a solvent. Both of the solvents
that have been utilized in commercial formu-
lations, cremophor (Taxol) and polysorbate 80
(Taxotere R
), have significant toxicities of their
own. Therefore, there has been high interest
in developing nanoparticle formulations of tax-
anes that are less toxic. NK105 is a PEG-poly
aspartate formulation of paclitaxel (62). Its
phase I data showed a good toxicity profile with
a plasma AUC much higher than cremophor-
paclitaxel. BIND-014 is a molecular targeted
polymeric nanoparticle formulation of doc-
etaxel. It has recently entered phase I clinical
investigation. There are a number of nanopar-
ticle formulations of paclitaxel and docetaxel in
www.annualreviews.org • Nanoparticle Chemotherapeutics 193
 ME63CH12-Wang
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ARI 12 December 2011 12:26
various stages of research and development
(63). Many of these will undoubtedly enter
clinical investigation and challenge estab-
lished formulations such as Abraxane and
Genexol-PM.
Nanoparticle Antibiotics
In addition to liposomal anthracyclines, recent
research has focused on developing polymeric
nanoparticle formulations of doxorubicin.
NK911 is a polymeric formulation of doxoru-
bicin composed of PEG-poly aspartate (64).
Although NK911 was well tolerated in the
phase I study, its maximum tolerated dose was
well short of that of liposomal doxorubicin.
SP1049C is a glycoprotein micelle formulation
of doxorubicin (65). In a recent phase II trial
studying SP1049C in patients with advanced
esophageal cancer, the therapeutic agent
demonstrated an overall response of 47% with
tolerable side effects. The results suggest fur-
ther clinical investigation is warranted. Aside
from these clinical studies, most of the novel
nanoparticle platforms utilize doxorubicin
as the model drug. These preclinical studies
have demonstrated superior drug loading and
preclinical efficacy compared with liposomal
doxorubicin. Thus, it is likely that many
nanoparticle formulations of doxorubicin will
enter clinical investigation in the near future.
Nanoparticle siRNA
Small interfering RNA (siRNA) holds great po-
tential in the treatment of many human ill-
nesses, including cancer. However, it is highly
unstable in vivo and is rapidly cleared by the
kidney. Furthermore, its mechanism of action
requires siRNA to be delivered directly to the
target cells’ cytoplasm. The biggest challenge
for clinical translation lies in the delivery of
siRNA. Nanoparticles present a unique solu-
tion to this challenge. Nanoparticles can en-
capsulate siRNA therapeutics, thus preventing
its degradation and rapid clearance. Nanopar-
ticle formulations of siRNA can also take ad-
vantage of the EPR effect for cancer treatment
(66). Indeed, since its recent discovery, siRNA’s
194 Wang · Langer · Farokhzad
first clinical translation has been in treatment
of malignancies. ALN-VSP and CALAA-01 are
siRNA therapeutics currently undergoing clin-
ical investigation (67). Many investigators are
awaiting the reports from these studies to gain
a better understanding of the challenges and
potential of siRNA therapeutics.
FUTURE DIRECTIONS
The unique properties of nanoparticle drug
carriers make them well suited for oncology
applications. Although nanomedicine is a rel-
atively new branch of science, its translation
into clinical care has been rapid. Nanoparti-
cle chemotherapeutics are poised to impact the
treatment of most cancers. However, there are
still limited clinical data and a limited num-
ber of nanotherapeutics approved for clinical
use. More clinical data are needed to fully un-
derstand the advantages and disadvantages of
nanoparticle therapeutics. Additional clinical
data can also identify the best applications for
nanochemotherapeutics. Thus, it is crucial to
develop and carry out well-designed clinical tri-
als to further the development of these drugs.
Clinical investigators should fully understand
the particular nanoparticles they are investi-
gating and design trials that take advantage of
nanoparticle properties.
The field of nanomedicine is moving at a
very rapid pace. New and improved nanopar-
ticle platforms are being developed; these
platforms quickly enter preclinical and clinical
investigation. This new generation of nanopar-
ticle platforms holds even more promise to
improve the treatment of cancer. For example,
molecular targeted nanoparticles were first
developed less than a decade ago and have
already entered clinical investigation. These
nanocarriers combine biological targeting and
nanomedicine, and they have the potential to
further improve the therapeutic ratio of nan-
otherapeutics. More complex targeted systems,
which can release therapeutics at a target site
when exposed to external stimuli such as light
and temperature, are also under development.
Another potential for improvement is the
 ME63CH12-Wang ARI 12 December 2011 12:26

development of more nanoparticles capable daunorubicin, showed promising results in its

of delivering combination chemotherapeutics.
Such nanotherapeutic agents can take full
advantage of synergistic effects of combina-
tion therapy, which in turn can significantly
improve the therapeutic efficacy. CPX-351,
a liposomal formulation of cytarabine and
first human study (68). Last, preclinical and
clinical investigators should also explore addi-
tional applications of nanotherapeutics for the
treatment of cancer. These indications include
utilizing nanotherapeutics as chemosensitizers
and radiosensitizers.

DISCLOSURE STATEMENT
O.C.F. and R.L. disclose their financial interest in BIND Biosciences and Selecta Biosciences, two
biotechnology companies developing nanoparticle technologies for medical applications. BIND
and Selecta are biopharmaceutical companies founded by O.C.F. and R.L., where they both serve
Annu. Rev. Med. 2012.63:185-198. Downloaded from www.annualreviews.org
Access provided by Syddansk University on 12/22/14. For personal use only.

as members of the Board of Directors and Scientific Advisory Board. A.Z.W. is a consultant for
Samyang Corp.

ACKNOWLEDGMENTS
This work was supported by National Cancer Institute Grants CA119349 (to O.C.F. and R.L.),
the National Institute of Biomedical Imaging and Bioengineering Grant EB003647 (to O.C.F.),
NHLBI-BAA-HV-10-08 (to O.C.F.), and the David H. Koch- Prostate Cancer Foundation Award
in Nanotherapeutics (to O.C.F. and R.L.). A.Z.W. is supported by NIH/NCI Paul Calabresi
Career Development Award for Clinical Oncology K12 and the University Cancer Research
Fund by the University of North Carolina.

LITERATURE CITED
1. Matsumura Y, Maeda H. 1986. A new concept for macromolecular therapeutics in cancer chemotherapy:
mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 46:6387–
92
2. Gradishar WJ, Tjulandin S, Davidson N, et al. 2005. Phase III trial of nanoparticle albumin-bound
paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J. Clin.
Oncol. 23:7794–803
3. Bangham AD. 1993. Liposomes: the Babraham connection. Chem. Phys. Lipids 64:275–85
4. Torchilin VP. 2005. Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug Discov.
4:145–60
5. Deleted in proof
6. Hofheinz RD, Gnad-Vogt SU, Beyer U, et al. 2005. Liposomal encapsulated anti-cancer drugs. Anti-
Cancer Drugs 16:691–707
7. Hawkins MJ, Soon-Shiong P, Desai N. 2008. Protein nanoparticles as drug carriers in clinical medicine.
Adv. Drug Deliv. Rev. 60:876–85
8. Desai N, Trieu V, Yao Z, et al. 2006. Increased antitumor activity, intratumor paclitaxel concentrations,
and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with
cremophor-based paclitaxel. Clin. Cancer Res. 12:1317–24
9. Kim SH, Jeong JH, Chun KW, et al. 2005. Target-specific cellular uptake of PLGA nanoparticles coated
with poly(L-lysine)-poly(ethylene glycol)-folate conjugate. Langmuir 21:8852–57
10. Zhang L, Gu FX, Chan JM, et al. 2008. Nanoparticles in medicine: therapeutic applications and devel-
opments. Clin. Pharmacol. Ther. 83:761–69

www.annualreviews.org • Nanoparticle Chemotherapeutics 195

 ME63CH12-Wang ARI 12 December 2011 12:26

11. Farokhzad OC, Jon S, Khademhosseini A, et al. 2004. Nanoparticle-aptamer bioconjugates: a new ap-
proach for targeting prostate cancer cells. Cancer Res. 64:7668–72
12. Gu F, Zhang L, Teply BA, et al. 2008. Precise engineering of targeted nanoparticles by using self-
assembled biointegrated block copolymers. Proc. Natl. Acad. Sci. USA 105:2586–91
13. Rolland JP, Maynor BW, Euliss LE, et al. 2005. Direct fabrication and harvesting of monodisperse,
shape-specific nanobiomaterials. J. Am. Chem. Soc. 127:10096–100
14. Baker JR Jr. 2009. Dendrimer-based nanoparticles for cancer therapy. Hematol. Educ. Program Am. Soc.
Hematol. Am. Soc. Hematol. pp. 708–19
15. Minelli C, Lowe SB, Stevens MM. 2010. Engineering nanocomposite materials for cancer therapy. Small
(Weinheim an der Bergstrasse, Ger.) 6:2336–57
16. Romond EH, Perez EA, Bryant J, et al. 2005. Trastuzumab plus adjuvant chemotherapy for operable
HER2-positive breast cancer. N. Engl. J. Med. 353:1673–84
17. Yang JC, Haworth L, Sherry RM, et al. 2003. A randomized trial of bevacizumab, an anti-vascular en-
dothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med. 349:427–34
18. Hurwitz HI, Fehrenbacher L, Hainsworth JD, et al. 2005. Bevacizumab in combination with fluorouracil
Annu. Rev. Med. 2012.63:185-198. Downloaded from www.annualreviews.org
Access provided by Syddansk University on 12/22/14. For personal use only.

and leucovorin: an active regimen for first-line metastatic colorectal cancer. J. Clin. Oncol. 23:3502–8
19. Coiffier B, Lepage E, Briere J, et al. 2002. CHOP chemotherapy plus rituximab compared with CHOP
alone in elderly patients with diffuse large-B-cell lymphoma. N. Engl. J. Med. 346:235–42
20. Druker BJ, Talpaz M, Resta DJ, et al. 2001. Efficacy and safety of a specific inhibitor of the BCR-ABL
tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344:1031–37
21. Wang AZ, Gu F, Zhang L, et al. 2008. Biofunctionalized targeted nanoparticles for therapeutic applica-
tions. Expert Opin. Biol. Ther. 8:1063–70
22. Service RF. 2010. Nanotechnology. Nanoparticle Trojan horses gallop from the lab into the clinic. Science
330:314–15
23. Jain RK, Stylianopoulos T. 2010. Delivering nanomedicine to solid tumors. Nat. Rev. 7:653–64
24. Hobbs SK, Monsky WL, Yuan F, et al. 1998. Regulation of transport pathways in tumor vessels: role of
tumor type and microenvironment. Proc. Natl. Acad. Sci. USA 95:4607–12
25. Jang SH, Wientjes MG, Lu D, et al. 2003. Drug delivery and transport to solid tumors. Pharm. Res.
20:1337–50
26. Maeda H, Wu J, Sawa T, et al. 2000. Tumor vascular permeability and the EPR effect in macromolecular
therapeutics: a review. J. Control. Release 65:271–84
27. Hume DA. 2006. The mononuclear phagocyte system. Curr. Opin. Immunol. 18:49–53
28. Peracchia MT, Vauthier C, Desmaele D, et al. 1998. Pegylated nanoparticles from a novel methoxy-
polyethylene glycol cyanoacrylate-hexadecyl cyanoacrylate amphiphilic copolymer. Pharm. Res. 15:550–
56
29. Gratton SEA, Ropp PA, Pohlhaus PD, et al. 2008. The effect of particle design on cellular internalization
pathways. Proc. Natl. Acad. Sci. USA 105:11613–18
30. Champion JA, Walker A, Mitragotri S. 2008. Role of particle size in phagocytosis of polymeric micro-
spheres. Pharm. Res. 25:1815–21
31. Wang M, Thanou M. 2010. Targeting nanoparticles to cancer. Pharmacol. Res. 62:90–99
32. Perrault SD, Walkey C, Jennings T, et al. 2009. Mediating tumor targeting efficiency of nanoparticles
through design. Nano Lett. 9:1909–15
33. Zauner W, Farrow NA, Haines AMR. 2001. In vitro uptake of polystyrene microspheres: effect of particle
size, cell line and cell density. J. Control. Release 71:39–51
34. Rejman J, Oberle V, Zuhorn IS, et al. 2004. Size-dependent internalization of particles via the pathways
of clathrin-and caveolae-mediated endocytosis. Biochem. J. 377:159–69
35. Gratton SE, Ropp PA, Pohlhaus PD, et al. 2008. The effect of particle design on cellular internalization
pathways. Proc. Natl. Acad. Sci. USA 105:11613–18
36. Young RC, Ozols RF, Myers CE. 1981. The anthracycline antineoplastic drugs. N. Engl. J. Med. 305:139–
53
37. Gaitanis A, Staal S. 2010. Liposomal doxorubicin and nab-paclitaxel: nanoparticle cancer chemotherapy
in current clinical use. Methods Mol. Biol. 624:385–92

196 Wang · Langer · Farokhzad

 ME63CH12-Wang ARI 12 December 2011 12:26

38. Singal PK, Iliskovic N. 1998. Doxorubicin-induced cardiomyopathy. N. Engl. J. Med. 339:900–5
39. Keller AM, Mennel RG, Georgoulias VA, et al. 2004. Randomized phase III trial of pegylated liposomal
doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced
breast cancer. J. Clin. Oncol. 22:3893–901
40. O’Brien ME, Wigler N, Inbar M, et al. 2004. Reduced cardiotoxicity and comparable efficacy in a phase
III trial of pegylated liposomal doxorubicin HCl (CAELYX/DOXIL) versus conventional doxorubicin
for first-line treatment of metastatic breast cancer. Ann. Oncol. 15:440–49
41. Gordon AN, Fleagle JT, Guthrie D, et al. 2001. Recurrent epithelial ovarian carcinoma: a randomized
phase III study of pegylated liposomal doxorubicin versus topotecan. J. Clin. Oncol. 19:3312–22
42. Krown SE, Northfelt DW, Osoba D, et al. 2004. Use of liposomal anthracyclines in Kaposi’s sarcoma.
Semin. Oncol. 31:36–52
43. Harris L, Batist G, Belt R, et al. 2002. Liposome-encapsulated doxorubicin compared with conventional
doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer
94:25–36
44. Batist G, Ramakrishnan G, Rao CS, et al. 2001. Reduced cardiotoxicity and preserved antitumor efficacy of
Annu. Rev. Med. 2012.63:185-198. Downloaded from www.annualreviews.org

liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and

Access provided by Syddansk University on 12/22/14. For personal use only.

cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J. Clin. Oncol. 19:1444–54
45. Gill PS, Wernz J, Scadden DT, et al. 1996. Randomized phase III trial of liposomal daunorubicin versus
doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi’s sarcoma. J. Clin. Oncol. 14:2353–64
46. Rowinsky EK, Eisenhauer EA, Chaudhry V, et al. 1993. Clinical toxicities encountered with paclitaxel
(Taxol). Semin. Oncol. 20:1–15
47. Runowicz CD, Wiernik PH, Einzig AI, et al. 1993. Taxol in ovarian cancer. Cancer 71:1591–96
48. Miele E, Spinelli GP, Miele E, et al. 2009. Albumin-bound formulation of paclitaxel (Abraxane ABI-007)
in the treatment of breast cancer. Int. J. Nanomed. 4:99–105
49. Sparreboom A, Scripture CD, Trieu V, et al. 2005. Comparative preclinical and clinical pharmacokinet-
ics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in
cremophor (Taxol). Clin. Cancer Res. 11:4136–43
50. Kim TY, Kim DW, Chung JY, et al. 2004. Phase I and pharmacokinetic study of Genexol-PM, a
cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies. Clin.
Cancer Res. 10:3708–16
51. Kim DW, Kim SY, Kim HK, et al. 2007. Multicenter phase II trial of Genexol-PM, a novel cremophor-
free, polymeric micelle formulation of paclitaxel, with cisplatin in patients with advanced non-small-cell
lung cancer. Ann. Oncol. 18:2009–14
52. Lee KS, Chung HC, Im SA, et al. 2008. Multicenter phase II trial of Genexol-PM, a cremophor-free,
polymeric micelle formulation of paclitaxel, in patients with metastatic breast cancer. Breast Cancer Res.
Treat. 108:241–50
53. Ravaioli A, Papi M, Pasquini E, et al. 2009. Lipoplatin monotherapy: a phase II trial of second-line
treatment of metastatic non-small-cell lung cancer. J. Chemother. 21:86–90
54. Mylonakis N, Athanasiou A, Ziras N, et al. 2010. Phase II study of liposomal cisplatin (Lipoplatin) plus
gemcitabine versus cisplatin plus gemcitabine as first line treatment in inoperable (stage IIIB/IV) non-small
cell lung cancer. Lung Cancer 68:240–47
55. de Jonge MJ, Slingerland M, Loos WJ, et al. 2010. Early cessation of the clinical development of LiPlaCis,
a liposomal cisplatin formulation. Eur. J. Cancer 46:3016–21
56. Plummer R, Wilson RH, Calvert H, et al. 2011. A phase I clinical study of cisplatin-incorporated polymeric
micelles (NC-6004) in patients with solid tumours. Br. J. Cancer 104:593–98
57. Dhar S, Kolishetti N, Lippard SJ, et al. 2011. Targeted delivery of a cisplatin prodrug for safer and more
effective prostate cancer therapy in vivo. Proc. Natl. Acad. Sci. USA 108:1850–55
58. Benesch M, Urban C. 2008. Liposomal cytarabine for leukemic and lymphomatous meningitis: recent
developments. Expert Opin. Pharmacother. 9:301–9
59. Svenson S, Wolfgang M, Hwang J, et al. 2011. Preclinical to clinical development of the novel camp-
tothecin nanopharmaceutical CRLX101. J. Control. Release 153(1):49–55
60. Batist G, Gelmon KA, Chi KN, et al. 2009. Safety, pharmacokinetics, and efficacy of CPX-1 liposome
injection in patients with advanced solid tumors. Clin. Cancer Res. 15:692–700

www.annualreviews.org • Nanoparticle Chemotherapeutics 197

 ME63CH12-Wang ARI 12 December 2011 12:26

61. Hamaguchi T, Doi T, Eguchi-Nakajima T, et al. 2010. Phase I study of NK012, a novel SN-38-
incorporating micellar nanoparticle, in adult patients with solid tumors. Clin. Cancer Res. 16:5058–66
62. Matsumura Y, Kataoka K. 2009. Preclinical and clinical studies of anticancer agent-incorporating polymer
micelles. Cancer Sci. 100:572–79
63. Safavy A. 2008. Recent developments in taxane drug delivery. Curr. Drug Deliv. 5:42–54
64. Matsumura Y, Hamaguchi T, Ura T, et al. 2004. Phase I clinical trial and pharmacokinetic evaluation of
NK911, a micelle-encapsulated doxorubicin. Br. J. Cancer 91:1775–81
65. Valle JW, Armstrong A, Newman C, et al. 2011. A phase 2 study of SP1049C, doxorubicin in P-
glycoprotein-targeting pluronics, in patients with advanced adenocarcinoma of the esophagus and gas-
troesophageal junction. Invest. New Drugs 29:1029–37
66. Ozpolat B, Sood AK, Lopez-Berestein G. 2010. Nanomedicine based approaches for the delivery of siRNA
in cancer. J. Intern. Med. 267:44–53
67. Davis ME, Zuckerman JE, Choi CH, et al. 2010. Evidence of RNAi in humans from systemically admin-
istered siRNA via targeted nanoparticles. Nature 464:1067–70
68. Feldman EJ, Lancet JE, Kolitz JE, et al. 2011. First-in-man study of CPX-351: a liposomal carrier con-
Annu. Rev. Med. 2012.63:185-198. Downloaded from www.annualreviews.org
Access provided by Syddansk University on 12/22/14. For personal use only.

taining cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory
acute myeloid leukemia. J. Clin. Oncol. 29:979–85

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Contents Volume 63, 2012

Huntington’s Disease: Advocacy Driving Science

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Human Genome Sequencing in Health and Disease
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The Genetic Architecture of Schizophrenia: New Mutations
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Laura Rodriguez-Murillo, Joseph A. Gogos, and Maria Karayiorgou p p p p p p p p p p p p p p p p p p p p63
CCR5 Antagonism in HIV Infection: Current Concepts
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New Paradigms for HIV/AIDS Vaccine Development
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Emerging Concepts on the Role of Innate Immunity in the Prevention
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Margaret E. Ackerman, Anne-Sophie Dugast, and Galit Alter p p p p p p p p p p p p p p p p p p p p p p p p p 113
Immunogenetics of Spontaneous Control of HIV
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Recent Progress in HIV-Associated Nephropathy
Christina M. Wyatt, Kristin Meliambro, and Paul E. Klotman p p p p p p p p p p p p p p p p p p p p p p p p 147
Screening for Prostate Cancer: Early Detection or Overdetection?
Andrew J. Vickers, Monique J. Roobol, and Hans Lilja p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 161
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Circulating Tumor Cells and Circulating Tumor DNA

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Carotid Stenting Versus Endarterectomy
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Mitral Valve Prolapse

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Abraham Aviv and Daniel Levy p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 293
Aquaporins in Clinical Medicine
A.S. Verkman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 303
Role of Endoplasmic Reticulum Stress in Metabolic Disease
and Other Disorders
Lale Ozcan and Ira Tabas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 317
Role of Fructose-Containing Sugars in the Epidemics of Obesity
and Metabolic Syndrome
Kimber L. Stanhope p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 329
Vaccines for Malaria: How Close Are We?
Mahamadou A. Thera and Christopher V. Plowe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 345
Crisis in Hospital-Acquired, Healthcare-Associated Infections
David P. Calfee p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 359
Novel Therapies for Hepatitis C: Insights from the Structure
of the Virus
Dahlene N. Fusco and Raymond T. Chung p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 373
Multiple Sclerosis: New Insights in Pathogenesis and Novel
Therapeutics
Daniel Ontaneda, Megan Hyland, and Jeffrey A. Cohen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 389
Traumatic Brain Injury and Its Neuropsychiatric Sequelae
in War Veterans
Nina A. Sayer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 405

vi Contents
 ME63-frontmatter ARI 20 December 2011 12:3

Eosinophilic Esophagitis: Rapidly Advancing Insights

J. Pablo Abonia and Marc E. Rothenberg p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 421
Physician Workforce Projections in an Era of Health Care Reform
Darrell G. Kirch, Mackenzie K. Henderson, and Michael J. Dill p p p p p p p p p p p p p p p p p p p p p p p 435
Reducing Medical Errors and Adverse Events
Julius Cuong Pham, Monica S. Aswani, Michael Rosen, HeeWon Lee,
Matthew Huddle, Kristina Weeks, and Peter J. Pronovost p p p p p p p p p p p p p p p p p p p p p p p p p p p p 447
Relationships Between Medicine and Industry: Approaches to the
Problem of Conflicts of Interest
Raymond Raad and Paul S. Appelbaum p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 465
Wireless Technology in Disease Management and Medicine
Annu. Rev. Med. 2012.63:185-198. Downloaded from www.annualreviews.org

Gari D. Clifford and David Clifton p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 479

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Geographic Variation in Health Care

Tom Rosenthal p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 493
Deep Brain Stimulation for Intractable Psychiatric Disorders
Wayne K. Goodman and Ron L. Alterman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 511
Contemporary Management of Male Infertility
Peter J. Stahl, Doron S. Stember, and Marc Goldstein p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 525

Indexes

Cumulative Index of Contributing Authors, Volumes 59–63 p p p p p p p p p p p p p p p p p p p p p p p p p p p 541

Cumulative Index of Chapter Titles, Volumes 59–63 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 545

Errata

An online log of corrections to Annual Review of Medicine articles may be found at

http://med.annualreviews.org/errata.shtml

Contents vii
 Annual Reviews
It’s about time. Your time. It’s time well spent.

New From Annual Reviews:

Annual Review of Statistics and Its Application
Volume 1 • Online January 2014 • http://statistics.annualreviews.org

Editor: Stephen E. Fienberg, Carnegie Mellon University

Associate Editors: Nancy Reid, University of Toronto
Stephen M. Stigler, University of Chicago
The Annual Review of Statistics and Its Application aims to inform statisticians and quantitative methodologists, as
Annu. Rev. Med. 2012.63:185-198. Downloaded from www.annualreviews.org

well as all scientists and users of statistics about major methodological advances and the computational tools that
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allow for their implementation. It will include developments in the field of statistics, including theoretical statistical
underpinnings of new methodology, as well as developments in specific application domains such as biostatistics
and bioinformatics, economics, machine learning, psychology, sociology, and aspects of the physical sciences.

Complimentary online access to the first volume will be available until January 2015.
table of contents:

• What Is Statistics? Stephen E. Fienberg
• A Systematic Statistical Approach to Evaluating Evidence
from Observational Studies, David Madigan, Paul E. Stang,
Jesse A. Berlin, Martijn Schuemie, J. Marc Overhage,
Marc A. Suchard, Bill Dumouchel, Abraham G. Hartzema,
Patrick B. Ryan
• The Role of Statistics in the Discovery of a Higgs Boson,
David A. van Dyk
• Brain Imaging Analysis, F. DuBois Bowman
• Statistics and Climate, Peter Guttorp
• Climate Simulators and Climate Projections,
Jonathan Rougier, Michael Goldstein
• Probabilistic Forecasting, Tilmann Gneiting,
Matthias Katzfuss
• Bayesian Computational Tools, Christian P. Robert
• Bayesian Computation Via Markov Chain Monte Carlo,
Radu V. Craiu, Jeffrey S. Rosenthal
• Build, Compute, Critique, Repeat: Data Analysis with Latent
Variable Models, David M. Blei
• Structured Regularizers for High-Dimensional Problems:
Statistical and Computational Issues, Martin J. Wainwright
• High-Dimensional Statistics with a View Toward Applications
in Biology, Peter Bühlmann, Markus Kalisch, Lukas Meier
• Next-Generation Statistical Genetics: Modeling, Penalization,
and Optimization in High-Dimensional Data, Kenneth Lange,
Jeanette C. Papp, Janet S. Sinsheimer, Eric M. Sobel
• Breaking Bad: Two Decades of Life-Course Data Analysis
in Criminology, Developmental Psychology, and Beyond,
Elena A. Erosheva, Ross L. Matsueda, Donatello Telesca
• Event History Analysis, Niels Keiding
• Statistical Evaluation of Forensic DNA Profile Evidence,
Christopher D. Steele, David J. Balding
• Using League Table Rankings in Public Policy Formation:
Statistical Issues, Harvey Goldstein
• Statistical Ecology, Ruth King
• Estimating the Number of Species in Microbial Diversity
Studies, John Bunge, Amy Willis, Fiona Walsh
• Dynamic Treatment Regimes, Bibhas Chakraborty,
Susan A. Murphy
• Statistics and Related Topics in Single-Molecule Biophysics,
Hong Qian, S.C. Kou
• Statistics and Quantitative Risk Management for Banking
and Insurance, Paul Embrechts, Marius Hofert

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