The growing interest in applying nanotechnology to
cancer is largely attributable to its uniquely appealing fea-
tures for drug delivery, diagnosis and imaging, synthetic
vaccine development and miniature medical devices, as
well as the therapeutic nature of some nanomaterials
themselves
1–6
(BOX1). Nanotherapies that incorporate
some of these features (for example, improved circula-
tion and reduced toxicity) are already in use today, and
others show great promise in clinical development, with
definitive results expected in the near future. Several
therapeutic nanoparticle (NP) platforms, such as lipo-
somes, albumin NPs and polymeric micelles, have been
approved for cancer treatment, and many other nano-
technology-enabled therapeutic modalities are under
clinical investigation, including chemotherapy, hyper-
thermia, radiation therapy, gene or RNA interference
(RNAi) therapy and immunotherapy (TABLE1).
Along with enormous progress in the field of can-
cer nanomedicine (FIG.1), we have also gradually real-
ized the challenges and opportunities that lie ahead.
Foremost, the complexity and the heterogeneity of
tumours make it clear that careful patient selection is
required to identify those most likely to benefit from
a given nanotherapy. This is analogous to the targeted
therapies approved or under development for use in
specific biomarker-defined patient populations. Most
therapeutic NPs for solid tumour treatment are admin-
istered systemically; they accumulate in the tumour
through the enhanced permeability and retention (EPR)
effect
7–10
, which is generally thought to be the product
of leaky tumour vasculature and poor lymphatic drain-
age. However, this interpretation of EPR is somewhat
oversimplified, as multiple biological steps in the sys-
temic delivery of NPs can influence the effect, such as
NP–protein interaction, blood circulation, extra vasation
into and interaction with the perivascular tumour
microenvironment (TME), tumour tissue pene tration
and tumour cell internalization. In turn, NP properties
(for example, size, geometry, surface features, elasticity,
stiffness, porosity, composition and targeting ligand)
can influence these biological processes, thus deter-
mining the EPR effect and therapeutic outcomes (FIG.2).
Nevertheless, it is important to point out that most of
our current understanding of NP behaviour invivo is
based on animal data, and its translation to NP behav-
iour in humans remains largely unexplored. Although
several studies have examined the pharmaco kinetics
(PK) of nanotherapeutics across species in preclinical
and clinical studies
11–13
, relatively few have correlated
data across species to determine whether and how NP
safety and efficacy in humans can be better predicted
from preclinical animalmodels.
This Review aims to identify gaps in our under-
standing of why cancer nanomedicine has yet to fulfil
its promise in prolonging patient survival, and to offer
an overview of our current grasp of tumour biology
and nano–bio interactions as they relate to maximization
of the impact of cancer nanotherapeutics. Given the
presumed crucial role of EPR, we present recent pro-
gress in exploring this effect and identifying markers
to predict responses to nanotherapies, and in develop-
ing new strategies to enhance systemic NP delivery for
more pronounced EPR and therapeutic benefit. We also
examine the fundamentals behind the development of
1
Center for Nanomedicine
and Department of
Anesthesiology, Brigham and
Women’s Hospital, Harvard
Medical School, Boston,
Massachusetts 02115, USA.
2
Department of Medicine,
Memorial Sloan Kettering
Cancer Center, New York,
New York 10065, USA.
3
Tarveda Therapeutics,
Watertown, Massachusetts
02472, USA.
4
King Abdulaziz University,
Jeddah 21589, Saudi Arabia.
Correspondence to O.C.F.
ofarokhzad@bwh.harvard.edu
doi:10.1038/nrc.2016.108
Published online 11 Nov 2016
Nanoparticle
(NP). Particle of any shape with
dimensions in the 1–100 nm
range, as defined by the
International Union of Pure and
Applied Chemistry (IUPAC).
Despite this size restriction, the
term nanoparticles commonly
applies to structures that are
up to several hundred
nanometres in size, although
key is that design of the
nanostructure produces a
unique function and property.
Cancer nanomedicine: progress,
challenges and opportunities
Jinjun Shi
1
, Philip W.Kantoff
2
, Richard Wooster
3
and Omid C.Farokhzad
1,4
Abstract
|
The intrinsic limits of conventional cancer therapies prompted the development and
application of various nanotechnologies for more effective and safer cancer treatment, herein
referred to as cancer nanomedicine. Considerable technological success has been achieved in this
field, but the main obstacles to nanomedicine becoming a new paradigm in cancer therapy stem
from the complexities and heterogeneity of tumour biology, an incomplete understanding of
nano–bio interactions and the challenges regarding chemistry, manufacturing and controls
challenges and opportunities in cancer nanomedicine and discusses novel engineering
approaches that capitalize on our growing understanding of tumour biology and nano–bio
interactions to develop more effective nanotherapeutics for cancer patients.
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Enhanced permeability and
retention (EPR) effect
The mechanism resulting from
pathophysiological processes
(for example, leaky tumour
vasculature, poor lymphatic
drainage and tumour
microenvironment interactions)
that leads to the accumulation
and retention of nanoparticles
or macromolecules in tumours.
Nano–bio interactions
The interactions between
nanoparticles and biological
systems (for example, serum
proteins, extracellular matrix,
cells and organelles) that
determine the biological fates
of nanoparticles, such as
circulation half-life,
biodistribution, tumour
accumulation, tumour cell
internalization and tumour
microenvironment distribution.
Excipients
Substances other than the
active pharmaceutical
ingredient (API) that are
included in the manufacturing
process of a medication or are
contained in a finished
pharmaceutical product
dosage form.
C
max
The maximum serum
concentration that a drug or
nanoparticle achieves after
administration.
nanotechnologies to target the TME, which has such an
important role in tumour progression and metastasis
14,15
,
and lastly, provide our perspective on challenges to the
clinical translation of cancer nanomedicines.
Arsenal of nanomedicine platforms
Nanotechnology has made important contributions to
oncology over the past several decades (FIG.1;TABLE1).
Liposomes (for example, liposomal doxorubicin (LD);
Doxil and Myocet) were the first class of therapeutic
NPs to receive clinical approval for cancer treatment
16
,
and along with other lipid-based NPs, still represent
a large proportion of clinical-stage nanotherapeutics.
Although encapsulating drugs in liposomes has been
broadly shown to improve PK and biodistribution, as yet
no marketed liposomal therapeutic agents have exhib-
ited an overall survival (OS) benefit when directly com-
pared with the conventional parent drug
17
. The recent
phaseIII results of liposomal cytarabine– daunorubicin
(Vyxeos; also known as CPX-351) compared with the
standard of care regimen of cytarabine and dauno-
rubicin in patients with high-risk acute myeloid leu-
kaemia, showed improved OS of9.56months versus
5.95months
18
. This is encouraging for the field of can-
cer nanomedicine and regulatory filing for theapproval
ofVyxeos is projected in late 2016. NP albumin-bound
paclitaxel (nab- paclitaxel; Abraxane) was the second
class of nanomedicines to be commercialized. The nab
platform enables formulation of hydrophobic drugs
while largely mitigating the need to use toxic excipients.
The result may be a better-tolerated drug that can be
used at higher doses and administered more quickly,
thus enabling a higher drug C
max
and plasma area
under the curve (AUC). Upon intravenous infusion,
nab- paclitaxel rapidly dissociates into its albumin
and paclitaxel constituents and has not been demon-
strated to substantially alter the PK and biodistribution
of paclitaxel. Although the every-3-week dosing sched-
ule of nab-paclitaxel is superior to paclitaxel in terms
of response rate and time to progression for patients
with breast cancer
19
, a once-per-week dosing schedule
did not show similar trends in progression-free survival
(PFS) or OS and furthermore, showed increased tox-
icity
20
. Polymeric micelles (for example, Genexol-PM
21
and NK105 (REF.22)) and polymeric NPs (for example,
CRLX101 (REF.23), BIND-014 (REF.11) and AZD-2811
Accurin
24
) are two newer classes of cancer nano-
therapeutic agent. Most recently, disappointing clinical
results have been reported for BIND-014, CRLX101 and
NK105, underscoring the need to rethink development
strategies, including potential patient selection to iden-
tify those most likely to respond to nano therapeutics.
Inorganic nanomaterials (for example, gold nanoshell
25
,
iron oxide NP
26
and hafnium oxide NP
27
) are also being
investigated for use in cancer patients, with the iron
oxide NP-based NanoTherm
26
already marketed in
Europe forglioblastoma.
More intriguingly, our understanding of nano– bio
interactions and the arsenal of nanomedicine platforms
are expanding rapidly. The total number of papers
related to ‘nanoparticle’ on PubMed nearly doubled
every 2years between 2000 and 2014, surpassing the
remarkable rise of the number of publications on ‘mono-
clonal antibody’ (mAb) in the 1980s. In the case of mAb
this translated to the development of important thera-
peutics, and we expect a similar transformative impact
from the rise of nanomedicine in the years tocome.
Beyond their widely reported use as carriers for
chemo therapeutics, NPs have shown potential for the
delivery of various new anticancer therapeutic agents,
including molecularly targeted agents
24
, antisense oligo-
nucleotides
28,29
, small interfering RNA (siRNA)
30–33
,
mRNA
34
and DNA inhibitor oligonucleotides
35
. Further-
more, the use of viral NPs for therapeutic delivery has
been facilitated by genetic and chemical engineer-
ing techniques
36
. Examples include the use of adeno-
associated virus, approved by theEuropean Commission
for lipoprotein lipase deficiency
37
, lentivirus currently
in various clinical trials for cell-based gene therapy and
immunotherapy of various diseases including cancer
38
,
and engineered plant viruses (for example, tobacco
mosaic virus and potato virus X) for cancer therapy in
animal models
39,40
. With their endo genous origin and
organ tropism, exosomes have also been proposed for
carrying anticancer payloads to target tumours
41
. Lastly,
novel inorganic NPs such as nano diamond
42,43
and
graphene
44,45
have received considerable attention for
cancer therapy.
We are also already seeing in-depth innovation in
nanomedicine strategies. By integrating diagnostic and
therapeutic functions into a single NP formulation,
theranostic nanomedicine offers a promising strategy to
monitor the PK and accumulation of therapeutics and
the progression of disease, giving important insights
into heterogeneities both within tumours and between
patients for potential personalized treatment
46,47
. By
co-delivering multiple active pharmaceutical ingre-
dients (APIs), NPs have also facilitated synergistic
Box 1
|
Distinctive features of nanotechnology in oncological applications
• Improvement of the drug therapeutic index by increasing efficacy and/or
reducingtoxicities
• Targeted delivery of drugs in a tissue-, cell- or organelle-specific manner
• Enhancement of the pharmaceutical properties (for example, stability, solubility,
circulating half-life and tumour accumulation) of therapeutic molecules
• Enabling of sustained or stimulus-triggered drug release
• Facilitation of the delivery of biomacromolecular drugs (for example, DNA, small
interfering RNA (siRNA), mRNA and protein) to intracellular sites of action
• Co-delivery of multiple drugs to improve therapeutic efficacy and overcome drug
resistance, by providing more precise control of the spatiotemporal exposure of each
drug and the delivery of appropriate drug ratio to the target of interest
• Transcytosis of drugs across tight epithelial and endothelial barriers (for example,
gastrointestinal tract and the blood–brain barrier)
• More sensitive cancer diagnosis and imaging
• Visualization of sites of drug delivery by combining therapeutic agents with imaging
modalities, and/or real-time feedback on the invivo efficacy of a therapeutic agent
• Provision of new approaches for the development of synthetic vaccines
• Miniaturized medical devices for cancer diagnosis, drug screening and delivery
• Inherent therapeutic properties of some nanomaterials (for example, gold nanoshells
and nanorods, and iron oxide nanoparticles) upon stimulation
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Table 1
|
Examples of clinical-stage nanomedicines for cancer therapy
Therapy
modality
Generic name
and/or proprietary
name
Nanotechnology
platform
Active
pharmaceutical
ingredients
Cancer type Status Refs
Chemotherapy:
non-targeted
delivery
Liposomal
doxorubicin (Doxil)
Pegylated
liposome
Doxorubicin HIV-related Kaposi sarcoma,
ovarian cancer, and multiple
myeloma
Approved by
FDA
6
Liposomal
daunorubicin
(DaunoXome)
Liposome Daunorubicin HIV-related Kaposi sarcoma Approved by
FDA
6
Liposomal vincristine
(Marqibo)
Liposome Vincristine sulfate Acute lymphoblastic leukaemia Approved by
FDA
6
Liposomal irinotecan
(Onivyde or MM-398)
Pegylated
liposome
Irinotecan Post-gemcitabine metastatic
pancreatic cancer
Approved by
FDA
230
Liposomal
doxorubicin (Myocet)
Liposome Doxorubicin Metastatic breast cancer Approved in
Europe and
Canada
6
Mifamurtide (Mepact) Liposome Muramyl tripeptide
phosphatidyl-
ethanolamine
Nonmetastatic, resectable
osteosarcoma
Approved in
Europe
6
Nab-paclitaxel
(Abraxane)
Albumin NP Paclitaxel Breast, lung and pancreatic
cancer
Approved by
FDA
6
SMANCS Polymer conjugate Neocarzinostatin Liver and renal cancer Approved in
Japan
6
Polymeric
micelle paclitaxel
(Genexol-PM)
Polymeric micelle Paclitaxel Breast cancer and NSCLC Approved in
Korea
6
Liposomal cisplatin
(Lipoplatin)
Pegylated
liposome
Cisplatin NSCLC 231
NK-105 Polymeric micelle Paclitaxel Metastatic or recurrent breast
cancer
232
Liposomal paclitaxel
(EndoTAG-1)
Liposome Paclitaxel Pancreatic cancer, liver
and triple-negative breast
cancer
233–236
Nab-rapamycin
(ABI-009)
Albumin NP Advanced malignant PEComa
mutations
237,238
Polymeric NP Camptothecin NSCLC, metastatic renal cell
carcinoma and recurrent ovarian,
tubal or peritoneal cancer
239–241
Chemotherapy:
targeted delivery
MM-302
liposome
Doxorubicin -positive breast cancer 242
BIND-014 PSMA-targeting
polymeric NP
Docetaxel 243–245
MBP-426
liposome
Oxaliplatin Gastric, oesophageal
and gastro-oesophageal
adenocarcinoma
246
immunoliposomes
loaded with
doxorubicin
liposome
Doxorubicin Solid tumours 247
Chemotherapy:
stimuli-responsive
delivery
ThermoDox Liposome Doxorubicin Hepatocellular carcinoma 248
Chemotherapy:
combinatorial
delivery
Liposomal
cytarabine–
daunorubicin
(CPX-351 or Vyxeos)
Liposome Cytarabine and
daunorubicin (5:1)
High-risk acute myeloid
leukaemia
249
CPX-1 Liposome Irinotecan and
floxuridine (1:1)
Advanced colorectal cancer 250
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cancer therapy and avoided some mechanisms of drug
resistance, as evidenced by the large number of invivo
examples (TABLE2). In addition to drug delivery, nano-
technology is gaining momentum in the area of cancer
immunotherapy. NPs have become increasingly attractive
as potent antigen or adjuvant carriers for the develop-
ment of synthetic vaccines, with enhanced tissue pene-
tration and/or access to lymphatics, preferential uptake
Therapy
modality
Generic name
and/or proprietary
name
Nanotechnology
platform
Active
pharmaceutical
ingredients
Cancer type Status Refs
Hyperthermia NanoTherm Iron oxide NP NA Glioblastoma Approved in
Europe
6
AuroLase Silica core with a
gold nanoshell
NA Head and neck cancer, and
primary and metastatic lung
tumours
Pilot study 251,252
Hafnium oxide NP NA Adult soft tissue sarcoma 253
therapy
SGT53
liposome
Plasmid encoding
normal human
wild-type p53 DNA
metastatic pancreatic cancer
254,255
PNT2258 Liposome DNA
oligonucleotide
against BCL-2
non-Hodgkin lymphoma and
diffuse large B-cell lymphoma
256,257
SNS01-T Polyethylenimine
NP
eIF5A and plasmid
expressing
malignancies
258
Atu027 Liposome
protein kinase N3
Advanced or metastatic
pancreatic cancer
259
TKM-080301 Lipid NP Neuroendocrine tumours,
adrenocortical carcinoma
and advanced hepatocellular
carcinoma
260,261
Lipid NP Dicer-substrate
Hepatocellular carcinoma 262
Liposome Primary liver cancer, solid
tumours and haematological
malignancies
263
CALAA-01
polymeric NP
ribonucleotide
reductase M2
Solid tumours 227
ALN-VSP02 Lipid NP
and VEGFA
Solid tumours 264,265
Liposome
EPHA2
Advanced cancers 266
Lipid NP
stathmin 1
cancer
267
Immunotherapy Tecemotide Liposome MUC1 antigen NSCLC 268
AS15 Liposome
and AS15 adjuvant
Metastatic breast cancer 269
DPX-0907 Liposome Multi-tumour
associated antigens
HLA-A2-positive advanced stage
ovarian, breast and prostate
cancer
270
Lipovaxin-MM Liposome Melanoma antigens Malignant melanoma 271
Lipid NP Plasmid DNA 272
Colloidal gold NP TNF Advanced solid tumours 273
co
Table 1 (cont.)
|
Examples of clinical-stage nanomedicines for cancer therapy
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Area under the curve
(AUC). The area between the
curve and the x-axis in a plot of
drug or nanoparticle blood
plasma concentration against
time.
Payloads
The therapeutic or diagnostic
agents carried by nanoparticles.
by antigen-presenting cells, sustained release of antigens
or adjuvants and NP-mediated phagosome escape of
antigens for cross-presentation
4,48–50
.
Nanotechnology may also hold great potential for
addressing the shortcomings associated with biologics,
including mAbs that are used for cancer immunotherapy.
For example, the administration of biologic drugs can
induce the formation of antidrug antibodies (ADAs) that
may adversely affect their safety and efficacy
51
. Recently
engineered tolerogenic NPs carrying rapamycin were
shown to abolish the formation of ADAs for biologics
in mice and non-human primates
52
, and human clinical
trials are currently ongoing
53
. Our expectation is that by
gaining a deeper insight into nano–bio interactions and
the personalization of nanomedicines, and through the
application of nanotechnology to existing and emerging
therapeutic modalities, we will begin to realize the true
potential of nanomedicine in cancer andbeyond.
The EPR effect in predictive nanomedicine
Despite efforts to develop non-invasive administration
(for example, oral, pulmonary, nasal and transdermal)
of NPs
54–56
, most cancer nanotherapeutics are delivered
intravenously for systemic transport to tumours. The
preferential accumulation of NPs in tumours is gener-
ally ascribed to defective tumour vessels and impaired
lymphatics in the tissue: enhanced permeability of the
abnormal tumour microvasculature enables NPs to
enter the tumour interstitial space, while suppressed
lymphatic drainage causes retention within the tissue.
The EPR effect
7–10
has become the foundation of NP
delivery to solid tumours. Nevertheless, it is increas-
ingly clear that EPR varies substantially between both
patients and tumour types, and even within the same
patient or tumour type over time. However, little effort
has been made to address the effect of EPR on nano-
therapeutic efficacy. Several preliminary clinical studies
have already suggested the value of stratifying subpopu-
lations of cancer patients according to their likelihood of
accumulating NPs through EPR
57–59
, implying that pre-
dictive markers for EPR may have a role in the clinical
success of cancer nanotherapies.
In our previous review of EPR
9
, we discussed the
parameters of the TME, some of which are well charac-
terized for their interactions with NPs, whereas others
are considered a ‘black box’ requiring extensive investi-
gation. Recently, there has been growing emphasis on the
role of tumour-associated macrophages (TAMs) in NP–
TME interactions
60–63
. TAMs have also been proposed as
a reservoir of nanotherapeutics from which the payload
is gradually released to neighbouring tumour cells
62
.
Using high-resolution intravital imaging microscopy,
a recent work systematically studied the extravasation
and intratumoural distribution of two different types of
NP
63
: the clinically approved 30 nm magnetic NP (MNP)
ferumoxytol
64
and a 90 nm poly meric NP composed of
poly(,-lactic-co- glycolic acid)-b-poly(ethylene gly-
col) (PLGA-PEG)
11,65,66
. Despite differences in both size
and composition, MNP and polymeric NP exhibited
similar PK after simultaneous intravenous injection,
and co localized to varying degrees in cancer cells and
TAMs. Furthermore, after co-administration of MNPs
and docetaxel-encapsulated PLGA-PEG NPs, tumour
MNP levels showed a significant correlation with NP
payload levels. Consequently, the MNP accumulation
level successfully predicted the anticancer efficacy of
the thera peutic polymeric NPs. A pilot clinical study
was also recently initiated to assess ferumoxytol as a
marker to predict tumour response to the nano liposomal
irinotecan MM-398 (REFS57,61,67). Preliminary analysis
1964 1976 1980 1986 1994 1995 2005 2007 2008 2010 2011 2014 2015
Liposome
structure
was
published
223
First controlled-
release polymer
system for ionic
molecule and
macromolecules
225
Liposomal
doxorubicin (Doxil)
approved by FDA
6
Protein
biomarkers
for predicting
73,74
First targeted siRNA
polymeric NP (CALAA-01)
entered clinical trials
227
Nab-paclitaxel
(Abraxane)
approved by FDA
6
Discovery
of the EPR
7,8
First targeted
liposomes
152,153
Long
circulating
PLGA-PEG
NPs
93
Polymeric micelle
paclitaxel
(Genexol-PM)
marketed in Korea
226
Ferumoxytol
as an imaging
agent to
predict EPR
and nano-
therapeutic
response
63
Iron oxide NP
(NanoTherm)
received
European
regulatory
approval for
cancer
treatment
228
PRINT technology
developed
212
First targeted, controlled-
release polymeric NP (BIND-014)
entered clinical trials
229
Cell membrane-coated
NPs developed to evade
immune response
100
Sustained
delivery of
low molecular
weight
compounds
using silicone
polymer
224
Figure 1
|
Historical timeline of major developments in the field of cancer nanomedicine.
PLGA-PEG, poly(,lactic-co-glycolic acid)-b
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