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Chinese Journal of Cancer

Review

Recent progress in nanotechnology for cancer therapy


MuFei Tang1, Lei Lei1, ShengRong Guo1, WenLin Huang2,3
1

School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, P. R. China 2 State Key Laboratory of Oncology in South China,

Guangzhou, Guangdong 510060, P. R. China 3 Research Department, Sun Yatsen University Cancer Center, Guangzhou, Guangdong
510060, P. R. China

Abstract

Key words:

In recent years, significant efforts have been devoted to


develop nanotechnology to enhance the delivery of
anticancer drug to tumor tissue while minimizing its
distribution and toxicity in healthy tissue. Many developed
innovative nanotechnology platforms, such as polymeric
nanoparticles, liposomes, dendrimers, nanoshells, carbon
nanotubes, superparamagnetic nanoparticles, and nucleic
acidbased nanoparticles [DNA, RNA interference (RNAi),
and antisense oligonucleotide (ASO)], have been applied to
the delivery of specific anticancer drugs, including small
molecular weight drugs and macromolecules (proteins,
peptides or genes). The physicochemical characteristics of
nanotechnology platforms, such as composition, particle
size, surface charge, surface functionalization with hydrophilic
polymers, and inclusion of tissuerecognition ligands, will
conduct their biodistribution and pharmacokinetics[1]. Hereby,

Correspondence to: ShengRong Guo Tel: +862134204793


Email:srguo@sjtu.edu.cn
This paper was edited byWei Liu.

These authors contributed equally to this work.

the nanotechnology platforms could serve as customizable,


targeted drug delivery vehicles capable of carrying large
dose of therapeutic agents into malignant cells while
avoiding healthy cells. This article overviewed current
nanotechnologies for cancer therapy, focusing on the wide
variety of nanotechnological platforms for anticancer drug
delivery and nanotechnologies for combination therapeutic
strategies.

The most common examples of nanotechnology


platforms
for
cancer
therapy
include
polymeric
nanoparticles, liposomes, dendrimers, nanoshells, carbon
nanotubes, and superparamagnetic nanoparticles. With
small size and various structural and physicochemical
features, these nanotechnology platforms can enter tumor
vasculature through enhanced permeability and retention
effect (EPR). The use of cancerspecific targeting residues
(e.g. antibodies, ligands, and lectins) can also achieve
tumor cell targeting.

Received: 20100220 Accepted: 20100705


Grants: National Natural Science Foundation of China (No. 30811120440)
Shanghai Science and Technology Committee (No. 08410701800)

www.cjcsysu.cn

Polymeric nanoparticles are prepared from natural or


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Chinese Journal of Cancer


synthesized
polymers.
Various
biodegradable
or
unbiodegradable polymers can be used to prepare
nanoparticles in order to achieve expected drug delivery
performance and therapeutic effect. Among these,
biodegradable polymeric nanoparticles for anticancer drug
delivery have attracted great interest in recent years since
they could provide controlled, sustained and targeted
delivery. Polymeric nanoparticles, the most effective
nanotechnology platforms, have emerged as a versatile
carrier system for targeted delivery of anticancer drugs[2,3].
Bernardi
.[4] investigated the effect of indomethacin
loaded nanocapsules on a xenograft glioma model in rats.
The rats presented a significant reduction in tumor size and
half of them presented just residual tumor cells moreover,
the animal survival rate was much larger in the drugloaded
nanocapsule group than in the control (untreated),
indomethacin and drugunloaded nanocapsule groups[4].
Polymeric nanoparticles can deliver not only small
molecular weight drugs but also macromolecules such as
genes and proteins. A system made up of poly (D,
Llactidecoglycolide) nanoparticles, a potent protease
inhibitor (cystatin) and cytokeratinspecific monoclonal
antibody, has been reported. It can neutralize the activity of
excessive proteolysis in order to prevent the metastatic and
invasive potential of breast tumor cells[5]. To stabilize the
surface of nanoparticle or achieve active targeting,
conjugating, grafting and adsorbing hydrophilic polymers,
such as polyethylene glycol (PEG), are usually used.
Copolymer pegylation and folate conjugation can improve
the stability of selfassemblies in aqueous medium and the
tumor site selectivity in vivo of ringopening metathesis
polymerizationbased copolymers[6]. By covalent coupling of
humanized monoclonal
antibodies
(antiHER2)
to
paclitaxelloaded poly (D, Llactic acid) nanoparticles,
immunonanoparticles were prepared to actively target tumor
cells which overexpress HER2 receptors[7]. Recently, Patil
.[8] produced PLAPEGligand conjugate nanoparticles by a
singlestep surface functionalizing technique, and found that
simultaneous functionalization with biotin and folic acid
induced great efficacy of paclitaxelloaded nanoparticles in a
MCF7 tumor xenograft model by enhancing drug
accumulation in tumors.
Mitoxantroneloaded polybutylcyanacrylate nanoparticles
(DHADPBCANPs) have presented a good effect on
orthotopically transplanted hepatocellular carcinoma (HCC)
in nude mice. Therefore, the activity and toxicity of
DHADPBCANPs in individuals with unresected HCC were
evaluated in a phase II clinical trial[9]. The median survival
was much longer in the DHADPBCANPs group than in the
DHAD injection group (5.46 months vs. 3.23 months)[9].
Polymeric nanoparticles are currently the most widely
investigated nanotechnology platform for cancer therapy,
despite many challenging defects or drawbacks need to be
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resolved before clinical application. It is also considered as


the most promising vehicle for sitetargeting anticancer
drug delivery and disease diagnosis because of its good
variability of chemical structures through chemical
modification and the resulting flexibility of physicochemical
characteristics
enabling
its
diverse drug
delivery
applications.

As closed spherical vesicles, liposomes consist of a


lipid bilayer which encapsulates an aqueous phase to store
drugs[10]. With the size (90150 nm) which is slightly bigger
than the conventional definition (100 nm), liposomes do
not constitute novel nanotechnology, but a large portion of
them are associated with nanotechnology research[11].
Forming lipid bilayers through hydrophobic interaction,
liposomes are considered as excellent platforms for the
delivery of hydrophobic and hydrophilic drugs. In particular,
liposomes present considerable persistence in the blood. It
facilitates efficient drug delivery to target tissues. Different
lipids have different fatty acid chain lengths, different head
groups, and different melting temperatures. Consequently,
temperature [12] or pH sensitive [1315] liposomes can be
constructed by manipulating the formulation. The
effectiveness of 1methylxanthine
(1MTX) as a
radiosensitizer and the in vivo efficacy of the
temperaturesensitive liposomal 1methylxanthine (tslMTX)
which combined with regional hyperthermia and ionizing
radiation were evaluated[12]. Intraperitoneal injection of the
tslMTX inhibited tumor growth in the mouse xenograft
tumor model moreover, the combination of tslMTX with
regional hyperthermia and ionizing radiation obviously
inhibited tumor growth[12]. Most recently, to target leukemic
cells, pHsensitive immunoliposomes (ILs) including a
terminally alkylated Nisopropylacrylamide (NIPAM) in the
bilayer were coupled with the antiCD33 monoclonal
antibody [15]. The pHsensitive ILsCD33 immunoliposomes
exhibited high cytotoxicity against HL60 cells, suggesting
that the pHsensitive immunoliposomes could be profitable
in acute myeloid leukemia therapy.
Commercial liposomes have already gained approval
from US Food and Drug Administration (FDA). The typical
example is doxorubicinencapsulated liposomes (Doxil),
which has strong antitumor activity against a wide range of
cancers.

As highly branched artificial macromolecules with


treelike structures, dendrimers
are monodisperse,
threedimensional molecules which have defined molecular
weights and hosteguest entrapment properties[16]. With the
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Chinese Journal of Cancer


size ranging from 1 to 10 nm, dendrimers with different
chemical structures and functional groups can be
synthesized. Through a series of repeating chemical
synthesis on the core, the size and shape of dendrimers are
determined by the generation. The key useful character of
dendrimers is the branches which can provide vast amounts
of surface area for drugs and targeting molecules[11,17].
Meanwhile, the surface functionalities, interior branching,
and chemical composition of the core play a significant role
in reactiviting the macromolecule[17].
Dendrimer is one of the most elegant nanotechnology
platforms for targeted drug delivery. Conjugated with biotin
as the targeting moiety, the in vitro targeting ability of
partially acetylated generation 5 polyamidoamine (PAMAM)
dendrimer (AcG5) in HeLa cells was assessed[18]. The
multifunctional
conjugate
AcG5biotinFITC
(fluoresceinisothiocyanate) showed much higher cellular
uptake
than
the
conjugate
without
biotin.
The
energydependent uptake process can be blocked effectively
by biotinpolymer conjugates, exhibiting an expected
doseresponse curve.

As the layerbylayer assembly of nanoparticles,


polymeric nanoshells (2060 nm) of diblock copolymers can
be made by selfassembly of oppositely charged polymers
forming a core/shell structure [19]. With a biodegradable
polymer core and mixed lipid monolayer shell, a system of
folic acidconjugated nanoparticles was developed for
targeted delivery of docetaxel[20]. Gold nanoshells (10 to 300
nm) are optically tunable nanoparticles comprising a
dielectric core with a thin gold shell surrounded[21]. In order
to achieving maximal penetration of light through tissue over
the nearinfrared, gold nanoshells can be designed by
adjusting the core radius and the shell thickness[21].
Laseractivated gold nanoshells thermal ablation is a
selective and effective technique for the ablation of prostate
cancer in an ectopic tumor model[22].

As a distinct molecular form of carbon atoms which


bond with each other via sp2 bonds and present a
hexagonal arrangement, carbon nanotubes were first
discovered in the late 1980s[11,23]. Conceptually, carbon
nanotubes are described as wellordered, hollow nanotubes
formed when single or multiple graphene sheets are rolled
into a cylinder[23,24]. The two forms of carbon nanotubes are
single and multiwalled carbon nanotubes. In the family of
nanotechnology platforms, carbon nanotubes have been
identified as a novel tool for anticancer drug delivery[25].
Apart from that, carbon nanotubes can immobilize
molecules, such as antibodies, DNA and drugs[2628], in order

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to penetrate cell membranes. Heister


.[26] have used an
oxidized singlewalled carbon nanotube, consisting of a
fluorescent marker and a monoclonal antibody at
noncompeting binding sites, to delivery anticancer drug
doxorubicin. However, because of the needlelike fiber
shape, the safety of carbon nanotubes is concerned.
Recently, the biological impacts (cytotoxicity, DNA damage,
and inflammation) induced by differentsized multiwalled
and singlewalled carbon nanotubes, have been studied[29].
The results demonstrate that long and thick multiwalled
carbon nanotubes probably induce severe biological effects
and may cause the augmentation of cancer risk.

Superparamagnetic nanoparticles, iron oxide magnetic


nanoparticles with particle sizes of about 20 nm, are
Fe3O
do not keep any
composed of Fe2O
3 or
4 and
magnetism after removal of the magnetic field, hence, may
be used in vivo[30]. Superparamagnetic nanoparticles can be
used as contrast agents for magnetic resonance imaging
(MRI), can be used for cancer thermal therapy, and can
concentrate in target sites through an external magnetic
field. Functionalized with recombinant single chain Fv
antibody fragments (scFv), superparamagnetic iron oxide
nanoparticles (SPIONs) could be used to target and image
cancer cells[31]. Conjugated to luteinizing hormone releasing
hormone (LHRH), SPIONs not only achieve breast cancer
cell targeting but also play the role as contrast agents in the
MRI of breast cancer xenografts[32]. The postmortem
neuropathologic studies of glioblastoma multiforme (GBM)
patients treated with thermotherapy using magnetic
nanoparticles were reported[33]. Magnetic nanoparticles were
injected into the tumor and then heated in an alternating
magnetic field. The instillation of magnetic nanoparticles in
GBM patients induced the uptake of nanoparticles in
macrophages to a major extent, and the uptake was further
promoted by magnetic fluid hyperthermia (MFH) therapy[33].

Gene therapy refers to the direct transfer and


expression of DNA into diseased cells for the therapeutic
. [35] have developed a ligand
applications[34]. Veiseh
mediated nanovector by binding the chlorotoxin (CTX)
peptide and pegylation of DNAcomplexing polyethylenimine
(PEI) in nanoparticles which functionalized with an Alexa
Fluor 647 near infrared fluorophore . Mixed nanoparticles,
prepared with generations 4 and 5 poly (amidoamine)
(PAMAM) dendrimers and plasmid DNA, were confirmed to
be effective for both in vitro and in vivo gene delivery to
colon and liver cancer cells[36]. Based on oligonucleotides,
RNAi and ASO ther apies can shut down the expression of
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Chinese Journal of Cancer


target genes to treat the disease[19]. Recently, siRNA
nanoparticles were first designed with Poly (Propyleneimine)
(PPI) dendrimers[37].

The resistance to chemotherapy is a substantial clinical


problem limiting the effectiveness of anticancer drug
treatment. Because of microenvironmental selection
pressures, tumor cells can generate multidrug resistance
(MDR). MDR of cancer cells refers to resilience against
functionally and structurally unrelated drugs[38]. The
mechanisms of MDR include sequestration, increased drug
efflux, decreased drug influx, binding site modification,
activation of detoxifying enzymes, blocked apoptotic
signaling, and DNA repair[39]. In order to overcome MDR, the
nanotechnology for combination therapeutics has attracted
increasing attention in these years. Drug delivery combined
with various modulations (e.g. modulation of drug efflux,
apoptotic threshold, and intracellular pH) and energy
therapies (e.g. ultrasound, hyperthermia, and photodynamic
therapy) have shown significant promise in enhancing MDR
cancer therapy.

Combining chemotherapeutic agent with MDR


modulator is a common solution for overcoming MDR in
cancer therapy. Overexpression of ATPbinding cassette
(ABC) transporters which are involved in drug efflux, is a
key factor in cancer MDR [40]. Among various ABC
transporters, Pglycoprotein
(Pgp/MDR1/ABCB1) is
commonly expressed in drugresistant cells. Tariquidar, one
of the third generation Pgp inhibitors, has shown marked
effectiveness in early clinical trials. Patil
. [41] have
investigated overcoming MDR by targeted delivery of
paclitaxel, using tariquidar as the Pgp modulator and poly
(D,Llactidecoglycolide) nanoparticles as the platform
which were functionalized with biotin on the surface. The
accumulation of paclitaxel in drugresistant tumor cells
resulted in enhanced therapeutic efficacy of the
nanoparticles[41]. After treatment with biotinfunctionalized
nanoparticles which loaded both paclitaxel and tariquidar
(the paclitaxel dose was ineffective without tariquidar), the
growth of drugresistant tumor in mice was significantly
inhibited[41]. Several other ABC transporters also contribute
to MRD, such as multidrug resistanceassociated protein
(ABCC1/MRP1) and breast cancer resistance protein
(ABCG2/BCRP)[40,42,43]. However, nonABC transporters were
also studied to develop combination therapeutics for the
modulation of drug efflux. One approach is the use of Cdc2.
RLIP76, a nonABC, stressresponsive drug transporter,
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conjugates glutathioneelectrophileconjugate (GSE), which


is overexpressed in various cancers. As a cell cycle check
point control kinase, Cdc2 can bind to RLIP76 during
mitosis and inhibit endocytosis[44]. Liposomal Cdc2 delivery
to H358 cells induced apoptosis, increased intracellular
accumulation of doxorubicin, and decreased drug efflux
from the cells[44]. The marked obstructing effect of liposomal
Cdc2 delivery on drug efflux indicates a big potential for a
novel MDR cancer therapy by combining chemotherapeutic
agent with Cdc2.
For MDR cancers, a high apoptotic threshold can be
caused by increased expression of antiapoptotic factors or
inhibition of proapoptotic factors. Survivin, a member of
inhibitor of apoptosis protein (IAP) family, is overexpressed
in MDR cancer cells. Codelivery of docetaxel and
iSurpDNA, a suppressor of survivin, showed combined
effect of anticancer drug and gene therapy[45]. A
folatemodified multifunctional nanoassembly (FNA) was
manufactured and used for the research of human HCC[45].
Compared with free docetaxel and FNAs loading only
iSurpDNA, FNAs loading both docetaxel and iSurpDNA
presented much higher cytotoxicity to HCC cells both in vitro
and in vivo[45]. The main challenge of gene therapy is the
effective delivery. Combining targeted delivery of anticancer
drug with the modulation of apoptotic threshold, FNAs is an
efficient strategy for overcoming MDR.
As one of the distinguishing characteristics of MDR
cells, decreased intracellular pH can be exploited to design
nanoparticulate delivery. In order to improve the therapeutic
efficacy of doxorubicin (DOX) on MDR cancers, two
polymeric nanoconjugates were developed and micelles
based on the conjugates were decorated with v3 integrin
targeting ligand (RGD4C) for active cancer targeting[46]. Using
the pHsensitive hydrazone bonds , DOX was conjugated
to the degradable poly (ethylene oxide)blockpoly (3
caprolactone) (PEObPCL) core in the first formulation,
which named RGD4CPEObP (CLHydDOX) the second
formulation, named RGD4CPEObP (CLAmiDOX), was
obtained by conjugating DOX to the core using the more
stable amide bonds[46]. Based on AFM and DLS, both two
block copolymerDOX conjugates selfassembled into
spherical nanoparticles (60 to 90 nm)[46]. Both micelles did
not release detectable DOX levels at physiological pH of
7.2, but the release significantly increased at pH 5.0 [46]. In
vitro studies showed that both micelles decorated with
RGD4C can effectively increase the therapeutic efficacy of
DOX on human MDA435/LCC6 MDR cancer[46]. The active
targeting of pHsensitive carriers may further decrease the
cytotoxicity to normal cells, thereby conferring a benefit on
the treatment of aggressive MDR cancers.

Ultrasound is used in many medical applications,


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Chinese Journal of Cancer


especially cancer therapy. Recently, the ability of ultrasound
to induce controlled release of tumorlocalized drugs from
nanotechnology platforms has been studied. Schroeder
.[47] exposed Stealth cisplatin to low frequency ultrasound
(LFUS) (3.3 W/cm2) for different periods of time (30180 s)
to induce a timedependent release, and achieved a release
amount of 62% after 180 s of LFUS irradiation. Then, the
ability of LFUS to improve the anticancer efficacy of
cisplatinloaded nano sterically stabilized liposomes (nSSL)
was studied[48]. In J6456 murine lymphoma tumors that
exposed to LFUS, about 70% of cisplatin was release,
which was much larger than those not exposed to LFUS (<
3% )[48]. The therapeutic efficacy of LFUSinduced localized
cisplatin release was studied on BALB/c mice bearing C26
colon adenocarcinoma[48]. Compared with other groups, the
group treated by cisplatinloaded nSSL combined with LFUS
had the best therapeutic effect that tumors not only
stopped proliferating but also regressed over time[48]. Using
ultrasound to enhance the drug release of targeting carriers
is probably a viable technique for MDR cancer therapy.
Many studies on overcoming MDR also focus on
combing drug delivery with hyperthermia. Combining
hyperthermia with folate receptortargeted thermosensitive
magnetic liposomes loaded with doxorubicin (MagFolDox)
was described [49]. At 42.5 and 43.5 , magnetic
hyperthermia significantly increased the tumor cytotoxicity of
MagFolDox[49]. It indicates that a system of physical and
biological drugtargeted delivery combined with hyperthermia
can be used advantageously for cancer therapy.
Photodynamic therapy (PDT) is a therapeutic modality
used in cancer treatment. Combination of drug delivery and
PDT has been used to target MDR cancer cells. Khdair
.[50] have studied the effect of doxorubicin nanoparticles in
combination with PDT on MDR cancer in a mouse tumor
model. Surfactantpolymer hybrid nanoparticles, which
composed of AerosolOTTM (AOT) and sodium alginate,
were used for synchronized delivery of doxorubicin and
methylene blue[50]. With Balb/c mice bearing mammary
adenocarcinoma as a MDR tumor model, the combination
therapy significantly enhanced drug accumulation and
inhibited tumor proliferation[50]. Combining PDT with
drugloaded nanoparticles may be a promising technique to
overcome MDR in cancer therapy.

Nanotechnology has many advantages in cancer


therapy. With small size, nanotechnology platforms can
enter tumor vasculature via EPR. Besides, functionalization
with hydrophilic polymer/oligomer can offer a long circulation
halflife and prolong the exposure time of tumor tissue to

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anticancer agents whereas inclusion of tissuerecognition


residues, such as antibodies, lectins and ligands which are
specific for cancer cells, can help nanotechnology platforms
achieve tumor cell targeting. For overcoming MDR of cancer
cells, a major challenge in effective cancer therapy,
combinations of multifunctional nanotechnology platforms
and other therapies have been developed and achieved
significant successes. However, there are still challenges to
the development and application of nanotechnology
platforms in cancer therapy, such as limited knowledge of
the cancer cell physiology, small variety and poor
functionalization of medical nanomaterials, and deficiency of
clinical evaluation criteria. Nonetheless, with further
advances
in
functionalization
base
on
thorough
understanding of the physiological features of cancer cells,
nanotechnology platforms hold the promise of essentially
changing the practice of oncology, allowing easy and
effective targeted therapies.

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2010 Vol. 29 Issue 9

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