Nanotechnology-An Emerging tool for effective cancer treatment
Published on: Mar 3, 2016
Transcripts - Nanotechnology-An Emerging tool for effective cancer treatment
Full Length Research Article
NANOTECHNOLOGY: AN EMERGING TOOL FOR EFFECTIVE CANCER TREATMENT
*1Mohammad Aamir Bhat, 2Aasim Wani, 3Uaise Farooq, 4Shabir Malik, 5Tribhuvna Singh
and 6Sobiya Hilal
1Department of Veterinary Pharmacology and Toxicology, COVAS, CSKHPKV, Palampur Kangra,
Himachal Pradesh, India 176062
2Department of Veterinary Microbiology and Immunology, COVAS, CSKHPKV, Palampur Kangra,
Himachal Pradesh, India 176062
3Department of Veterinary Surgery and Radiology, COVAS, CSKHPKV, Palampur Kangra, Himachal Pradesh,
4Department of Veterinary Anatomy and Histology, COVAS, CSKHPKV, Palampur Kangra, Himachal Pradesh,
5Department of Veterinary Pathology, COVAS, CSKHPKV, Palampur Kangra, Himachal Pradesh, India 176062
6Department of Veterinary Public Health, SKUAST-J, Jammu and Kashmir, India, 180009
ARTICLE INFO ABSTRACT
Nanotechnology is rapidly progressing and is being implemented to solve the problems related to
conventional chemotherapeutic agents such as low safety margin, poor water solubility, poor oral
availability, normal tissue toxicity and tumor resistance. Nanotechnology promises targeted
delivery of drugs and significant improvement in cancer diagnosis, treatment and management.
Nanoparticle assisted combination therapies promotes synergism, enhances therapeutic
effectiveness, improves pharmacokinetics and suppresses drug resistance. This review sheds light
on various nanotechnological platforms as anticancer drug delivery vehicles, raises awareness of
the advantages of therapeutic applications of anticancer agents using nanoparticles, minimizing
the normal tissue toxicity, drug resistance and treatment of disseminated metastatic cells through
Copyright © 2016 Mohammad Aamir Bhat et al. This is an open access article distributed under the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Cancer is a leading cause of death globally and remains one of
the world’s most devastating diseases, with more than 10
million new cases every year (WHO, 2015). Cancer can
originate in various organs as its primary location in the body
and becomes intractable when it spreads from the primary
tumor site to various organs (such as bone, lung, liver, and
then brain). Metastasis, the spread of cancer cells from a
primary tumor to seed secondary tumors in distant sites, is one
of the greatest challenges in cancer treatment today. For many
patients, by the time cancer is detected, metastasis has already
occurred and few patients with metastatic cancer are cured by
surgical intervention (Sharp et al., 2011).
*Corresponding author: Mohammad Aamir Bhat
Department of Veterinary Pharmacology and Toxicology, COVAS,
CSKHPKV, Palampur Kangra, Himachal Pradesh, India 176062.
Although cancer therapies are improving, many drugs are not
reaching the sites of metastasis, and doubt remains over the
efficacy of those that do. Methods that remain effective for
treating large, well-vascularized tumors may be inadequate
while dealing with small clusters of disseminated malignant
cells and treatment of disseminated cells is also controversial,
since they are to cancer stem-like cells, resistant to current
therapies that consequently cannot be eradicated by
conventional treatments (Chaffer and Weinberg, 2011;
Anderson et al., 2011). Chemotherapy is a major therapeutic
approach for the treatment of localized and metastasized
cancers but the current clinical cancer treatments (either
radiation therapy or chemotherapy) are “blind” as harmful
chemicals and ionizing radiation affects the whole treated area
regardless of whether the tissue in the area is benign or
malignant because of lack of specificity they fail to
differentiate between healthy and cancer cells leading to
ISSN: 2230-9926 International Journal of Development Research
Vol. 06, Issue, 01, pp. 6499-6505, January, 2016
International Journal of
Received in revised form
Published online 31st
Available online at http://www.journalijdr.com
Tumor, drug resistance,
severe adverse effects. Cell resistance, lack of specificity and
severe adverse effects to conventional chemotherapeutic
agents present an urgent need for innovative, more efficient
and effective alternatives for cancer metastasis.
Nanomedicine is an emerging multidisciplinary field that
offers unprecedented access to living cells and promises the
state of the art in cancer detection and treatment.
Nanoparticles have been of significant interest over the last
decade as they offer great benefits for drug delivery to
overcome limitations in conventional chemotherapy (Subbiah
et al., 2010; Yoo et al., 2010). Over last two decades, a large
number of nanoparticle delivery systems have been developed
for cancer therapy and their use is attractive for several
reasons: they have high surface-to-volume ratios enabling
surface functional group modification to internalize or
stabilize therapeutic agents for drug delivery; exhibit unique
pharmacokinetics and minimal renal filtration; and may be
used to encapsulate or solubilize the therapeutic agents for
drug delivery. In this review, we will focus on types and
character of nanoparticles and nanotechnological development
as drug delivery systems for cancer therapy applications and to
overcome drug resistance.
Types of Nanoparticles Used as Drug Delivery Systems for
The most common examples of nanoparticles applied as drug
delivery systems for cancer therapy application can be made of
variety of materials. The technology of nanocarrier drug
delivery system includes polymeric nanoparticles, dendrimers,
lipid nanoparticles, viral, bacterial, organometallic
nanoparticles (nanotubes), hybrid, magnetic and
inorganic/metallic nanoparticles. The diversity of delivery
systems allows nanoparticles to be developed in diverse array
of shapes, sizes, and components that enables them to be
tailored for specific applications.
Polymer based nanoparticles are one of the most investigated
types of nanocarriers and the drug is either physically
entrapped in or covalently bound to the polymer matrix
(Rawat et al., 2006). Polymer nanoparticles improve stability
of the attached drug, improving intracellular penetration,
preventing side effects, minimizing the non-specific uptake,
address their low solubility and prolonging the circulation time
(Duncan, 2006). Polymers used as drug conjugates can be
divided into two groups of natural and synthetic polymers.
Polymeric nanoparticles can be prepared from natural or
synthesized polymers and may represent the most effective
nanocarriers for prolonged drug delivery and materials of
choice for the delivery of anticancer agents have been
albumin, chitosan and heparin. Incorporation of antineoplastic
agents into polymeric nanoparticles may significantly increase
their cytotoxic effect and modify their release pattern.
Paclitaxel loaded poly(lactic-co-glycolic acid) nanoparticle
formulation In vitro exhibited a biphasic release pattern
characterized by an initial fast release during the first 24 hours,
followed by a slower and continuous release and significantly
enhanced the cytotoxic effect of the drug against human small
cell lung cancer cell line (NCI-H69 SCLC) as compared to
free drug (Fonseca et al., 2002). Several polymeric
nanoparticles are now in various stages of preclinical and
clinical development for cancer therapy. Recently, albumin
based nanoparticle formulation of paclitaxel (Abraxane) has
been applied in the clinical treatment of metastatic breast
cancer and has shown increased cancer cytotoxicity and
therapeutic index as compared to paclitaxel cremophor-EL
formulation (Gradishar et al., 2005).
Polymeric nanoparticles provide significant flexibility in
design and can be made of biodegradable or nonbiodegredable
materials. Biodegradable polymeric nanoparticles for
anticancer drug therapy have attracted a great deal of interest
in recent years since they could provide controlled, sustained
and targeted drug delivery. The physicochemical properties of
nanoparticles such as mechanical flexibility, shape and size
contribute to their interactions with cell membranes and
control their internalization pathways (Gratton et al., 2008a).
The design and synthesis of precisely defined micro and
nanoparticles has led to the foundation of “PRINT”
technology (Particle Replication In Non-wetting Templates)
for cancer therapy and other diseases.
Micelle nanoparticles are amphiphilic molecules and their
functional properties are based on amphiphilic block
copolymers such as poly (ethylene oxide)-poly(β-benzyl-L-
aspartate) and poly (N-isopropylacrylamide)-polystyrene, that
self-assembles in aqueous media to form nanoparticles
composed of hydrophilic shell and hydrophobic core which
acts as a reservoir for hydrophobic drugs. The hydrophilic
shell stabilizes the core region in aqueous media and renders
nanoparticles appropriate candidates for intravenous drug
delivery (Adams et al., 2003; Aliabadi et al., 2008). Drug
release from the micelles can be precisely controlled by
altering the ambient environment by an external stimulus like
pH, temperature, and also by ultrasound and enzymes
Genexol-PM (PEG-poly (D,L-lactide)-paclitaxel), is a
cremephor-free polymeric micelle-formulated paclitaxel and is
the first non-targeted micellar formulation approved for cancer
therapy (Kim et al., 2014). It has shown higher maximum
tolerated dose, median lethal dose, differential tumor
cytotoxicity and reduction in tumor volume as compared to
free paclitaxel (Kim et al., 2001). Biocompatible and
biodegradable formulation makes them excellent nanocarriers
but low drug incorporation stability and low drug loading
limits the targeting ability of polymeric micelles (Yamamoto
et al., 2007).
Dendrimers are highly branched synthetic globular
macromolecules with tree like structures. They possess well
defined branching architectures and these polymers are made
of macromolecules such as poly (N-isopropylacrylamide)-
polystyrene and poly (ethylene oxide)- poly (β-benzyl-L-
6500 Mohammad Aamir Bhat et al. Nanotechnology: An emerging tool for effective cancer treatment
aspartate), with size ranging from between 5-15 nm (Ochekpe
et al., 2009). Dendrimers are monodisperse, three dimensional
molecules and offer enormous capability for solubulization of
hydrophobic anticancer agents, and can be modified with guest
agents (Cheng et al., 2008). The structure of dendrimers can
be defined by an initiator core, layers of branching repeating
units and functional eng groups on the outer most layer. The
branches can provide vast amounts of surface area for
anticancer drug delivery (Kim, 2008).
Dendrimers are one of the most advanced nanotechnological
platforms for targeted drug delivery and address the controlled
drug release by external stimuli. For example, co-
encapsulation of methotraxate and all-trans retinoic acid, with
methotraxate was loaded into the hydrophobic cavity and
retinoic acids lodged into the voids between branching clefts,
gave rise to a pH dependent drug-release profile. Acidic
conditions accelerated the release while as neutral and alkaline
conditions showed much slower drug release kinetics.
The decrease in premature drug release during the circulation
period, by pH-triggered drug-release, could reduce the
systemic toxicity (Tekade et al., 2009). Dendrimers may be
used for therapeutic as well as for imaging purposes. In one
study, dendrimers conjugated with fluoresein and folic acid,
and linked with complimentary DNA oligonucleotides to
produce molecules that target cancer cells over expressing
high affinity for foliate receptors (Choi et al., 2005). The
modifiable surface characteristics of dendrimers makes them
elegant nanoparticles for anticancer drug delivery but because
of limited number of clinical and preclinical studies of
dendrimers as drug delivery agents, it is not possible to make
any conclusions about their safety and efficacy for human use.
Liposomes are the one of the most established and used drug-
delivery vehicle. Liposomes consist of amphiphilic lipid
molecules that assemble into bi-layered spherical vesicles
through self-reorganization of amphiphilic lipids and
excipients (Kim, 2007). Phosphatidylcholine,
phosphatidylethanolamine, phosphatidylserine and
phosphatidylglycerol are common building blocks of
liposomes and other molecules such as cholesterol are
incorporated into the liposomal membrane to enhance their
stability and rigidity (Couvreur and Vauthier, 2006). Owing to
their unique structure, hydrophilic molecules can be
encapsulated in the inner aqueous phase while hydrophobic
molecules can be carried in the hydrophobic domains of the of
the lipid bilayer (Zhang et al., 2009).
Lipid-based vesicles pose several challenges such as instability
in the blood stream and a rapid, burst release of the drug but
emergence of poly-ethyleneglycol-coated liposomes,
revolutionized the liposomal drug delivery as they increased
the circulation half life of liposomes from a few hours to
approximately 45 hours and reduce the recognition by
macrophages (Couvreur and Vauthier, 2006). Currently,
liposomal-drug formulations used for cancer treatment include
DaunoXome (liposomal daunorubicin) (Guaglianone et al.,
1994), for blood tumors and Doxil (PEGylated liposomal
doxorubicin) for ovarian and breast cancers (Judson et al.,
2001). Other anticancer liposomal formulations are currently
in different clinical trials. For example, SPI-077 (liposomal
cisplatin) for solid tumors, Thermodox (thermosensitive
liposomal doxorubicin) for hepatocellular carcinoma, CPX-
351 (liposomal cytarabine-doxorubicin) for acute myloid
leukemia, lipoplatin (liposomal cisplatin) for NSCLC and
Stimulax (liposomal-anti-MCU1 cancer vaccine) for NSCLC
(Judson et al., 2001; Prados, 2015).
Fullerenes include buckyball clusters and nanotubes, entirely
composed of carbon atoms linked with each other via sp2
hybridized bonds (Kim, 2007; Tardi et al., 2009).
Conceptually, carbon nanotubes are described as well ordered
carbon coaxial graphite sheets of less than 100 nm rolled up
into cylinders (Tran et al., 2009). Based on their structure, two
forms of carbon nanotubes are single- and multi-walled
nanotubes. They can be used as biosensors for proteins and
DNA and also as carriers. Apart from acting as a novel tool for
anticancer drug delivery, carbon nanotubes can be used to
immobilize molecules such as anticancer drugs, in order to
penetrate the cell membranes. For example, delivery across the
membrane was studied in case of doxorubicin linked to an
oxidized SWCNT covalently linked to FITC and a monoclonal
antibody at non-competing binding sites (Heister et al., 2009).
There is a striking evidence that fullerenes especially
MWCNTs can induce cell cytotoxicity, DNA damage and
inflammation and in vivo safety and efficacy of fullerenes
require further studies (Yamashita et al., 2009).
Metal-based nanoparticles have been extensively studied as
diagnostic and drug delivery systems. Most of these
nanoparticles have been studied for imaging using magnetic
resonance and high-resolution superconducting quantum
interference devices. Metallic nanoparticles upon
monochromatic infrared light excitation or oscillating
magnetic field stimulation, are able to convert energy into heat
to kill cancer cells (Cheng et al., 2008). For example, silica
nanoparticles coated with gold upon near-infrared excitation
produce heat to kill tumors and are currently under study for
head and neck cancer therapy (Johannsen et al., 2005).
Most common metallic nanoparticles used as anticancer drug
delivery systems are gold, silver, iron oxide, silicon, titanium
dioxide and gadolinium particles (Doria et al., 2012). The
large surface area of metallic nanoparticles has been used for
the delivery of surface-bound therapeutics. Aurimune (TNF-
alpha bound to PEG-coated nanoparticles) requires
incorporation into a nanocarrier formulation to reduce
systemic cytotoxicity and results show that nanoparticles
formulations delayed tumor growth with local heating (42ο
for 1 hour) using a SCK mammary tumor xenograft of mouse
model (Visaria et al., 2007; Paciotti et al., 2004). Metallic
nanoparticles may be inert vehicles and biocompatible but
after drug administration they can exhibit cumulative toxicity,
have no controlled release properties and they may not provide
advantageous over other types of nanoparticles (Wang et al.,
2012) so the use of metallic nanoparticles is a concern for
anticancer drug delivery.
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The growing interest in nanotechnology has produced a
variety of nanoparticulate systems in addition to the
aforementioned types of nanoparticles. Hybrid nanoparticles
are composed of polymeric materials forming the core
surrounded by a single or multiple lipid layers forming a
protective membrane (corona) (Chan et al., 2009). In a study
involving, melanoma and Lewis Lung carcinoma models, a
significant delay in tumor growth and increased survival time
was observed upon exposure to doxorubicin and combrestatin.
Doxorubicin conjugated with PLGA to form core and
combrestatin mixed with phospholipids and encapsulated in
the lipid bi-layer to form nanoparticles described as
“nanoshells”. Drugs were released over a period of three days
with combrestatin released first to reduce the vascular density
followed by doxorubicin to kill the cancer cells (Sengupta et
Nanoparticles as Anticancer Drug Delivery System
The physicochemical properties of a drug determines the in
vivo fate of a drug i.e., absorption, distribution, metabolism
and elimination, when given orally or distribution, metabolism
and elimination, when given intravenously. Numerous
biological factors especially associated with tumors influence
the delivery of the drugs inside the tumor cells. Physiological
barriers at the tumor level such as poorly vascularized regions,
acidic environment etc, as well as at the cellular level such as
alteration in the enzyme systems, altered apoptosis etc, and in
the body such as distribution, biotransformation and clearance
of the agent, must be overcome to deliver anticancer agents
inside the tumor cell in vivo (Brigger et al., 2002).
Nanoparticles loaded with anticancer agents can successfully
increase the drug concentration in cancer tissues enhancing
antitumor potency. The size and surface characteristics greatly
influence the distribution pattern of nanoparticles. For
example, conventional nanoparticles (surface non-modified
nanoparticles) are rapidly opsonized and cleared by
macrophages. Nanoparticles with modified surface properties
(stealth carriers) have been developed to reduce recognition by
macrophages, predisposition of plasma proteins and to prolong
the half-life in the blood compartment as well as in the extra-
vascular tissues, since the usefulness of conventional
nanoparticles is limited because of macrophage clearance
(Shenoy et al., 2005).
Strategies for cancer therapy using Nanoparticles
Metastasis, the spread of cancer cells from a primary tumor to
seed secondary tumors in distant sites, is one of the greatest
challenges in cancer treatment today. Despite significant
increase in understanding of metastatic cancer pathogenesis,
metastasis evolution, early diagnosis, tumor
microenvironment, signaling pathways and irradiation
treatment, most cancer deaths are due to metastasis. Reasons
for this include resistance to chemotherapeutic agents, tumor
microenvironment, and difficulty in removing all cancer cells
by surgery or physiological barriers hindering access of drugs
to the tumor (Brigger et al., 2002).
Multiple therapeutic approaches have been approved or are in
clinical development but improving therapy for metastatic
cancer is still a challenge.
The enhanced permeability and retention effect (EPR)
significantly increases the bioavailability and improves the
accumulation of non-targeted nanoparticles in tumors due to
passive diffusion from blood to tumors because of
pathological abnormalities in tumor vasculature such as inter-
endothelial gap defects, allowing extravasation of
nanoparticles and due to subsequent poor lymphatic drainage,
accumulation of nanoparticles is enhanced in the tumor
environment (Maeda, 2001). The nanoparticle shape, size,
surface charge and stealth properties are the critical factors
affecting the pharmacokinetic properties. Smaller
nanoparticles (70nm) have higher surface curvature reducing
the protein adsorption of the surface while as particles with
size of 200nm adsorbed more albumin on the surface
(Lundqvist et al., 2008).
The shape of nanoparticles may dramatically affect the
internalization pathways. Rod shaped were internalized more
efficiently than spherical shapes in Hela cell line suggesting
that nanoparticles geometry is an important factor determining
the rate of internalization (Chithrani and Chan, 2007). The
stealth property of nanoparticles (sterically stabilized carriers)
significantly increase circulation half-life as it reduces the
protein predisposition and renders them passive for
macrophage phagocytosis hence decreasing the clearance rate.
So, such long acting nanoparticles are supposed to act
efficiently on tumors located outside the mononuclear
phagocyte system (Moghimi et al., 2001).
For example, Paclitaxel loaded poly(lactic-co-glycolic acid)
coated nanoparticle formulation in vitro exhibited a biphasic
release pattern characterized by an initial fast release during
the first 24 hours, followed by a slower and continuous release
and significantly enhanced the cytotoxic effect of the drug
against human small cell lung cancer cell line (NCI-H69
SCLC) as compared to free drug (Fonseca et al., 2002). The
surface structure of a nanoparticles can also affect its cellular
uptake and recent studies have shown that nanoparticles
coated with sub-nanometer striations demonstrate enhanced
cellular uptake as compared with random surface structures
(Verma et al., 2008).
Nanoparticle delivery has provided an enormous level of
control over the pharmacokinetics of chemotherapeutic agents.
Co-encapsulation of many drugs in nanoparticles makes them
more potent against cancer cells but there is always possibility
of normal tissue damage by these particles. Paul Erlich
introduced the concept of “magic bullets”-targeted therapy,
referring to surface modification or surface functionalized with
biological agents for specific cell targeting (Strebhardt and
Ullrich, 2008). Non-targeted nanoparticles can passively
accumulate at the tumor site through EPR effects but targeting
can enhance the process and reduce the collateral damage to
the normal tissue.
6502 Mohammad Aamir Bhat et al. Nanotechnology: An emerging tool for effective cancer treatment
Nanoparticles can be targeted to concentrate drug within a
particular organ and diffuse into a specific target tissue. For
example, nanoparticles can be targeted for foliate receptors as
it is overexpressed in many tumor cells (Stella et al., 2000).
Receptor-mediated targeting can be approached by targeting
the surface receptors of endothelial cells of tumor blood
vessels, extracellular matrix i.e. tumor microenvironment or
by targeting the tumor cell surface receptor for signal-pathway
inhibitors or cytotoxic drugs. Doxorubicin showed enhanced
accumulation in cancer cells and decreased tumor weight in
primary and metastatic sites of hepatic lymph nodes upon
employing integrin receptor mediated delivery of doxorubicin
nanoparticles (Murphy et al., 2008). Targeting tumor
environment is efficient for the delivery of anti-angiogenesis
agents while as tumor cell receptors can be targeted for the
delivery of therapeutic concentrations of anti cancer agents,
Polymeric nanoparticles, dendrimers, liposomes all contain
surface functional groups that can be employed to target
receptors or ligands specific to tumor cells. Examples of
targeting ligands for nanoparticles delivery include peptides,
aptamers (oligonucleotides), antibodies, diabodies and single-
chain variable fragments (antibody variants) and can be
directed against specific surface receptor on tumor cells to
achieve precise killing, minimizing the normal tissue toxicity,
optimum intracellular therapeutic concentrations of anticancer
agents and reducing the drug resistance.
Cancer is an extremely complex disease with many challenges
still remaining. The hope for fighting cancer is still sustained
because of enormous development in anticancer therapy with
more than 50 new agents approved in past 10 years and many
more in clinical development. This review has shown
liposomes, polymeric nanoparticles, dendrimers etc to
encapsulate and act as a vehicle for variety of anticancer and
Precise control over formulation and release of combination of
drugs from nanoparticles can lead to significant tumor
reduction with minimal cytotoxic effects on normal cells upon
targeted delivery and can provide approaches to overcome
cancer resistance. Nanoparticle drug delivery has provided the
gift of unprecedented control over the pharmacokinetics and
drug combinations can now be optimized and delivered in a
more effective way. By the improvement of knowledge of
tumor microenvironment, signaling-pathways, proto-
oncogenes, tumor suppressor genes i.e. cancer biology,
nanoparticles can be produced with improved efficacy.
Nanoparticle drug delivery against cancer has already
produced some exciting results and holds even greater promise
in the future but there is still an increasing need in evaluating
the toxicity inflicted by these nanoparticles on various tissues
of the body.
I am highly thankful to all of the co-authors that participated
in framing this article with proper guidance and help. I owe
my gratitude towards, Dr. Aasim Wani, Dr. Uiase Farooq and
Dr. Shabir Malik for their courteous, moral and timely
support. The authors declare no conflict of interest.
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