PLGA Nanoparticles Containing Various An

Advanced Drug Delivery Reviews 63 (2011) 170–183
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r
PLGA nanoparticles containing various anticancer agents and tumour delivery by

EPR effect☆
Sarbari Acharya, Sanjeeb K. Sahoo ⁎
Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, India
a r t i c l e i n f o s u m m a r y
Article history: As mortality due to cancer continues to rise, advances in nanotechnology have significantly become an
Received 29 December 2009 effective approach for achieving efficient drug targeting to tumour tissues by circumventing all the
Accepted 13 October 2010 shortcomings of conventional chemotherapy. During the past decade, the importance of polymeric drug-
Available online 20 October 2010
delivery systems in oncology has grown exponentially. In this context, poly(lactic-co-glycolic acid) (PLGA) is a
widely used polymer for fabricating ‘nanoparticles’ because of biocompatibility, long-standing track record in
Keywords:
Chemotherapy
biomedical applications and well-documented utility for sustained drug release, and hence has been the
Nanotechnology centre of focus for developing drug-loaded nanoparticles for cancer therapy. Such PLGA nanoparticles have
Drug Delivery also been used to develop proteins and peptides for nanomedicine, and nanovaccines, as well as a
Drug-loaded nanoparticles nanoparticle-based drug- and gene-delivery system for cancer therapy, and nanoantigens and growth factors.
EPR Effects These drug-loaded nanoparticles extravasate through the tumour vasculature, delivering their payload into
the cells by the enhanced permeability and retention (EPR) effect, thereby increasing their therapeutic effect.
Ongoing research about drug-loaded nanoparticles and their delivery by the EPR effect to the tumour tissues
has been elucidated in this review with clarity.
© 2010 Elsevier B.V. All rights reserved.
Contents
1. Approaches to drug targeting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

1.1. Microparticles and NPs for drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
1.2. NP platform for therapeutic application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
2. PLGA NPs for tumour targeting and delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
2.1. Physicochemical and biological advantage of PLGA-engineered therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
2.2. Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
2.3. Escape from reticuloendothelial system (RES) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
2.4. Endolysosomal escape of PLGA NPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
3. PLGA NPs for tumour targeting and delivery (by EPR effect). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
4. Drug- and gene-loaded PLGA NPs for tumour delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
5. PLGA NPs as imaging agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
6. Implication and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
Rapid advances in cell and molecular biology have allowed us to diseases [1]. As mortality due to cancer continues to rise, progress of
develop a better understanding of the pathophysiology of various research in this area requires a new paradigm in the diagnosis and
therapy of the disease. Although chemotherapy has an important
place in the clinical management of cancer, the molecular complexity
☆ This review is part of the Advanced Drug Delivery Reviews theme issue on "EPR effect associated with drugs and the inaccessibility of most physiological
based drug design and clinical outlook for enhanced cancer chemotherapy". targets have resulted in the development of alternative therapies as
⁎ Corresponding author. Laboratory for Nanomedicine Institute of Life Sciences Nalco
Square, Chandrasekharpur Bhubaneswar Orissa, India. Tel.: + 91 674 2302094;
an approach to medical intervention [2]. On the one hand, genomics
fax: + 91 674 2300728. and proteomics research are identifying new tumour-specific molec-
E-mail address: [email protected] (S.K. Sahoo). ular targets and, on the other, innovative drug-delivery systems are
0169-409X/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2010.10.008
S. Acharya, S.K. Sahoo / Advanced Drug Delivery Reviews 63 (2011) 170–183 171
being designed to guide drugs more precisely to tumour cells and retention time and improvement of intracellular penetration [11].
away from sites of toxicity to maintain drugs at a therapeutic Several disease-related drugs/bioactive molecules are successfully
concentration over long periods of time [3]. encapsulated to improve bioavailability, bioactivity and control
The long-cherished goal of targeting drugs to specific sites in the delivery. Nanomedicines for dreadful diseases such as cancer,
body, where the pharmacological action is desired, sparing other acquired immune deficiency syndrome (AIDS), diabetes, malaria,
tissues, has been actively pursued all these years. The concept of prion disease and tuberculosis are in different trial phases for testing,
‘magic bullets’ given by Ehrlich has now seen a metamorphosis to and some of them are commercialised [10].
‘magic wands,’ in the form of drug-delivery systems [4]. Advances in Stemming from the nanotechnology revolution, nanovehicles
nanotechnology have significantly impacted the field of therapeutics came onto the scene as a type of drug-delivery vector [7]. While the
delivery significantly. The medical application of nanotechnology (i.e., claimed goal of drug-delivery systems was to reduce adverse side
‘nanomedicine’) has enormous potential to improve health care, effects and improve the bioavailability of chemotherapeutic agents
particularly in cancer. The last few decades have hosted a revolution (which seem promising in the test tube), ultimately leading to higher
in materials science by the miniaturisation of devices for use as efficacy of the drug with a lower overall toxicity, the potential benefits
diagnostics, biosensors and imaging agents on the one hand, and, on of NP technology with respect to drug delivery are manifold [12]. Over
the other, ever more sophisticated synthetic chemistry is producing the last several decades, numerous nanocarrier platforms have been
nanocarriers for drug delivery. At present, non-invasive imaging studied for their use as therapeutic agents with great enthusiasm in
approaches, including X-ray-based computer-assisted tomography both academic and industrial applications [6,13]. These nanocarrier
(CT), positron emission tomography (PET), single-photon emission platforms include liposomes, polymer therapeutic conjugates, poly-
tomography and magnetic resonance imaging (MRI), are used as meric micelles, dendrimers, nanoshells and nucleic acid-based NPs
important tools for detection of human cancer [5]. The development [14,15]. These polymeric nanocarriers bear great potential for
of tumour-targeted contrast agents based on a nanoparticle (NP) biomedical applications owing to their biomolecular design and
formulation may offer enhanced sensitivity and specificity for in vivo small size, and are known to have shown exciting results in preclinical
tumour imaging using currently available clinical imaging modalities. studies, demonstrating their potential as therapeutic carriers.
As drug-delivery agents, these multifunctional nanocarriers are capable The rationale behind the association of drugs with colloidal
of targeting cancer cells, delivering and releasing drugs in a regulated carriers such as NPs or liposomes is due to the limited success of
manner and detecting cancer cells with enormous specificity and conventional drug therapy. Systemically administering bolus doses of
sensitivity. Nanovehicles of the mesoscopic size range of 5 – 200 nm powerful chemotherapeutics often results in intense side effects due
result in unique interaction with biological systems at the molecular to the action of the drugs on sites other than the intended target sites
level. As a result of their material composition, these nanocarriers are [2]. With such nonspecific drug action, the concentration of the drug
also capable of self-assembly and maintaining stability and specificity, administered to the patient is a vicious predicament between
which are crucial to drug encapsulation and biocompatibility. Therefore, choosing a near-toxic effective dose and a comfortable ineffective
their application as cancer cell-specific delivery vehicles is a significant dose. Moreover, multidrug resistance (MDR) due to P-glycoproteins
addition to the currently available armoury for cancer therapeutics and resulting in exudation of drug from tumoural cells ‘enhances’ the
imaging [6,7]. difficulties associated with conventional chemotherapy [16–19].
Among the nanoparticulate carriers, poly(lactic-co-glycolic acid) However, NPs of biodegradable polymers provide a way of sustained,
(PLGA) NPs have tremendous potential in the applications combining controlled and targeted drug delivery by being localised in the
targeting, imaging, diagnostics and therapy [8]. Conjugation or cytoplasm or lysosomes after being endocytosed, thereby resulting in
encapsulation of drugs in PLGA nanocarriers reduces the undesirable enhanced therapeutic action and reduced side effects of the
shortcomings of these therapeutic agents, such as short circulation formulated drugs, avoiding MDR. New research shows that NPs
half-life and non-site-specific targeting, resulting in undesired may be able to insert anticancer drugs into cells without triggering the
systemic side effects. These drug-loaded PLGA conjugates not only P-glycoprotein pump, as they are internalised into the target cells by
prolong the in vivo circulation time of the therapeutics from several endocytosis [20–22]. The researchers studied the in vivo efficacy of
minutes to several hours but also reduce cellular uptake along the paclitaxel-loaded NPs in paclitaxel-resistant human colorectal
endocytic route [9]. Thus, these unique nanoparticulate carrier tumours. Paclitaxel entrapped in emulsifying wax NPs was shown to
systems have the potential to change the current scenario of cancer overcome drug resistance in a human colon adenocarcinoma cell line
research and diagnosis in real time. (HCT-15) [23]. Therefore, in an attempt to circumvent the limitations
of conventional drug therapy, the Food and Drug Administration
1. Approaches to drug targeting (FDA) has nowadays commercialised new macromolecular drug-delivery
formulations, such as albumin–taxol NPs (Abraxane or ABI-007) [24],
Nanotechnology has become a rapidly growing field with potential doxorubicin long-circulating liposomes (DOXIL) or Rapamune, a formu-
applications ranging from electronics to cosmetics [10]. Creating lation of rapamycin encapsulated in microemulsion system, in the market
nanomaterials such as NPs, nanorods, nanowires, nanotubes and thin for cancer therapy with an aim to improve the therapeutic index of drugs
films is the key component for the successful development of by preferential localisation at target sites.
nanotechnology, owing to their extraordinary physical and chemical
properties resulting from the nanosize effect. Fuelled by flourishing 1.1. Microparticles and NPs for drug delivery
development in the preparation of nanomaterials, a number of
applications in the biomedical field have been proposed, and some Submicrometre or microparticulate systems might be a step
of them, such as DNA sensors, controlled drug delivery and tumour forward towards improved drug delivery [25]. In particulate drug
therapy, are coming close to successful development. The most delivery, the distinction is often made between microparticles and
promising and most widely explored application of nanomaterials has NPs. Some authors reserve the term ‘nanoparticles’ for specific size
been drug delivery [6]. Nanoencapsulation of medicinal drugs cut-offs, with some justification: the larger the particles (i.e., of
(nanomedicines) increases drug efficacy, specificity, tolerability and micrometer size) are, the more likely they are to behave as
therapeutic index of the corresponding drugs [5]. These nano- microparticles, and require the same production processes. The
medicines have many advantages in the protection of premature difference in size between microparticles and NPs has numerous
degradation and interaction with the biological environment, en- effects. The smaller the particle, the greater the proportion of drug
hancement of absorption into a selected tissue, bioavailability, that will have access to the external aqueous phase. This can lead to
172 S. Acharya, S.K. Sahoo / Advanced Drug Delivery Reviews 63 (2011) 170–183
substantial loss of payload, or to a lower maximal drug loading for variant properties allow for the trend towards multiple functionality
smaller rather than larger particles. Moreover, microparticles injected of NPs (Fig. 1) [5,37,38].
into a variety of tissues tend to stay where they are placed. NPs used for anticancer drug delivery can be made from a variety
Comparative studies conducted by Kohane et al. proved the localised of materials, including polymers, dendrimers, liposomes, viruses,
presence of microparticles when they injected a particular concen- carbon nanotubes and metals such as iron oxide and gold [2]. Based on
tration of microparticles into the peritoneum of mice, which remained the manufacturing methods and materials used, these particles can
there for at least 2 weeks while, by contrast, an equal mass of NPs of adopt diverse shapes and sizes with distinct properties. Almost all the
the same material showed almost complete clearance from the NP delivery systems, which have been approved by the FDA or are
peritoneum in the same time period [26]. Similarly, size has a currently in clinical trials, are based on liposomes or polymers [39].
noticeable effect on the fate of particles injected into the vasculature. Synthetic and natural polymers have been recognised to have an
Large microparticles can embolise vessels with the same diameter, important role in biomedical materials, including their use to fabricate
and this property can be used to intentionally occlude blood flow, prostheses and soft contact lenses [40], and as pharmaceutical
with or without simultaneous drug delivery. This could lead to excipients in drug formulations [41]. Currently, more than 10
particles lodging in end organs, causing infarction (e.g., stroke). NPs formulations of anticancer polymeric NPs have entered clinical
are generally too small to cause embolic phenomena, and can circulate development, including paclitaxel poliglumex (Xyotax) [42,43], N-
throughout the vasculature [26]. Another major difference between (2-hydroxypropyl) methacrylamide (HPMA), copolymer-camptothe-
the two remains the efficiency to cross biological barriers. In general, cin (MAG-CPT) [44,45] and HPMA-DOX (N-(2-hydroxypropyl)metha-
microparticles are unlikely to cross most biological barriers, and, crylamide copolymer doxorubicin (PK1)) [46].
hence, must often be delivered directly to the site of interest. NPs, by During the past decade, the importance of polymeric drug-delivery
virtue of their smaller size, can cross such barriers getting directly systems in oncology has grown exponentially. The polymers selected
delivered to their site of action by passive diffusion mechanisms. for the parenteral administration must meet several requirements
Accordingly, microparticles can only be delivered into cells that are such as biocompatibility, drug compatibility, suitable biodegradation
phagocytic, whereas NPs can be delivered to all. Some investigators kinetics and mechanical properties and ease of processing [2].
have taken advantage of this difference by using microparticles to Synthetic biodegradable polymers have been increasingly used to
provide passive targeting to antigen-presenting cells. NPs, as a deliver drugs, as they are free from most of the problems associated
delivery system, may also offer other benefits compared with with natural polymers (albumin, chitosan, heparin, etc.). Poly
microparticles, even though the immunogenicity is comparable [27]. (amides), poly(amino acids), poly(alkyl-a-cyano acrylates), poly
NPs from preformed polymers are easier to produce compared with (esters), poly(orthoesters), poly(urethanes) and poly(acrylamides)
microparticles. The high shear required for microparticles is un- have been used to prepare various drug-loaded devices [38]. Amongst
necessary for NPs. The large surface area provided by NPs facilities them, the thermoplastic aliphatic poly(esters) such as polylactic acid
encapsulation of more payload than microparticles. Although when (PLA), polyglycolic acid (PGA) and, especially PLGA, have generated
efficacy of both the particles was examined at the in vitro level by tremendous interest due to their excellent biocompatibility and
Wendorf et al., there were very few differences between the NPs and biodegradability and toxicologically safe by-products, which are
the microparticles [27]. These results are not surprising, based on a further eliminated by the normal metabolic pathways [47]. Polymeric
survey of the literature, where there was only weak evidence for the NPs have been formulated to encapsulate either hydrophilic or
advantages of NPs compared with microparticles. In spite of this, hydrophobic small drug molecules, as well as macromolecules such
biodegradable microparticles are well-established delivery systems as proteins and nucleic acids. Drugs formulated in polymeric devices
for therapeutics, and have high potential for peptide, protein and are released either by dilution through the polymer barrier or by
nucleic acid vaccines [28]. The properties of these microparticles can
be controlled by using a range of PLGA chemistries and altering the
synthesis conditions, producing microparticles with variable release
kinetics and sizes for different uses.
1.2. NP platform for therapeutic application
Despite extensive innovation over the past decade, there remains a

need for integrated, easily adaptable drug delivery and imaging
modalities. It is already known that polymeric NPs serve as a versatile
medium for the delivery and monitoring of highly toxic compounds
in vivo due to their enhanced drug loading capacity, biological stability
and extended in vivo circulation, and account for more than 80% of the
available therapeutics in clinical use. NPs were initially developed
approximately 35 years ago [29] to act as carriers for vaccines and
cancer chemotherapy agents [30–32]. In this form, they are used as a
subcutaneous depot for the slow and sustained release of luteinising
hormone-releasing hormone (LHRH) analogues for the treatment of
prostate and other hormone-dependent cancers [33,34], and, when
implanted post surgery, they provide local delivery of chemotherapy
for the treatment of brain cancer [35,36]. NPs are colloidal systems of
submicron size that can be constructed from a large variety of
materials. Depending on the chemical composition of the NPs, these
can carry a wide variety of compounds, making them efficient drug-
delivery vehicles. In addition, there also exists the ability to introduce Fig. 1. Multifunctional PLGA nanoparticles used as diagnostics and imaging agents on
one hand and as specific drug delivery agents on other hand as both drug and contrast
into the particle a metallic core or shell, giving the particle optical, agents can be encapsulated in the core of nanoparticles helping them serve the dual
magnetic or hyperthermic properties; or to covalently bind antibodies purpose. Moreover, surface modification of PLGA nanoparticles facilitates attachment of
or lectins, enhancing the targeting efficiency of the particle. Such targeting ligand for site specific delivery of drug to cancer tissues.
erosion of the polymer material, or by a combination of both dilution chain, molecular weight of polymer, the degree of crystallinity and the
and erosion mechanisms. glass transition temperature (Tg) of the polymer. By manipulating the
molecular weight and lactide/glycolide ratio, the degradation time of
PLGA and, subsequently, the release profile can be varied accordingly
2. PLGA NPs for tumour targeting and delivery [50]. Many approaches are proposed for the preparation of PLGA
particles. The emulsification–evaporation method [32], the sponta-
The success of any medical treatment depends not only on the neous emulsification–solvent diffusion method (SESD) [51], the
pharmacokinetic/pharmacodynamic activity of the therapeutic agent, nanoprecipitation method [52,53] and the spray-drying method
but to a large extent, on its bioavailability at the site of action in the [54,55] are all widely used in preparing PLGA nano/microparticles of
human system. In this context, PLGA is a widely used polymer for various size. Polyvinyl alcohol (PVA) is most commonly used as the
fabricating NPs because of biocompatibility, long-standing track emulsifier during the formulation of PLGA NPs because the particles
record in biomedical applications and well-documented utility for formed using this emulsifier are relatively uniform and smaller in size,
sustained drug release compared to the conventional devices up to and are easy to redisperse in aqueous medium [56]. A wide variety of
days, weeks or months, and ease of parenteral administration via therapeutic agents, including low-molecular-weight lipophilic or
injection. Macromolecular drugs such as proteins, peptides, genes, hydrophilic drugs, high-molecular-weight DNA or antisense DNA,
vaccines, antigens and human growth factors, are successfully can be encapsulated inside NPs. The entrapped moiety in the
incorporated into PLGA or PLGA-based nano/microparticles [48]. polymeric matrix of NPs is released at a sustained rate by diffusion
Several anticancer drugs including paclitaxel, doxorubicin, 5-fluorouracil or by degradation of the polymeric matrix [37], thereby giving a
and dexamethasone have been successfully formulated using PLGA. In sustained release formulation to elicit enhanced therapeutic efficacy.
1999, the US FDA approved a PLGA microsphere formulation, Nutropin Thus, due to their nontoxic behaviour and excellent biocompatibility
Depot, as a once-a-month alternative to daily injections of human growth and biodegradability properties, PLGA NPs have been most exten-
hormone. sively studied among all the commercially available polymers. This
PLGA is a copolymer of lactic acid and glycolic acid. Depending on wide acceptance of the lactide/glycolide has made them an attractive
the ratio of lactide to glycolide, different forms of PLGA can be candidate for biomedical applications such as ligament reconstruc-
obtained, which are usually identified with regard to the monomers tion, tracheal replacement, ventral herniorrhaphy, surgical dressings,
ratio used (e.g., PLGA 75:25 identifies a copolymer whose composition vascular grafts, and nerve, dental and fracture repairs [57–59]. Several
is 75% lactic acid and 25% glycolic acid). PLGA is one of the most studies have investigated the mechanism of intracellular drug
successfully used biodegradable polymers for the development of delivery by PLGA NPs. It is generally thought that PLGA NPs are
nanomedicines because it undergoes hydrolysis in the body to taken up by endocytosis, which then release the drug at intracellular
produce the biodegradable metabolite monomers, lactic acid and locations. Many studies demonstrated rapid and efficient cellular
glycolic acid, which are effectively processed by the body, resulting in uptake of PLGA NPs, based on microscopic observation of PLGA NPs
minimal systemic toxicity (Fig. 2) [49]. The degradation rate of PLGA encapsulating a fluorescent probe and/or measurement of the
depends on the molar ratio of lactic and glycolic acids in the polymer intracellular level of the probe [6,56,60].
2.1. Physicochemical and biological advantage of PLGA-engineered

therapy
PLGA NPs have been the centre of focus for developing NPs
encapsulating therapeutic drugs in controlled release applications due
to their inherent advantages over conventional devices. Some of the
physicochemical and biological advantages of PLGA-engineered
therapy are summarised below.
2.2. Size
Particle size is a key factor in the biodistribution of long-circulating

NPs and in achieving therapeutic efficacy. PLGA NPs smaller than
~100 nm have reduced plasma protein adsorption on their surface
and also have reduced hepatic filtration. Recently, Bilati et al.
demonstrated that in the case of PLGA NPs, formulation and
processing parameters of the water/oil/water (w/o/w) double-
emulsion method affect their size and encapsulation efficiency. It
was observed that smaller-sized NPs showed higher uptake, than the
bigger ones, but a combination of surface charge and polymer
hydrophilicity is favourable to drug delivery [61]. The review by
Jung et al. discusses the role of polymers and formulation parameters
such as size, surface charge and hydrophobicity affecting the intestinal
absorption of NPs [62]. PLGA polymers should have considerable
mechanical strength, as the drug-delivery devices formulated using
them are subjected to significant physical stress. Different factors such
as the molecular weight, copolymer composition (lactide/glycolide
ratio), crystallinity and geometric regularity of individual chains
Fig. 2. (a) Schematic representation of chemical structure of PLGA polymer where, m
represents number of units of lactic acid and n represents number of units of glycolic
significantly affect the mechanical strength of the polymer. PLGA
acid (b) One representative transmission electron microscope (TEM) picture of PLGA chain lengths and compositions can also be varied in addition to
nanoparticles. charge modification to provide optimal oral delivery.
2.3. Escape from reticuloendothelial system (RES) anatomical and pathophysiological abnormalities of tumour vascula-
ture, such as the enhanced permeability and retention (EPR) effect.
Nanocarriers must be hidden from the reticuloendothelial system The EPR effect seems to bridge the advances in nanotechnology and
(RES), which destroys any foreign material through opsonisation, the advances in the understanding of tumour vascular biology and,
followed by phagocytosis by macrophages. Intravenously injected NPs hence, is regarded as a ‘gold standard’ in the design of new anticancer
are mostly taken up by the macrophages present in the liver and the agents [69–71]. This approach can effectively enhance drug bioavail-
spleen within minutes of drug administration [11]. RES uptake of NPs ability and efficacy. Maeda and his colleagues were the first group to
depends on the particle size, surface charge and surface hydropho- devise a nano-sized anticancer drug and target it highly selectively to
bicity. Particles of 100 nm size with hydrophilic surfaces undergo tumour tissues by the EPR effect [72–77]. Characteristics of the EPR
relatively less opsonisation and clearance by RES uptake. This effect include extensive angiogenesis, defective vascular architecture
prolongs the circulation time of NPs in the blood and allows the and impaired lymphatic drainage/recovery system of the tumours.
targeting of NPs to tissues other than the RES [63,64]. Different reports Moreover, most solid tumours have elevated levels of vascular
demonstrate that the rapid RES uptake of PLGA NPs could be permeability factors such as bradykinin, nitric oxide (NO) [78,79]
significantly reduced by modifying their surface with poly(ethylene and, more recently, peroxynitrite (ONOO–) [14]. Proteinaceous
glycol) (PEG) [65,66]. The most widely accepted theory for this vascular permeability factor (VPF) [80], which is identical to vascular
increased circulation time is that PEG reduces the protein interactions endothelial growth factor (VEGF [81], is also known to be produced
on the surface by preventing opsonin binding [67]. PEG-modified PLGA actively in tumour tissue; its effect is most likely mediated indirectly
NPs, prepared mostly by using a di-block copolymer of PLGA-b-PEG as by the extensive production of NO [82]. The enhanced production of
an additive, prolonged their half-life considerably in the circulation due these permeability mediators augments the permeability of tumour
to the presence of highly mobile and flexible PEG chains on the surface. tissues in comparison to normal tissue, thereby also contributing to
the EPR effect [83]. Solid and rapidly growing tumours suffer from an
2.4. Endolysosomal escape of PLGA NPs inadequate supply of nutrients and oxygen. Accordingly, they possess
an extensive angiogenesis, resulting in a high vascular density. The
This mechanism of action of NPs is an important advantage in the formation of tumour blood vessels proceeds in a chaotic manner and,
use of PLGA NPs as cytoplasmic delivery vehicles. Studies conducted hence, a defective architecture of the vascular endothelium with large
by Panyam et al. showed that PLGA NPs were internalised by vascular gaps in endothelium cell–cell junctions is the consequence, leading to
smooth muscle cells (VSMCs) in an energy-dependent manner, which hyperpermeability. The EPR effect provides an opportunity for more
suggests an endocytic process [60]. This result was further confirmed selective targeting of NPs (lipid- or polymer- conjugated anticancer
by the fact that NPs, once internalised, were found in the endosomal drugs) to the tumour [74,84].
and lysosomal compartments. Unlike cationic lipids or polymers, The influence of different factors on the EPR-mediated uptake of
PLGA NPs are cationic only in the endosomal compartment and do not the particles in solid tumours is, however, not yet fully understood.
destabilise the lysosomes. This reduces the chances of toxicity For extravasation of the drug-loaded carrier more selectively at
commonly associated with the use of cationic lipids and cationic tumour tissues, at least some properties of nanocarriers are
polymers [68]. Further, the intracellular uptake of NPs is unaffected by particularly important. Size and surface of the nanoparticulate carrier
serum and, hence, PLGA NPs are suitable for in vivo applications play a very crucial role with respect to uptake by the tumour. Particles
(Fig. 3) [60]. of size b200 nm with hydrophilic surfaces tend to exhibit an
improved EPR effect, which has been attributed to the increased
3. PLGA NPs for tumour targeting and delivery (by EPR effect) residence time of the carrier in blood. However, in studies conducted
by Yazawa et al., Bifidobacterium longum, a non-pathogenic and
In general, NP delivery of anticancer drugs to tumour tissues can be anaerobic bacteria with size as large as 2 μm, was found to be
achieved by either passive or active targeting. Passive targeting takes concentrated in mice tumour more than in normal tissues when the
the advantage of the inherent size of NPs and exploits the unique bacteria was injected intravenously [85], thus indicating that even
Fig. 3. Schematic representation of rapid endolysosomal escape of nanoparticles. Nanoparticles enter the cell through receptor mediated endocytosis and get localized in the
endolysosomal compartment. During later stages, charge reversal of PLGA nanoparticles occur in acidified endosomes, leading to destabilization of endolysosomal membrane
leading to efflux of nanoparticles and drug release.
larger-sized particles can accumulate in the tumour tissues. Moreover, breast cancer in rats [91]. Their studies showed that particles of
this increased plasma half-life of the particulate drug carrier as well as 120 nm used for the animal experiment had improved efficacy in
accumulation in tumour is strictly correlated to the molecular weight comparison with IV native paclitaxel; and the EPR effect might be the
of the macromolecule or polymer used for making the NPs long key prospective explanation for the enhanced efficacy of these NP
circulating. It is now almost certain that polymeric drugs having a formulations because of their preferential accumulation in tumours.
molecular weight above the renal threshold (i.e., N40 kDa) accumu- Moreover, Danhier et al. observed that non-targeted NPs loaded with
late in tumour tissues for prolonged time periods following I.V. paclitaxel could reach the tumour site through the EPR effect and
injection; however, the maximum molecular weight limit to be used maintain the effective therapeutic concentration for a long period.
for intratumoural extravasation has always been a subject of much These paclitaxel NPs were more effective than Taxol® at delaying
debate [86–88]. tumour growth [92].
The targeting effect of nanocarriers is achieved as they remain in
the bloodstream, where the vessel structure is normal, but would 4. Drug- and gene-loaded PLGA NPs for tumour delivery
extravasate through the leaky vasculature at the tumour site. Upon
arrival at the target sites, the nanocarriers release the drug in the PLGA NPs have been used to develop proteins and peptides
vicinity of the tumour cells. The absence of lymphatic drainage from nanomedicine and nanovaccines, and NP-based gene delivery
the tumours contributes to retention of the nanocarriers, ultimately systems, nanoantigens and growth factors. Protocols have been
leading to the accumulation of high concentrations of drug at the optimised for synthesis of PLGA NPs, and numerous cancer-related
tumour site (Fig. 4) [74,83]. To take advantage of the EPR effect, it is drugs have been incorporated in the NPs. The therapeutic efficacy of
critical for the nanocarriers to evade immune surveillance and such drug-loaded NPs and gene-delivery systems has been widely
circulate for a prolonged period. On the other hand, the kidneys are studied, and some of them have been exemplified in this review. (An
capable of filtering particles smaller than 10 nm and the liver can overview of all the drug-loaded NPs related to cancer targeting is
capture particles larger than 100 nm. Therefore, the ideal nanocarrier provided in Table 1.)
size is somewhere between 10 and 100 nm. Clearance organs (such as
the kidneys) can filter nanocarriers not only based on their size, but (1) Dexamethasone (a glucocorticoid) acts as a chemotherapeutic
also by their surface charge. As positively charged particles can bind agent having both anti-proliferative and anti-inflammatory effects.
easily to the large numbers of cells in the body, including endothelial PLGA-based NPs have been formulated to encapsulate dexameth-
cells, before reaching the target tumour cells, therefore, it is important asone, with an intracellular site of action. The drug binds to the
to maintain the nanocarriers as either neutral or anionic for successful cytoplasmic receptors, and the subsequent drug–receptor complex
evasion of renal elimination. By designing such nanocarriers, an is transported to the nucleus, resulting in the expression of certain
improved biodistribution and activity, as well as a prolonged in vivo genes that control cell proliferation [93]. These drug-loaded NP
half-life, can be reached. Another prerequisite for the EPR effect to formulations that released higher doses of drug for a prolonged
take place is that the plasma concentration of the drug must remain period of time completely suppressed proliferation of VSMCs as
high, for more than 6 h in mice and rat, measured by the area under also studied by Panyam et al [94]. Butoescu et al. and Patil et al. have
the time–concentration curve (AUC) [74,77,89]. also shown the enhanced in vivo efficacy of drug-loaded
Following the revolutionary work of Maeda, many other groups nanocarriers for the local treatment of arthritis and angiogenesis,
were also able to reproduce the EPR effect in a range of experimental respectively [95,96].
settings. For example, Stroh et al. have shown that dextran with a (2) Paclitaxel is a taxane plant product that promotes the
molecular weight as high as 2000 kDa, conjugated to a dye (cascade stabilisation of tubulin polymerisation [97]. The microtubule
blue), readily entered and stained the tumour interstitium within formed in the presence of paclitaxel is exceptionally stable and
30 min [90]. Bhardwaj et al. synthesised paclitaxel-loaded PLGA NPs dysfunctional; consequently, cell cycle arrest at the G2/M
stabilised with cationic surfactants, and applied this formulation to phase and inhibition of mitosis occurs after paclitaxel treat-
increase the oral bioavailability of the drug to treat chemical-induced ment [98]. Paclitaxel has been shown to exhibit significant
Fig. 4. Passive targeting of NPs by EPR effect utilizing the anatomical and pathophysiological abnormalities of tumor vasculature. Gaps are present in the endothelial cells of tumor
blood vessels and nanoparticles take advantage of this leaky vasculature to extravasate efficiently into the tumor tissues and absence of lymphatic drainage from the tumors,
contributes to retention of the nanocarriers ultimately leading to accumulation of high concentrations drug.
Table 1
Overview on successful cancer targeting and cancer therapy in vitro and in vivo using various anticancer drugs.
Drug loaded in Major In vitro application In vivo application Authors and

PLGA targets Reference No
nanoparticles
Dexamethasone Cytoplasmic Efficient suppression proliferation of vascular Enhanced in vivo efficacy of drug loaded nanocarriers for Panyam et al. [94]
receptors smooth muscle cells by drug loaded NP the local treatment of arthritis and angiogenesis was studied Butoescu et al. [95]
using these NPs
Patil et al. [96]
Paclitaxel Microtubules Efficacy of paclitaxel mediated NP delivery was In vivo efficacy of paclitaxel-loaded nanoparticles was Feng et al. [106]
tested on human small cell lung cancer (NCI-H69 accessed on transplantable liver tumor in male NMRI Fonseca et al. [107]
SCLC), human adenocarcinoma (HT-29), human mice and in model glioblastoma tumors Danhier et al. [109]
laryngeal cancer (Hep-2), breast carcinoma Jin et al. [110]
(MCF-7) and carcinoma cervicis (HeLa) cell lines. Ranganath et al. [112]
Ong et al. [113]

Vincristine Tubulin PLGA nanoparticles simultaneously loaded with Moreover studies also showed that PLGA NPs simultaneously Song et al. [116,117]
sulfate vincristine sulfate and verapamil hydrochloride loaded with anticancer drug and chemo sensitizer might be
for cancer therapy the most potential formulation in the treatment of drug
resistant cancers in vivo
Curcumin Cytoplasmic Nanoparticle encapsulation improves oral Shaikh et al. [122]
In vivo bioavailability of curcumin-loaded PLGA nanoparticles
proteins bioavailability of curcumin and was effective Yallapu et al. [123]
was performed in Balb/c mice. Another independent study
against metastatic ovarian , breast cancer and proved the marked anticancer efficacy of curcumin Mukerjee et al. [124]
prostate cancer cells Anand et al. [125]
microparticles in nude mice bearing MDA-MB-231 xenografts
Bisht et al. [126]
Shahani et al. [127]
Camptothecin Topo I Efficacy of PLGA NPs were investigated on B16 The in vitro antitumor characteristics of methoxy poly Tong et al. [131]
melanoma cells murine and human oral squamous (ethylene glycol)-PLGA nanoparticles containing camptothecin Mallery et al. [132]
cell carcinoma have been examined in mice bearing sarcoma solid tumor Miura et al. [133]
Doxorubicin Topo II Multifunctional PLGA nanoparticles were used In vivo pharmacokinetics of DOX loaded NPs was evaluated in Park et al. [137]
against MDA-MB-231 breast cancer cells and female SD and in intracranial 101/8 glioblastoma in rats Yoo et al. [138]
against human hepatocellular liver carcinoma Kalaria et al. [139]
(HepG2) cell line Gelperina et al. [140]
Avgoustakis et al. [142]
Cisplatin DNA adducts Cisplatin in PLGA nanoparticles exhibited higher Pharmacodynamics of cisplatin-loaded PLGA or PLGA-mPEG Agrahari et al. [143]
therapeutic efficacy on human prostate cancer nanoparticles upon administration to tumor-bearing mice/Balb Moreno et al. [144]
LNCaP cells C mice was investigated by different groups Mattheolabakis et al.
[145]
Etoposide Topo II Drug was loaded in PLGA in presence of Pluronic Etoposide loaded PLGA nanoparticulate formulations were Reddy et al. [146]
F68 for efficient cancer therapy radio labeled and their biodistribution and pharmacokinetics Snehalatha et al. [147]
were studied after intravenous administration in healthy mice
and rabbits
Rapamycin Tyrosine Enhanced suppressive activity on dendritic cells , Improved in vivo retention and uptake of nanoparticles in the Haddadi et al. [153]
kinase vascular smooth muscle cell (HUASMC) and arterial walls for efficient localization of the therapeutic agents Miao et al. [154]
MCF 7 breast cancer was investigated using in restenosis site Zou et al. [155]
these Np Acharya et al. [156]
activity against a variety of solid tumours, including breast developed PLGA NP formulation incorporating paclitaxel has been
cancer, advanced ovarian carcinoma, lung and head and neck also been assessed on a human adenocarcinoma cell line (HT-29)
carcinomas and acute leukaemias [99,100]. However, the and a human small-cell lung cancer cell line (NCI-H69 SCLC) and
success of its clinical application is mainly restricted due its compared with the in vitro antitumoural activity of the
low therapeutic effect and low solubility in water as well as in commercial formulation by Feng et al. and Fonseca et al.,
many other pharmaceutical solvents acceptable for intravas- respectively [106,107]. Similarly, Gao et al. demonstrated higher
cular (i.v) administration [101]. Presently, the only available in vitro cytotoxicity of paclitaxel-loaded methoxy poly(ethylene
formulation for clinical use consists of a solution of paclitaxel glycol)-poly(lactic-co-glycolic acid) (PEG-PLGA) NPs over native
(6 mg ml− 1) in a Cremophor EL with dehydrated alcohol at a paclitaxel on human laryngeal cancer Hep-2 cells [108]. The
50:50 volume/volume (v/v) ratio. However, this vehicle has in vivo efficacy of paclitaxel-loaded polyethylene glycol (PEG)
been associated with severe hypersensitivity reactions and ylated PLGA-based NPs was accessed on transplantable liver
incompatibility upon intravenous administration [102]. PLGA tumour (TLT) implanted in the gastrocnemius muscle in the
NPs encapsulated with paclitaxel were prepared as an answer posterior leg of 8-week-old male NMRI mice by Danhier et al.,
to the shortcomings of the native drug and its in vitro efficacy and their studies proved that paclitaxel-loaded NPs inhibited
was tested on different tumours [103]. In a recent study, PLGA tumour growth more efficiently than native drug [109]. Better
NPs were prepared using a quaternary ammonium salt, in vitro and in vivo efficacy of paclitaxel-loaded nanocarriers was
didodecyl dimethylammonium bromide (DMAB), and their also confirmed by Jin et al. using breast carcinoma (MCF-7) and
utility was checked to deliver paclitaxel by the oral route to carcinoma cervicis (HeLa) cell lines. Based on these results, it was
treat chemical-induced breast cancer in rats [104]. The develop- concluded that paclitaxel incorporated in PLGA NPs might be
ment of drug resistance is also another major obstacle to the considered as a promising system to eradicate hypoxic
success of cancer chemotherapy. To counteract this, NP-mediated tumour cells [110]. Zhao and Feng studied the in vitro viability
simultaneous and targeted delivery of paclitaxel and tariquidar of the MCF-7 human breast cancer cell line using paclitaxel-
(inhibitor of P-glycoprotein) to tumour drug resistance has been loaded NPs with vitamin E TPGS as emulsifier. They also
studied by Patil et al [105]. The in vitro antitumoural activity of a demonstrated that such a nanoparticulate formulation could
enhance the oral bioavailability of the drug up to 10 times, which mice by Anand et al [125]. Their results clearly indicate that
resulted in around ninefold higher therapeutic effect than native serum levels of curcumin were almost twice as high in the case
drug [111]. Recently, the use of submicron/nanoscale PLGA of curcumin-loaded NPs when compared with native curcumin.
implants to deliver paclitaxel to intracranial glioblastoma in mice In addition, the half-life of curcumin-loaded NP was substan-
was studied by Ranganath et al. Their studies showed that the tially longer than that of curcumin, proving that, in animals,
nanoscale implants were able to demonstrate optimal paclitaxel curcumin-loaded NP was more bioavailable and has a substan-
pharmacokinetics in BALB/c nude mice with intracranial human tially longer half-life, which was in agreement with Bisht et al
glioblastoma (U87 MG-luc2) with significant tumour inhibition [126]. Another independent study conducted by Shahani et al.
in the xenograft model and, hence, could be potentially useful to proved the marked anticancer efficacy of curcumin micro-
treat highly recurrent glioblastomas [112]. Moreover, Ong et al. particles in a nude mice xenograft model [127].
delivered paclitaxel-loaded PLGA foams and used it in post- (5) Camptothecin (CPT) selectively inhibits mammalian topoisom-
surgical chemotherapy against glioblastoma multiforme [113]. erase I, a DNA replication enzyme overexpressed in a wide range of
(3) Vincristine sulphate (VCR) is an effective chemotherapeutic tumours, including advanced human colon, ovarian and oesopha-
agent, which has been used extensively for the treatment of geal carcinomas [128]. CPT exhibits antitumourigenic effects by
various cancers, including AIDS. Unfortunately, many tumour trapping topoisomerase-I with DNA in topoisomerase I-cleavage
cells are not sensitive to VCR because of efflux from the tumour complexes [129]. Drug-loaded NPs were prepared by the nano-
cells mediated by P-glycoprotein and associated proteins precipitation method and examined for particle characteristics and
[114,115]. The rationale behind the association of drugs with in vitro release in phosphate-buffered saline. Prepared NPs
colloidal carriers against drug resistance comes from the fact described were considered potentially useful in both stabilising
that P-glycoprotein probably recognises the drug to be effluxed and delivering 9-nitrocamptothecin (a modified form of CPT), thus
out of the tumoural cell only when this drug is present in the enhancing the efficacy of this drug for cancer treatment [130].
plasma membrane, and not when it is located in the cytoplasm PLGA microspheres containing various CPT loadings were prepared
or lysosomes, after endocytosis. As a drug-loaded NP is mostly and characterised, and the cytotoxicity of these microspheres was
present in the endolysosomal complex after internalisation by then evaluated on B16 melanoma cells by Tong et al. Their studies
cells, it probably escapes the P-glycoprotein pump. Based on indicated the superior antiproliferative activity of drug-loaded
the optimal parameters, it was found that vincristine-loaded microspheres for cancer therapy [131]. Similarly, Mallery et al.
PLGA NPs could be formulated with expectable properties by verified the higher potency of 10-hydroxycamptothecin, delivered
combining the o/w emulsion–solvent evaporation method and from locally injectable PLGA microspheres in a murine human oral
the salting-out method. This study also showed that two squamous cell carcinoma regression model. Their studies showed
hydrophilic low-molecular-weight drugs, VCR and verapamil that PLGA microspheres were not only capable of maintaining
(VRP), a chemosensitiser, could be simultaneously entrapped higher intratumour concentrations of drug relative to local bolus
into PLGA NPs, with a relatively high entrapment efficiency of and intra-peritoneal routes but also significantly reduced tumour
55.35 ± 4.22% for VCR and 69.47 ± 5.34% for VRP, respectively, volume in comparison to native drug [132]. The in vitro and in vivo
in small-sized particles of 100 nm. Moreover, their studies antitumour characteristics of mPEG-PLGA NPs containing CPT have
showed that PLGA NPs simultaneously loaded with an been examined by Miura et al. After intravenous administration in
anticancer drug and a chemosensitiser might be the formula- rats, CPT-loaded NPs showed longer plasma retention than CPT
tion with the most potential in the treatment of drug-resistant solution with high and long tumour localisation. In both single and
cancers in vivo [116,117]. double administration to mice bearing sarcoma solid tumour, CPT-
(4) Curcumin, derived from the common food spice turmeric, has loaded NPs were much more effective than CPT solution; in
been used for centuries as a remedy for many disorders particular, the tumour disappeared completely in three of the four
including neurodegenerative, cardiovascular, pulmonary, auto- mice after double administration of CPT-loaded NPs [133].
immune and neoplastic diseases where the process of inflam- (6) Doxorubicin, an anthracycline antibiotic and one of the most
mation plays an important role in the aetiology of the disease widely used anticancer agents, shows high antitumour activity.
[118]. Scientific research over the past decade has shown the However, its therapeutic effects are limited due to its dose–
compound to possess preventive and therapeutic value against dependent cardiotoxicity and myelosuppression [134]. Numer-
wide variety of diseases including cancer. Despite its promising ous publications have indicated improved anticancer activity
pharmacological activity, slow oral bioavailability of curcumin for liposome-associated doxorubicin, including its metastatic
has remained as a major hurdle, which needs to be overcome to inhibition activity. However, the two main factors that have
enhance the therapeutic efficacy of this potent anticancer limited the development of liposomes are the instability of the
compound [119–121]. Nanotechnology-based carriers (PLGA drug in solution within the vesicles and the rapid leakage of
NPs) emerged as a new hope in curcumin delivery to tumour compounds across the phospholipidic bilayer. Under optimal
sites. Curcumin-loaded PLGA NPs were prepared by the conditions, the drug carried within the liposomal aqueous
emulsion diffusion evaporation method using different stabi- space should leak at a sufficient rate to become bioavailable on
lisers such as cetyl trimethylammonium bromide (CTAB) or arrival at the tumour; however, rapid leakage before reaching
PVA or PEG-5000. The present comprehensible data certainly the tumour site makes the drug vulnerable to the metabolic
testifies a well-established product profile, opening up new enzymes present in the body, leading to their inactivation in
avenues for the miracle molecule curcumin on PLGA due to the plasma. In this regard, PLGA NPs containing doxorubicin
higher cellular uptake and increased in vitro bioactivity and (DOX) were successfully formulated, characterised and evalu-
superior in vivo bioavailability in comparison to native ated in vitro [135,136]. These NPs promise to be an effective
curcumin [122]. Yallapu et al., in their studies, proved the system for the targeted and controlled release of doxorubicin
enhanced therapeutic efficacy of curcumin-encapsulated PLGA with reduced systemic toxicity, increased therapeutic efficiency
NPs against metastatic ovarian and breast cancer cells [123]. and increased patient compliance. Moreover, multifunctional
Similarly, curcumin-loaded PLGA nanospheres were used as an PLGA NPs for combined doxorubicin and photothermal treat-
adjuvant therapy for clinical application in prostate cancer by ments were studied by Park et al. to deliver both drug and heat
Mukerjee and Vishwanatha [124]. Superior in vivo bioavail- simultaneously to a selected tumourigenic region [137]. Studies
ability of curcumin-loaded PLGA NPs was observed in BALB/c also showed that doxorubicin, when conjugated chemically to a
terminal end group of PLGA by an ester linkage and then breast cancer cells efficiently [148]. Clinically, rapamycin
formulated into NPs, showed increased uptake by a human analogues with improved stability and pharmacological proper-
hepatocellular liver carcinoma (HepG2) cell line with a slightly ties have been well tolerated by patients in Phase I trials, and
lower half-maximal inhibitory concentration (IC50) than free these agents have shown a promising antitumour effect in breast
doxorubicin. An in vivo antitumour activity assay also showed cancer [149–151]. However, despite the potency of rapamycin in
that a single injection of the NPs had comparable activity to that preclinical studies, the clinical development of rapamycin
of free doxorubicin administered by daily injection [138]. The floundered due to its poor solubility in water (2.6 μg ml− 1)
in vivo pharmacokinetics, toxicity and the blood persistence [152], no tumour tissue specificity, low bioavailability and dose-
properties of DOX-loaded NPs were evaluated in female limiting toxicity. Nowadays, nanoparticulate drug-delivery sys-
Sprague–Dawley (SD) rats by Kalaria et al. The results confirmed tems are being developed to deliver smaller doses of rapamycin
that NPs showed promise in improving the oral bioavailability of in an effective form with a controlled drug distribution within the
doxorubicin and reduced cardiotoxicity, though the tissue body to treat different diseases. Recently, the therapeutic utility
distribution of these particles remained to be investigated of rapamycin has been optimised by developing efficient delivery
[139]. The feasibility of drug delivery to the brain using the system for the drug, that is, nanoscale delivery vehicles (such as
surfactant-coated DOX-loaded PLGA NPs was investigated by PLGA NPs), which are capable of controlled release of the drug,
Gelperina et al. where binding of doxorubicin to the surfactant- thereby enhancing its suppressive activity on dendritic cells by
coated PLGA NPs enabled a high antitumour effect against an altering their maturation profile [153]. The effect of rapamycin-
intracranial 101/8 glioblastoma in rats [140]. loaded PLGA NPs on the proliferation, distribution in cell cycle
(7) Cisplatin is one of the most potent anticancer agents known and expression of p27 protein in human umbilical arterial
[141]. However, its use is associated with serious side effects, vascular smooth muscle cell (HUASMC) in in vitro conditions
including renal and auditory toxicity, nausea and vomiting. was also investigated by Miao et al [154]. Furthermore, it was
Using long-circulating PLGA-mPEG NPs, the selective delivery found that rapamycin-loaded PLGA NPs improved the in vivo
of cisplatin to tumour cells significantly reduced drug toxicity retention and uptake of NPs in the arterial walls for efficient
by passive targeting of cisplatin to tumours after I.V. admin- localisation of the therapeutic agents at the restenosis site [155].
istration [142]. The NPs exhibited rapid degradation and Recently, our group tested the efficacy of such rapamycin-loaded
sustained drug release properties with prolonged drug resi- NPs in breast cancer cells, suggesting that such drug-loaded NPs
dence in blood after I.V. administration in mice. Moreover, can also be used for treating a wide spectrum of cancers in the
Agrahari et al. encapsulated cisplatin in PLGA NPs exhibiting near future [156].
higher therapeutic efficacy, and lesser side effects, and with (10) The application of protein drugs in the therapy of cancer and
further development with respect to advances in targeted other diseases faces a number of limitations associated with the
chemotherapy. Moreover, they also investigated the in vitro low stability of proteins in the circulation and poor uptake by
anticancer activity of such drug-loaded NPs on human prostate targeted cells. The encapsulation of proteins in PLGA NPs
cancer LNCaP cells, thus confirming that such a strategy might constitutes such a system, which is safe for human application,
prove to be useful in site-specific delivery of drugs whose site of biodegradable, able to increase the shelf-life of the proteins and
pharmacological activity is the cell nucleus [143]. The pharma- to protect and release them over a longer period of time
codynamics of cisplatin-loaded PLGA NPs upon administration [157,158], and, hence, have been investigated extensively for
to tumour-bearing mice was studied by Moreno et al [144]. protein drug delivery and proposed as the most suitable
Moreover, the tolerance of BALB/c mice to different doses of candidates for pharmaceutical purposes. PLGA NPs were used
cisplatin-loaded PLGA-mPEG NPs and the in vivo anticancer as a carrier system for delivering cysteine protease inhibitor
activity of these NPs on severe combine immunodeficiency cystatin into tumour cells, and the efficacy of this delivery
(SCID) mice xenografted with colorectal adenocarcinoma HT system was evaluated on ras-transformed human breast
29 cells were investigated by Mattheolabakis et al [145]. epithelial cells MCF-10A. The results indicate that the uptake
(8) Etoposide is an anticancer agent used in the treatment of a of protease inhibitors by tumour cells can be greatly facilitated
variety of malignancies, including malignant lymphomas. It by a nanoparticulate carrier system protecting the protein
acts by inhibition of topoisomerase-II and activation of against proteolytic degradation and aggregation, and enabling
oxidation–reduction reactions to produce derivatives that its sustained release inside the cells [159].
bind directly to DNA and cause DNA damage. The effective (11) Gene therapy is a method used to induce specific genes related
chemotherapy of tumours depends on continuous exposure to to the diseases by introducing genetic material (DNA or RNA)
anticancer agents for prolonged periods. Etoposide has a short to activate cellular processes for reducing or eliminating the
biological half-life (3.6 hour), and although intra-peritoneal disease. Gene therapy has demonstrated a significant potential
injection would result in initial high local tumour concentra- in the treatment of genetic, acquired and neurodegenerative
tions, prolonged exposure of tumour cells may not be possible. disorders. However, the efficient in vivo delivery of genes
It is envisaged that intra-peritoneal delivery of etoposide remains a major limitation for its therapeutic application. To
through NPs would be an improved approach for effectual prevent the degradation of oligonucleotides/genes, it was
treatment of peritoneal tumours. In this perspective, etopo- proposed to associate them with NPs [94]. Delivery systems
side-loaded NPs were prepared applying nanoprecipitation and are necessary for molecules such as antisense oligonucleotides/
emulsion–solvent evaporation techniques using PLGA in the genes as they are susceptible to nuclease-mediated degrada-
presence of Pluronic F68 by Reddy et al. The methods produced tion in the circulation, and penetrate poorly through the
NPs with good entrapment efficiency of around 80% with membranes. They are also susceptible to nuclease attack within
sustained release of the drug up to 48 hour [146]. Moreover, the lysosomes, and their site of action is either in the cytoplasm
etoposide-loaded PLGA nanoparticulate formulations were in the case of an antisense strategy or in the nucleus for gene
radio labelled, and their biodistribution and pharmacokinetics replacement or antigene therapy. At present, it is widely
were studied after I.V. administration in healthy mice and accepted that the success of gene therapy and genetic
rabbits, respectively, by Snehalatha et al [147]. vaccination depends strongly on the design of a carrier that
(9) Currently, rapamycin and its analogues serve as promising new could efficiently protect and deliver DNA to the target cells
drugs that use alternative mechanisms to inhibit the growth of [160]. PLGA nanospheres have been suggested to be a good
gene delivery carrier because of the safety and the achievement modified with PLGA NPs were studied by Guoa et al., which may prove
of sustained release [161] and improved intracellular capture. advantageous in the near future for simultaneous drug delivery and
The combination of the diagnostic capabilities of the PLGA NPs imaging applications [175]. Similarly, viability, proliferation and
with the gene- and drug-delivery effects may yield a powerful differentiation capability, along with imaging competency of PLGA-QD
tool for image-guided, efficient tumour chemo- and biotherapy. NPs, were studied in human mesenchymal stem cells [176]. In another
study, paclitaxel-loaded stabiliser-free PLGA NPs, conjugated with QDs
Bioadhesive PLGA NPs, using carbopol as bioadhesive agent for for reversion of anticancer drug resistance and cancer cell imaging, were
efficient gene therapy for lung cancer, were recently studied by Zou et studied by Kuo et al [177].
al [162]. Such bioadhesive PLGA NPs demonstrated a high DNA- Likewise, superparamagnetic iron oxide or iron oxide NPs are
binding efficiency (N80%) at an optimal concentration, protection becoming an increasingly attractive modality for the development of a
from enzymatic degradation or in vitro release DNA stability, better target-specific MRI contrast agent [50,178]. In recent years, significant
buffering capacity and, most importantly, a higher transfection efforts have been made to develop target-specific MRI contrast agents
efficiency in A549 cells. Chumakova et al. demonstrated an enhanced using PLGA NPs, which will facilitate their use in biomedical applications
in vivo gene delivery and tumour cell transfection by using a as contrast agents for MRI and for targeted drug delivery in tumour
combination of ultrasonication with complex NPs consisting of two therapy [179]. Wang et al., in their studies, used PLGA-mPEG NPs to
types of NPs: poly(ethyleneimine)/deoxyribonucleic acid (PEI/DNA) formulate superparamagnetic iron oxides for MRI. This system
b-gal plasmid and PLGA particles, with a focus on the suitability and improved the imaging effects along with increasing the half-life of the
application of this gene carrier for lung cancer [163]. Gene therapy is NPs in circulation, thereby reducing their side effects [180]. In another
also recognised as one of the most potential approaches for the study, doxorubicin was loaded onto the magnetite NPs that were
treatment of serious diseases, including monogenic diseases, infec- embedded in PLGA through hydrophobic interaction. Results showed
tious diseases and cancer [164]. In this respect, hepatocellular that doxorubicin encapsulated in polymeric NPs was released sustain-
carcinoma (HCC) is the most common primary liver malignancy, ably without any inhibition due to the presence of magnetic
with a rising incidence worldwide [165], and gene therapy strategies nanocapsules. These superparamagnetic iron oxides have not only
have become a chief alternative. PLGA, a biocompatible and been injected in mice and rats but also in 14 patients (through I.V.
biodegradable polymer that is approved for in vivo applications, has injection very close to the tumour site) for targeting an anticancer drug
been used for the encapsulation of genes, and has shown good to locally advanced tumours [181,182].
promise in the treatment of HCC. In another study, Dıez et al. Besides this, modern ultrasound contrast agents primarily com-
synthesised a novel targeted lipopolymeric vector, which significantly prised of microbubble (microspheres with a porous or hollow inner
improved the levels of luciferase gene expression in the liver upon I.V. structure) formulation that circulates in the intravascular compart-
administration [166]. Moreover, breast cancer cells (MDA-MB-435 S) ment are being designed to enhance acoustic signals reflected from
transfected with wt-p53 plasmid DNA-loaded NPs showed signifi- the blood pool. Biodegradable PLGA microcapsules are also being
cantly higher and more sustained (7 days) intracellular DNA levels as developed to be used as ultrasound contrast agents to improve
opposed to transfection with naked DNA and DNA-Lipofectamine™ ultrasound imaging. Cui et al. fabricated a kind of absorbable PLGA
complex [167]. This has significant implications in cancer gene microbubble-based contrast agent (PLGA microspheres with a porous
therapy, where sustained gene expression is of importance for greater or hollow inner structure) by an improved double emulsion–solvent
therapeutic benefit. evaporation method. These PLGA microbubble-based contrast agents
confirmed that these polymer-based agents were not only capable of
5. PLGA NPs as imaging agents showing good scatter ability during in vitro acoustic measurements
but also demonstrated greater stability during in vivo imaging
Tumour imaging plays a key role in clinical oncology by helping to experiments, thereby detecting myocardial perfusion defects effi-
identify solid tumours, determine recurrence and monitor therapeutic ciently [183]. Wheatley et al. also developed the PLGA microbubbles
responses [168,169]. Despite continuous improvements with ad- used as ultrasound contrast agents. Significant acoustic enhancements
vanced imaging equipment, imaging modalities such as CT and MRI (up to 24 dB) were reported both in in vitro and in in vivo conditions
that use non-targeted contrast agents have limited sensitivity and without the observation of any adverse side effects from multiple
ability to provide specific and functional information on the disease, injections of the agent [184].
which is increasingly recognised to be a major impediment for earlier
diagnosis and monitoring of treatment responses. The development of 6. Implication and future directions
non-invasive molecular imaging methods capable of determining the
clinical stage of cancerous tumours would represent a significant As the field of nanotechnology is relatively young, the long-term
improvement over the currently available clinical diagnostic methods. health effects due to NPs are unknown. NPs have the potential for
The development of NPs as imaging contrast agents also makes it advancing the diagnosis, operative management and adjuvant
possible for the production of multifunctional NPs with the capacity of therapy for cancer treatment in the future. Drug delivery using
targeted tumour imaging and delivery of therapeutic agents [170]. PLGA or PLGA-based polymers is an attractive area with innumerable
Recent advances have led to the development of biodegradable opportunities for biomedical research with the primary goal of
nanostructures of iron oxide NPs for MRI and luminescent quantum increasing therapeutic (antitumour) effect while minimising side
dots (QDs) for multiplexed molecular diagnosis and in vivo imaging effects. The therapeutic advantages of PLGA NPs are becoming
[171,172]. apparent and will soon be associated with every route of drug
QDs, tiny light-emitting particles on the nanometre scale, are administration, making them feasible candidates for drug-delivery
emerging as a new class of fluorescent probes for in vivo biomolecular systems. The medical management of malignancies has already been
and cellular imaging [173]. The basic rationale for using QDs arises greatly impacted by PLGA-based drug-delivery systems, but, soon,
from their unique and fascinating optical properties that are not other medical specialties will use these novel forms of drug delivery to
generally available for individual molecules or bulk semiconductor achieve optimal treatment success. Although there are certain critical
solids [174]. A new structural design involves encapsulating lumi- questions and many challenges remaining as regards the clinical
nescent QDs with amphiphilic block copolymers, and linking the development of PLGA NPs, as more clinical data will become available,
polymer coating to tumour-targeting ligands and drug-delivery our knowledge of their pharmacology and long-term health effects
functionalities. Preparation and characterisation of novel CdSe QDs will expand, leading to the development of more rational design of
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Advanced Drug Delivery Reviews 63 (2011) 170–183

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

PLGA nanoparticles containing various anticancer agents and tumour delivery by

1. Approaches to drug targeting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

1.2. NP platform for therapeutic application

Despite extensive innovation over the past decade, there remains a

2.1. Physicochemical and biological advantage of PLGA-engineered

Particle size is a key factor in the biodistribution of long-circulating

Drug loaded in Major In vitro application In vivo application Authors and

Ong et al. [113]

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