14

Biodegradable PLGA/PLA
Nanoparticles for Anti-Cancer
Therapy
Sanjeeb K. Sahoo and Vinod Labhasetwar
CONTENTS
14.1 Introduction ....................................................................................................................... 243
14.2 General Principles of Drug Targeting to Cancer.............................................................. 244
14.2.1 Passive Targeting ................................................................................................ 244
14.2.2 Active Targeting.................................................................................................. 244
14.3 PLGA as a Polymer for Nanoparticles ............................................................................. 244
14.4 Application of PLGA/PLA Nanoparticles as Drug Delivery Vehicles
to Cancer Tissues .............................................................................................................. 245
14.5 PLGA Nanoparticles for Gene Delivery to Cancer .......................................................... 247
14.6 PLGA Nanoparticles for Photodynamic Therapy............................................................. 248
14.7 Concluding Remarks ......................................................................................................... 248
Acknowledgments ........................................................................................................................ 248
References..................................................................................................................................... 249
14.1 INTRODUCTION
Despite signicant efforts in the eld of oncology, cancer remains one of the leading causes of death
in industrialized countries.
1
Of the various options available, surgery and radiation therapy are
commonly used to treat localized tumors whereas chemotherapy is primarily used in the manage-
ment and elimination of hematological malignancies and metastasized tumors.
2
The major
limitation of the current cancer chemotherapeutics is their high pharmacokinetic volume of distri-
bution and rapid elimination rates, requiring more frequent and high dose administration of these
agents.
3
Therefore, cancer chemotherapeutics cause unacceptable damage to normal tissue when
used at doses required to eradicate cancer cells. Furthermore, multidrug resistance in tumor cells
exacerbates the problem of cancer chemotherapy.
47
Selective delivery of anti-cancer drugs to the
tumor tissue offers a formidable solution to the problem. This could signicantly enhance the
therapeutic efcacy of these drugs and diminish their toxicity.
8,9
The overall goal of drug delivery
strategies is to selectively attack cancer cells while saving normal tissue from drug toxicity.
10,11
The other issue with cancer chemotherapeutics is their systemic delivery, as most of these agents
are poorly water soluble. Hence they require adjuvant or excipients to dissolve, which are often
associated with serious side effects.
12
Therefore, drug carrier systems which would address the
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above problem of delivery as well as target drugs selectively to the tumor would be a major
advancement in cancer chemotherapy. Many macromolecular carriers, including soluble synthetic
and natural polymers, implants, liposomes, microspheres, dendrimers, nanoparticles, etc., have
been tested for selective delivery of drugs to the tumor tissue.
13
14.2 GENERAL PRINCIPLES OF DRUG TARGETING TO CANCER
14.2.1 PASSIVE TARGETING
Passive targeting refers to the accumulation of drug or drug-carrier system at a particular site due to
physicochemical or pharmacological factors. Permeability of the tumor vasculature increases to the
point where particulate carriers such as nanoparticles can extravasate from blood circulation and
localize in the tumor tissue.
14,15
This occurs because as tumors grow and begin to outstrip the
available supply of oxygen and nutrients, they release cytokines and other signaling molecules that
recruit new blood vessels to the tumor, a process known as angiogenesis.
16
Angiogenic blood
vessels, unlike the tight blood vessels in most normal tissues, have gaps as large as 600800 nm
between adjacent endothelial cells. Drug carriers in the nanometer size range can extravasate
through these gaps into the tumor interstitial space.
17,18
Because tumors have impaired lymphatic
drainage, the carriers concentrate in the tumor, resulting in higher drug concentration in the tumor
tissue (10-fold or higher) than that can be achieved with the same dose of free drug. This is
commonly referred to as enhanced permeability and retention, or the EPR effect.
14.2.2 ACTIVE TARGETING
Active targeting to the tumor can be achieved by molecular recognition of cancer cells either via
ligandreceptor or antibodyantigen interactions. Active targeting may also lead to receptor-
mediated cell internalization of drug carrier system. Nanoparticles and other polymer drug-
conjugates offer numerous opportunities for targeting tumors through surface modications
which allow specic biochemical interactions with the proteins/receptors expressed on target
cells.
19,20
For active and passive targeting of drug carrier systems, it is essential to avoid their
uptake by the reticuloendothelial system (RES) so that they remain in the blood circulation and
extravasate in the tumor vasculature. Particles with more hydrophobic surfaces are preferentially
taken up by the liver, followed by the spleen and lungs.
21,22
Size of nanoparticles as well as their
surface characteristics are the key parameters that can alter the biodistribution of nanoparticles.
Particles smaller than 100 nm and coated with hydrophilic polymers such as amphiphilic polymeric
compounds which are made of polyethylene oxide such as poloxamers, poloxamines, or polyethy-
lene glycol (PEG) are being investigated to avoid their uptake by the RES. To improve the efcacy
of targeting cancer chemotherapeutics to the tumor, a combination of passive and active targeting
strategy is being investigated where long-circulating drug carriers are conjugated to tumor cell-
specic antibody or peptides.
23
In addition to the above approach, direct intratumoral injection of
the carrier system is feasible if the tumor is localized and can be accessed for administration of a
carrier system.
24
14.3 PLGA AS A POLYMER FOR NANOPARTICLES
A number of different polymers, both synthetic and natural, have been utilized in formulating
biodegradable nanoparticles. Synthetic polymers have the advantage of sustaining the release of
the encapsulated therapeutic agent over a period of days to several weeks as compared to natural
polymers which, in general, have a relatively short duration of drug release. The polymers used for
the formulation of nanoparticles include synthetic polymers such as polylactidepolyglycolide
copolymers, polyacrylates, and polycaprolactones, or natural polymers such as albumin, gelatin,
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alginate, collagen, and chitosan. Of these polymers, polylactides (PLA) and poly (D,L-lactide-co-
glycolide) (PLGA) have been most extensively investigated for drug delivery applications.
19
PLGA/PLA-based polymers have a number of advantages over other polymers used in drug and
gene delivery, such as their biodegradability, biocompatibility, and approval by the FDA for human
use.
19,25
PLGA/PLA polymers degrade in the body through hydrolytic cleavage of the ester linkage
to lactic and glycolic acid, although there are reports of involvement of enzymes in their biode-
gradation.
19,25
These monomers are easily metabolized in the body via Krebs cycle and eliminated
as carbon dioxide and water. Biodegradation products of PLGA and PLA polymers are formed at a
very slow rate, and they therefore do not affect normal cell function.
26
Furthermore, these polymers
have been tested for toxicity and safety in extensive animal studies and are currently used in
humans for resorbable sutures, bone implants and screws, contraceptive implants,
27,28
and also
as graft materials for articial organs and supporting scaffolds in tissue engineering research.
2830
Long-term biocompatibility of these polymers was demonstrated by the absence of any untoward
effects on intravascular administration of nanoparticles formulated using these polymers to the
arterial tissue in pig and rat models of restenosis.
31
14.4 APPLICATION OF PLGA/PLA NANOPARTICLES AS DRUG DELIVERY
VEHICLES TO CANCER TISSUES
There are several studies regarding PLGA/PLA nanoparticles or some modication of these poly-
mers for delivery of anti-cancer agents and other therapeutic agents.
19
We have recently
demonstrated increased efcacy of transferrin conjugated paclitaxel-loaded PLGA nanoparticles
(Figure 14.1a and b) both in vitro and in an animal model of prostate carcinoma.
24
Transferrin
receptors are over-expressed in most cancer cells by two to tenfold more than in normal cells. We
have demonstrated that transferring-conjugated nanoparticles have enhanced cellular uptake
(Figure 14.1c) and retention than unconjugated nanoparticles.
4
A single-dose intratumoral injection
of transferrin conjugated nanoparticles in animal models of prostate carcinoma demonstrated
complete tumor regression and higher survival rate than animals that received either drug in
solution or unconjugated nanoparticles.
24
The IC
50
for paclitaxel with transferrin conjugated nano-
particles was vefold lower than that with unconjugated nanoparticles or with drug in solution in
PC3
24
(Figure 14.1d) and in MCF-7 cells.
4
Kim et al. have demonstrated enhanced intracellular
delivery of PLGA nanoparticles, which were surface-coated with cationic di-block copolymer,
poly(L-lysine)poly(ethylene glycol)folate (PLLPEGFOL), in KB cells that overexpress
folate receptors.
32
In another study, paclitaxel-loaded PLGA nanoparticles, which were conjugated
to wheat germ agglutinin (WGA), demonstrated greater anti-proliferation activity in A549 and
H1299 cells as compared to the conventional paclitaxel formulations. This enhanced activity of
WGA-conjugated nanoparticles was attributed to greater intracellular accumulation of drug via
WGA-receptor-mediated endocytosis of conjugated nanoparticles.
33
Cegnar et al. have developed
cystatin-loaded PLGA nanoparticles with the strategy of inhibiting the tumor-associated activity of
intracellular cysteine proteases cathepsins B and L. In an in vitro study, cystatin-loaded PLGA
nanoparticles demonstrated 160-fold greater cytotoxic effect in MCF-10A neoT cells than free
cystatin.
34
Similarly, interferon-alpha (IFN-alpha) loaded PLGA nanoparticles are being developed
to improve the therapeutic efcacy of IFN-alpha while reducing its dose-related side effects.
35
In
studies by Yoo et al., doxorubicin was chemically conjugated to a terminal end group of PLGA by
an ester linkage and the doxorubicinPLGA conjugate was formulated into nanoparticles. Nano-
particles containing the conjugate exhibited sustained doxorubicin release proles over a one-
month period, whereas those containing unconjugated doxorubicin showed a rapid drug release
within ve days. The conjugated doxorubicin nanoparticles demonstrated increased drug uptake in
HepG2 cell line and exhibited slightly lower IC
50
value compared to that of free doxorubicin.
Biodegradable PLGA/PLA Nanoparticles for Anti-Cancer Therapy 245
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The in vivo anti-tumor activity assay showed that a single injection of these nanoparticles had
comparable activity to that of free doxorubicin when administered by daily injection.
36
Thus
different strategies are being investigated using biodegradable PLGA-based nanoparticles to
deliver anti-cancer drugs more effectively, both at the cellular level and also to the tumor tissue.
0
10
20
30
40
50
60
70
80
90
1 10 100 1000
Paclitaxel concentration (ng/ml)
%

G
r
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t
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(c)
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60
0 10 20 30 40 50 60 70
Time (Day)
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%

r
e
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a
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e
(b)
(a)
(d)
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NP NP-Tf NP-Tf+freeTf
Treatments
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e

(

g
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g

c
e
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p
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FIGURE 14.1 (a) Transmission electron micrographs of paclitaxel-loaded PLA nanoparticles (NPs) (bar Z
100 nm). (b) Cumulative release of paclitaxel (Tx) from NPs in vitro. Tx loading in NPs is 5.4% (w/w). Data as
mean (Gs.e.m. (nZ3). (c) Uptake of unconjugated (NPs) and conjugated (NPsTf) in PC3 cells. A suspension
of NPs (100 mg/mL) was incubated with PC3 cells (5!10
4
cells) for 1 h, cells were washed, and the NP levels
in cells were determined by HPLC. To determine the competitive inhibition of uptake of Tf-conjugated NPs,
excess dose of free Tf (50 mg) was added in the medium prior to incubation with NPsTf. Data as mean G
s.e.m. (nZ6).* p!.05 NPsTfC free Tf vs. NPs, ** p!.005 NPsTf vs. NPs. NPs contain a uorescent
marker, 6-coumarin, to quantify their uptake. (d) Dose-dependent cytotoxicity of paclitaxel (Tx) in PC3 cells.
Different concentration of Tx either as solution (%) or encapsulated in NPs (TxNPs (&) or TxNPsTf, (:)
was added to wells with NPs (without drug) or medium acting as respective controls. The medium was changed
at two days and then on every alternate day with no further dose of the drug added. The extent of growth
inhibition was measured at ve days. The percentage of survival was determined by standardizing the absor-
bance of controls to 100% (nZ6). Data as mean Gs.e.m. * p!.005 TxNPsTf vs. Txsol and TxNPs. (Data
reproduced from Sahoo, S. K. and Labhasetwar, V., Mol. Pharm., 2, 373, 2005; Sahoo, S. K., Ma, W., and
Labhasetwar, V., Int. J. Cancer, 112, 335, 2004. With permission.)
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14.5 PLGA NANOPARTICLES FOR GENE DELIVERY TO CANCER
Gene therapy to cancer represents one of the most rapidly developing areas in pre-clinical and
clinical cancer research. Crucial to the success of any gene therapy strategy is the efciency with
which the gene is delivered.
37
This in turn is dependent upon the type of delivery vector used. Many
vectors have been developed based on either recombinant viruses or non-viral vectors. Research
utilizing viral vectors has progressed much more rapidly than that with non-viral vectors. This is
reected in the fact that approximately 85% of current clinical protocols involve viral vectors.
However, these vectors are still limited in many ways, particularly in relation to issues of safety,
immunogenicity, limitations on the size of the gene that can be delivered, specicity, production
problems, toxicity, cost and others.
38,39
Although various polymeric systems are under investigation,
40
our efforts are focused on
investigating biodegradable nanoparticles as a gene delivery system in cancer therapy.
19,4143
These nanoparticles are formulated using PLGA and PLA polymers, with plasmid DNA (pDNA)
entrapped into the nanoparticle matrix. The main advantage of PLGA or PLA-based nanoparticles
for gene delivery is their non-toxic nature. Furthermore, the slow release of the encapsulated DNA
from nanoparticles is expected to provide sustained gene delivery (Figure 14.2a). Blends of PLGA
and polyoxyethylene derivatives such as poloxamer and poloxamine are also being used to
modulate DNA release from nanoparticles.
44
In our study we demonstrated anti-proliferative
activity of wild-type (wt) p53 gene-loaded nanoparticles in breast cancer cell line.
45
Cells trans-
fected with wt-p53 DNA-loaded nanoparticles demonstrated sustained and signicantly greater
anti-proliferative effect than those treated with naked wt-p53 DNA (Figure 14.2b) or wt-p53
DNA complexed with a commercially available transfecting agent (Lipofectamine). This effect
was attributed to sustained nanoparticles-mediated gene expression. This was evident from
sustained p53 mRNA levels observed in cells transfected with nanoparticles compared with
levels in cells which were transfected with naked wt-p53 DNA.
0
0.2
0.4
0.6
0.8
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1.2
0.08 1 3 5 7
Time (day) (a) (b)
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DNA
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8
Time (day)
%

P
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p53 DNA
p53-Nanoparticles
FIGURE 14.2 (a) Quantitative determination of intracellular DNA levels. Cells transfected with YOYO-
labeled DNA-loaded nanoparticles demonstrated sustained and increase in intracellular DNA levels as
opposed to transient DNA levels in the cells transfected with naked DNA. Data represented as mean G
s.e.m., nZ6, * p!.001. (b) Anti-proliferative activity of wt-p53 DNA-loaded nanoparticles (NPs) and
naked wt-p53 DNA (DNA) in MDAMB-435S cells. Cells (2500 cells/well) grown in a 96-well plate were
incubated with DNA-loaded NPs or equivalent amount of naked DNA Cell growth was followed using a
standard MTS assay. NPs demonstrated increase in anti-proliferative activity with incubation time. Data
represented as meanGs.e.m., nZ6, * p!.01. (Data reproduced from Prabha, S. and Labhasetwar, V., Mol.
Pharm., 1, 211, 2004. With permission.)
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Recently, He et al. have formulated thymidine kinase gene (TK gene)-loaded nanoparticles and
investigated the expression of TK gene in hepatocarcinoma cells.
46
The expression of DNA
encapsulated in nanoparticles was signicantly greater than that with naked DNA. In another
study, Cohen et al. have demonstrated signicantly greater gene transfection (12 orders of magni-
tude) with PLGA nanoparticles than that with a liposomal formulation following their
intramuscular injection in rats. Furthermore, the nanoparticle-mediated gene transfection was
seen up to 28 days in the above study. Recently Kumar et al. have prepared cationic PLGA
nanoparticles modied with cationic chitosan and demonstrated gene expression in A549 epithelial
cells.
47
14.6 PLGA NANOPARTICLES FOR PHOTODYNAMIC THERAPY
Photodynamic therapy (PDT) is a promising new treatment modality
48
which involves adminis-
tration of a photosensitizing drug.
49
Upon illumination at a suitable wavelength, it induces a
photochemical reaction resulting in generation of reactive oxygen species (ROS) that can kill
tumor cells directly as well as the tumor-associated vasculature, leading to tumor infarction.
Targeting is essential in PDT as singlet oxygen is extremely reactive. Several strategies such as
chemical conjugation with various water-soluble polymers and encapsulation into colloidal carriers
have been considered for the parenteral administration of photosensitizers. These colloidal carriers
include liposomes, emulsions, polymeric micelles and nanoparticles. PLGA nanoparticles were
evaluated for PDT using meso-tetra(4-hydroxyphenyl) porphyrin as photosensitizer.
50
Vargas et al.
have encapsulated porphyrin in PLGA nanoparticles and demonstrated enhanced photodynamic
activity against mammary tumor cells than free drug.
51
Colloidal carrier associated with photo-
sensitizer showed enhanced photodynamic efciency and selectivity of tumor targeting as
compared with dye administered in homogenous aqueous solution.
52,53
Recently, Saxena et al.
have formulated PLGA nanoparticles loaded with indocyanine green (ICG) and determined their
biodistribution in mice. The results demonstrated that the nanoparticle formulation signicantly
increased the ICG concentration and circulation time in plasma as well as the ICG uptake, accumu-
lation and retention in various organs as compared to ICG solution.
54
Such a formulation can be
explored in tumor-diagnosis as well as for PDT.
14.7 CONCLUDING REMARKS
It is essential to understand the molecular mechanisms involved in nanoparticle-mediated drug or
gene delivery to explore their therapeutic potentials for cancer therapy. Also, the important ques-
tions we need to address are: What are the barriers in targeted cancer drug therapy? What is the
efciency of drug targeting with carrier systems? Can it provide a therapeutic dose of the drug in the
tumor tissue? How long should the drug effect in the tumor tissue be sustained to regress it
completely? Is a combination of drugs, especially those that work by different pathways, more
effective than single-drug therapy? These and other questions are critical as we move from a
conceptual stage to reality. With better understanding of molecular targets, discovery of more
potent drugs and simultaneous developments in nanotechnology it seems that an effective cancer
therapy is forthcoming.
ACKNOWLEDGMENTS
Grant support from the National Institutes of Health (R01 EB003975) is gratefully acknowledged.
The authors also thank Ms. Elaine Payne and Ms. DeAnna Loibl for providing
administrative support.
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