Pegylation in Anti-Cancer Therapy: An Overview: Sciencedirect

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asian journal of pharmaceutical sciences (2015)
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Review
PEGylation in anti-cancer therapy: An overview

Prajna Mishra a, Bismita Nayak b, R.K. Dey a,*
a
b
Centre for Applied Chemistry, Central University of Jharkhand, Ranchi 835 205, Jharkhand, India
Department of Life Science, National Institute of Technology, Rourkela 769 008, Odisha, India
A R T I C L E
I N F O
A B S T R A C T
Article history:
Advanced drug delivery systems using poly(ethylene glycol) (PEG) is an important devel-
Received 1 July 2015
opment in anti-cancer therapy. PEGylation has the ability to enhance the retention time of
Received in revised form 20 August
the therapeutics like proteins, enzymes small molecular drugs, liposomes and nanoparticles
2015
by protecting them against various degrading mechanisms active inside a tissue or cell, which
Accepted 26 August 2015
consequently improves their therapeutic potential. PEGylation effectively alters the phar-
Available online
macokinetics (PK) of a variety of drugs and dramatically improves the pharmaceutical values;
recent development of which includes fabrication of stimuli-sensitive polymers/smart poly-
Keywords:
mers and polymeric micelles to cope of with the pathophysiological environment of targeted
PEG
site with less toxic effects and more effectiveness. This overview discusses PEGylation in-
PEGylation
volving proteins, enzymes, low molecular weight drugs, liposomes and nanoparticles that
Targeted drug delivery
has been developed, clinically tried for anti-cancer therapy during the last decade.
Polymers
2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Shenyang Pharmaceutical University. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
1.
Introduction
Cancer is one of the leading causes of death worldwide. Metastases are the primary cause of death from cancer. Cancer
cells proliferate at much faster rate than the normal cells. The
available traditional cancer chemotherapy is not essentially selective as it depends on the kinetics of the cell growth. Targeted
cancer therapies are expected to be more effective and beneficiary in comparison to available conventional treatment
procedures.
The last few decades of research in the particular area are
focused on exploring the treatment of cancer at its molecular level. This will be helpful in developing better therapeutics.
Polymer therapeutics is establishing as an innovative and
reliable method for its ability to conjugate with protein,

enzymes, nanoparticles, liposomes and low molecular weight
drugs. In this regard, polyethylene glycol (PEG), a watersoluble and biocompatible polymer, is the most commonly used
non-ionic polymer in the field of polymer-based drug delivery [1]. Passive targeting with PEGs in combination with active
targeting (entry into the tumor cell via ligand receptor, antigen
antibody interaction) delivery systems has been effectively employed to achieve better therapeutic index of anti-cancer drugs.
Further, with the introduction of stimuli-responsive chemical moiety in PEGylated prodrugs, the sensitiveness of the drug
molecule toward the pathophysiological environment of tumor
cells in vivo evolved as a new era of site-specific targeted drug
delivery system. Hence this overview deals with the development and recent advancement in various aspects of PEGylation
* Corresponding author. Centre for Applied Chemistry, Central University of Jharkhand, Ranchi 835 205, Jharkhand, India. Tel.: +91 8987727378;
fax: +91-671-2306624.
E-mail address: rkdey@rediffmail.com; ratan.dey@cuj.ac.in (R.K. Dey).
Peer review under responsibility of Shenyang Pharmaceutical University.
http://dx.doi.org/10.1016/j.ajps.2015.08.011
1818-0876/ 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of Shenyang Pharmaceutical University. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Prajna Mishra, Bismita Nayak, R.K. Dey, PEGylation in anti-cancer therapy: An overview, Asian Journal of Pharmaceutical Sciences (2015),
doi: 10.1016/j.ajps.2015.08.011
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2
in cancer treatment and its future prospective in a comprehensive way.
2.
PEGylation and its significance
The technique of covalently attaching polyethylene glycol (PEG)

to a given molecule is known as PEGylation and is now a wellestablished method in the field of targeted drug delivery
systems. The general structure of monomethoxy PEG (mPEG)
can be represented as CH3O(CH2-CH2O)nCH2-CH2OH. At the
beginning of PEG chemistry, in the late1970s, Professor Frank
Davis and his colleagues had shown that the immunological
properties as well as the stability of bovine serum albumin and
bovine liver catalase can be successfully altered by covalently linking them to methoxy PEG (mPEG) [2,3] using cyanuric
chloride as an activating agent. The process of PEGylation can
be extended to liposomes, peptides, carbohydrates, enzymes,
antibody fragments, nucleotides, small organic molecules and
even to different nanoparticle formulations [48]. mPEG is the
most useful unit for polypeptide modification [9]. Now several
derivatives of PEG molecules are available that vary in molecular weight and structure, such as linear, branched, PEG
dendrimers and more recently multi-arm PEGS [9]. The first step
of PEGylation is to activate PEG by conjugating a functional derivative of PEG at one or both the terminals of PEG chain.
PEGylation conjugation techniques can be classified into two
categories: i) first-generation random PEGylation, and ii) secondgeneration site-specific PEGylation. Thanks to the second
generation PEGylation processes that resulted in well-defined
conjugated products with improved product profiles over those
obtained through non-specific random conjugations.
PEG
SPACER/LINKER
Drug
Irreversibly conjugating PEGs had some adverse effects on

the specific biological activity of many therapeutics. Thus, to
minimize the loss of activity, a reversible (or releasable prodrug)
PEGylation concept has been formulated. Reversible PEGylation
concept deals with attachment of drugs to PEG derivatives
through cleavable linkages (Fig. 1). The release of drug occurs
by therapeutic agents through enzymatic, hydrolytic cleavage or reduction in vivo at a predetermined kinetic rate over
a time period [10].
The objective of most PEG conjugation techniques aims at
increasing the circulation half-life without affecting activity.
It is to be noted that the distinct advancement in the PEG conjugation processes and diversity in the nature of the PEGs used
for the conjugation has attributed to the increased demand for
PEGylated pharmaceutical products.
PEGylation enhances the therapeutic efficacy of the drugs
by bringing in several advantageous modifications over the nonPEGylated products. The systematic classification is illustrated
in Fig. 2. Increase in the serum half-life of the conjugate is the
major way of enhancing therapeutic potential of the PEGylated
conjugate. PEGylation prolongs the circulation time of conjugated therapeutics by increasing its hydrophilicity and reducing
the rate of glomerular filtration [11,12]. Few factors such as protection from reticuloendothelial cells, proteolytic enzymes and
decreased formation of neutralizing antibodies against the
protein by masking antigenic sites by formation of a protective hydrophilic shield are the key components of PEG molecule
that attributes to the improved pharmacokinetic profile (PK)
of the conjugates [1316]. It has also been reported that
PEGylation increases the absorption half-life of subcutaneously administered agents and is associated with a decreased
volume of distribution [11]. PEG is a non-biodegradable polymer
PEG
Linker
Drug
(PEG-Prodrug)
Fig. 1 PEG-prodrug.
Fig. 2 Significance of PEGylated therapeutics.

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that puts limits on its use. It has been shown that PEGs (up
to molecular weight 20 kDa) is primarily excreted through the
renal system, whereas higher molecular weight PEG chains get
eliminated by fecal excretion [17]. PEGylation proved to be the
most promising approach for increasing the serum half-life of
the conjugated therapeutics, which is related to enhancement of efficacy of the conjugate. However, PEGylation imposes
certain disadvantages on liposomes, especially for the delivery of genes and nucleic acids in anti-cancer therapy as its
surface hydrophilic shield reduces the cellular uptake and improves the stability of the lipid envelope, and the process results
in poor endosomal escape via membrane fusion and degradation of cargos in lysosomes [18,19]. Hence the use of PEG in
gene and nucleic acid delivery to cancer cell is referred to as
PEG dilemma [20]. The issue can be efficiently addressed by
designing pH-sensitive and tumor-specific targeted PEGylated
therapeutics [2123].
2.1.
drugs
Role of PEGylation in passive and active targeting of
Passive targeting drug delivery technique, as illustrated in Fig. 3,

mostly depends upon the concentration gradient between the
intracellular and extracellular space, created due to high concentration of the drug in the tumor area [24]. PEG conjugates
takes the advantage of enhanced permeation and retention
(EPR) effect executed by the tumors and gets accumulated in
the pathophysiological environment of tumor vessels through
leaky vasculature and poor lymphatic drainage. However, this
effect cannot be studied with low molecular weight drugs that
freely extravagate causing systemic toxicity, and this is a sizedependent effect. PEGylation increases the solubility, size,
molecular mass and serum stability of the drugs. For all these
reasons, PEGylation is considered to be one of the best methods

for passive targeting of anticancer therapeutics.
The concept of active targeting of drugs is based on the idea
of conjugating drug molecules to targeting entities (antibodies, ligands, etc.) for specific interaction with the structures
present on the cell surface for targeted delivery of the anticancer agent [25,26]. The fate of the pro-drug is dictated by
the targeting molecule and the linker molecule present on the
pro-drug. The targeting moiety essentially decides the type of
cancer cell for the act of therapeutics. Further, depending on
the linker molecule, the drug gets entry into the tumor cell by
either of the two ways: (i) receptor-mediated internalization
of the whole pro-drug by endocytosis and subsequent degradation by endosomal/lysosomal pathway (Fig. 4), or (ii) receptorindependent internalization of the drug into targeted cells after
extracellular cleavage of the pro-drug (Fig. 5) [27]. PEGylated
pro-drugs can be efficiently conjugated to targeting moieties
by different conjugation chemistry in order to achieve the goal
of active targeting. The targeted delivery of the PEGylated drugs
at the desired site causes high bioavailability and low systemic toxicity.
3.
PEGylated proteins in anti-cancer therapy
PEGylation of proteins is a well-established method in the pharmaceutical field, but the significance of PEGylated peptides and
proteins for anti-cancer therapy has only been realized in the
last several years as more and more PEG conjugates make it
to late-phase clinical trials. Enzymes, monoclonal antibodies
and cytokines are the three major class of proteins used in anticancer therapy or as adjuvant therapy (Table 1).
Fig. 3 A schematic illustration of passive targeting with acid-sensitive PEG-prodrugs that cleave in the extracellular space.
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Fig. 4 A schematic illustration of receptor mediated internalization and endosomal/lysosomal degradation of the pro-drug
during active targeting.
Fig. 5 A schematic illustration of Active Targeting with acid sensitive PEG- prodrugs which cleaves in the extracellular
space.
3.1.
PEGylated monoclonal antibody fragment
In the field of anti-cancer therapy, monoclonal antibodies represent the major class of protein therapeutics. Antibodies act
by binding to the specific antigens/cell surface receptors. This
task is taken care by the fragment antigen-binding (Fab) region
on an antibody. Depending upon the receptor and the binding
site on the receptor against which the antibody is designed,
it can either activate cellular signaling pathways leading to
apoptosis, cell growth arrest, or block the pathways leading to
cell growth that eventually causes tumor cell death (apoptosis). This event is illustrated pictorially in Fig. 6. The major
drawback associated with Fabs antibody fragment is its short

serum half-life as it lacks the Fc region of the antibody that
limits its potential as a therapeutic agent. Hence, suitable
PEGylation methods and PEGs are used to ensure minimal loss
of the antibody-antigen/cell surface receptor interaction keeping
in view the enhancement of serum half-life. It has been reported that the hinge region cysteine residues on immunoglobulin G (IgG antibody isotype) Fab antibody fragments can
tolerate attachment of one or two PEG moieties (up to a total
of 40 kDa molecular weight) with little effect on antigen binding
affinity. This process also enables significant increase in the
half-life of the circulating plasma antibodies by reducing the
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Table 1 PEG protein/enzyme conjugates in clinical development as anticancer therapy.

Trade name
Conjugate
Protein/Enzyme
Sylatron
PEG-interferon -2b
PEG-interferon -2b
Pegasys
Neulasta
PEG-interferon -2a
PEG-filgrastim
Oncaspar
PEG-asparaginase
Interferon -2a
G-CSF(granulocyte-colony
stimulating factor)
Asparaginase
FDA approved date/clinical trial status and use

March 9, 2011, approved as adjuvant therapy for resected stage III
melanoma
Phase I for melanoma and phase II as for chronic myelogenous leukemia
2002, to treat neutropenia during chemotherapy
February 1994, acute lymphoblastic leukemia, and in July 24, 2006 first-line
treatment for acute lymphoblastic leukemia
Fig. 6 (a) IgG full length antibody and (b) PEGylated IgG Fab antibody fragmentcell surface receptor interaction and its
outcome.
glomerular filtration and lower immunogenicity than the parent

IgG [28].
The example of use of PEG-antibody fragment angiogenesis inhibitor (CDP791) is illustrated as follows: CDP791
PEGylated diFab antibody fragment antagonizes the effect of
vascular endothelial growth factor receptor-2 (VEGFR-2), which
is a prominent angiogenesis stimulatory molecule responsible for tumor progression. The short plasma half-life of the
unmodified CDP791 antibody fragment, which lacks Fc region,
has a low molecular weight and responsible for low therapeutic index. PEGylation of the cysteine amino acid present at the
C-terminus of the native antibody could be able to resolve this
issue by reducing its kidney clearance. This is demonstrated
by the clinical studies for patients with colorectal, ovarian, renal
cancer or other tumors [29].
3.2.
PEGylated cytokines
Cytokines represent another class of protein therapeutics employed mainly as adjuvant therapy in classical anti-cancer
chemotherapy protocols either to control or bring improvements in patient conditions. These small secreted proteins
belong to the immunotherapy category and mobilizes the bodys
immune system to fight cancer. The process is illustrated pictorially in Fig. 7.
3.2.1.
PEG-interferon-alpha conjugates
This process is illustrated as PEG-interferon-2b (PEG-INTRON/

Sylatron) and PEG-interferon-2a (Pegasys), which are
discussed as follows:
3.2.1.1. PEG-interferon-2b (PEG-INTRON/Sylatron). The

PEGylated version of interferon-2b was synthesized by conjugating interferon-2b, with a single chain 12 kDa PEG-SC via
a urethane bond [30]. It displayed a half-life of 2737 h with
10-fold lower clearance and minor change in the volume of distribution in comparison to native form [31]. Based upon the
outcome of clinical studies in the year 2011, the PEGylated drug
peginterferon alfa-2b (PEG-IFN) got FDA approval for adjuvant treatment of melanoma patients with microscopic or gross
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Fig. 7 Representing PEGylated cytokines in anticancer therapy.
nodal involvement following definitive surgical resection including complete lymphadenectomy [32]. Sylatron is another
brand name for peginterferon alfa-2b exclusively approved by
FDA for adjuvant therapy in cancer treatment.
3.2.1.2. PEG-interferon-2a (Pegasys). Another PEGylated interferon, Pegasys, is prepared by mono-PEGylation of

interferon--2a with an N-hydroxysuccinimide (NHS) activated 40 kDa branched PEG molecule [33]. PEGylation prolonged
the serum half-life from 3.8 to 65 h, slowing down the clearance by more than 100-fold. This has also reduced the volume
of distribution to fivefold with respect to the native interferon2b [31]. PEGASYS was efficient in improving the patient
compliance by enabling once-weekly dosing while maintaining acceptable safety, tolerability, and activity profiles in clinical
studies [34]. Currently, PEGASYS is under evaluation as adjuvant therapy for patients with intermediate and high-risk
melanomas [35].
3.2.2. PEG-granulocyte colony stimulating factor
(PEG-filgrastim)
PEG-filgrastim was synthesized by conjugating a linear 20 kDa
mPEG-aldehyde derivative to an N-terminal methionine residue
of filgrastim through reductive alkylation under mild acidic conditions [36,37]. It is to be noted that a single dose of PEGfilgrastim per chemotherapy cycle could be able to reduce the
risk of febrile neutropenia significantly with respect to the native
protein (11% vs. 19%) [3840]. Currently, PEGylated-G-CSF
(Pegfilgastrim, Neulasta) is used as an adjuvant therapy for
patients with non-myeloid malignancies receiving myelosuppressive chemotherapy (bone marrow suppression as a side
effect of chemotherapy) associated with a 20% risk of febrile
neutropenia [41,42].
3.3.
PEGylated enzymes in anti-cancer therapy
Therapeutic enzymes represent a growing class of biopharmaceuticals, and PEGylation has played a major role in
improving several of these products [43]. Many depleting

enzymes are active against tumors. Enzymes intrinsic property of degrading amino acids is essential for cancer cells
existence. The fate of the tumor cell is dictated by the different cellular pathways regulated by the substrate (amino acid)
to be degraded, and the process of degradation is illustrated
in Fig. 8. The normal cells are not affected because the normal
cells can synthesize the amino acids for their growth. This situation is particularly the most advantageous aspect of using
depleting enzymes in cancer therapy (Table 1). Therefore, during
PEGylation procedure, a combination of these enzymes, low
molecular weight (510 kDa) PEGs and random amine conjugation strategies are employed.
3.3.1.
PEG-arginine depleting enzymes
Arginine is a nonessential amino acid in humans. It has been

reported that arginine deficiency inhibits tumor growth, angiogenesis and nitric oxide synthesis [44]. Two types of arginine
degrading enzymes, i.e. i) arginine deiminase (ADI) and ii) arginase (ARG), which can be utilized as antitumor agents, are
discussed below:
3.3.1.1. PEG-arginine deiminase. The PEGylation of arginine

deiminase proved to be a better therapeutic approach for
anticancer treatment. Among the several PEGylated ADI formulations the ADI-PEG20000, formulated by conjugating
1012 chains of 20 kDa PEG with ADI by using the succinimidyl
succinate linker, is proved to be the acceptable one from
in vivo study results [45]. Clinical studies have shown better efficacy of ADI PEG 200,000 in terms of antitumor activity and
tolerability [46,47]. Currently, ADI PEG 200,000 versus placebo
is under phase III clinical trial for advanced hepatocellular carcinoma. Further, Phase II for acute myeloid
leukemia/non-Hodgkins lymphoma and Phase I (for metastatic melanoma in combination with cis-platin; for solid
tumors in combination with docetaxel) are under trial
[48].
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Fig. 8 Representing PEGylated depleting enzymes in anticancer therapy.
3.3.1.2. PEG-arginase. The depleting enzyme arginase is an endogenous protein expressed in humans. The conjugate, PEGrhArg, has 10 to 12 polymer chains of PEG 5000 per protein
molecule that is covalently attached via a succinamide propionic acid (SPA) linker. This conjugate remains in fully active
condition [49]. The PEGylated form executes sufficient catalytic activity at physiological pH with a prolonged plasma halflife of 3 days in comparison to the native form, which has a
half-life of several minutes only. Currently, this conjugate is
under phase I/II clinical trials.
3.3.2. PEG-asparagine depleting enzyme
(PEG-L-asparaginase)
Depletion of asparagine eventually results in leukemic cell
death. Leukemic cells lack the enzyme asparagine synthetase, an enzyme required for asparagine synthesis, and depend
on the exogenous supply of asparagine for their growth and
survival. Therefore, asparaginase, the depleting enzyme for asparagine, plays a critical role as a therapeutic enzyme in treating
acute lymphoblastic leukemia (ALL). Oncaspar is a modified
form of the enzyme L-asparaginase approved by FDA in 1994.
Oncaspar consists of tetrameric enzyme L-asparaginase derived
from E. coli, and it is covalently conjugated with approximately 6982 molecules of monomethoxy polyethylene glycol
(mpeg), each having molecular weight of 5 kDa [50]. Oncaspar
proved to be a better treatment option for patients who were

allergic to the native form of the drug. The U.S. Food and Drug
Administration granted approval to pegaspargase (Oncaspar,
Enzon Pharmaceuticals, Inc) in July 2006 for the first-line treatment of patients with acute lymphoblastic leukemia (ALL) as
a component of a multi-agent chemotherapy regimen [51].
4.
PEGYLATED low molecular weight
anticancer drugs
Various PEGylated low molecular weight anti-cancer drugs are
currently under development. For example, topoisomerase I inhibitor camptothecin-based drugs (irinotecan, topotecan, SN38,
exetecan, etc.) is reported to be useful in the treatment of many
solid tumors. However, the hydrophobicity of such material
limits their therapeutic efficacy. Few of the examples, listed in
Table 2, are discussed below:
4.1.
PEG-SN38 (EZN-2208)
EZN-2208, the product Enzon Pharmaceuticals, Inc, is a

PEGylated SN38 (10-hydroxy-7-ethyl-camptothecin (a derivative of camptothecin)). SN38 is the active moiety of CPT-11
Table 2 PEGylated low molecular weight drugs/liposomal derivatives/thermo-sensitive conjugates and nanoparticles in
clinical development as anticancer therapy.
Trade name
Conjugate
EZN-2208
PEG-SN38
NKTR-102
Irinotecan
PEG-irinotecan
Doxil (Caelyx)
ThermoDox
PEG-liposomal doxorubicin
PEG-thermosensitive
liposomal doxorubicin
Pegylated cyclodextrin
nanoparticle
CALLA 01
Parent drug
SN38 (camptothecin
derivative)
Irinotecan
FDA approved date/clinical trial status

Phase II, various cancer
Doxorubicin
Doxorubicin
Phase III, metastatic or locally recurrent breast cancer and Phase II,
solid tumor malignancies, including ovarian, colorectal, glioma,
small cell and non-small cell lung cancers
November 1995 for ovarian/breast cancer and Kaposis sarcoma
Phase III, hepatocellular carcinoma
SiRNA
In clinical phase I for solid tumors
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(Camptosar, irinotecan) and reported to be a potent

topoisomerase I inhibitor. In this PEGylated product, the 20OH group of SN38 was selectively coupled with a 4 arm PEG
of 40 kDa through a glycine spacer to preserve the E ring of
SN38 in the active lactone form while leaving the drug 10-OH
free [52]. PEGylation was able to enhance the solubility of SN38
by about 1000-fold. In fact, EZN-2208 showed a 207-fold higher
exposure to SN38 compared to irinotecan in treated mice [53].
The conjugate showed promising antitumor activity both in vitro
and in vivo. However, following phase II trial, Enzon Pharmaceuticals, Inc. announced the discontinuance of its EZN-2208
clinical program [54].
4.2.
PEG-irinotecan (NKTR-102, Etirinotecan pegol)
NKTR-102 was developed by Nektar Therapeutics as a PEGylated

formulation for the treatment of colorectal cancer and other
solid tumors using the architecture of new multi-arm PEGs. It
is the first long-acting topoisomerase I inhibitor. It is synthesized by covalently conjugating irinotecan to a four-arm PEG
[55]. SN38 (10-hydroxy-7-ethyl-camptothecin, a derivative of
camptothecin) is the active metabolite of NKTR-102. It is reported in both Phase I and II studies for NKTR-102 that
sustained exposure of the active drug was associated with
promising anti-tumor activity [5658]. Currently NKTR-102 is
in Phase III clinical trial for patients with metastatic or locally
recurrent breast cancer and Phase II clinical trial for patients
with solid tumor malignancies that include ovarian, colorectal,
small cell and non-small cell lung cancers [59].
5.
PEGylated nanoparticles in anti-cancer
therapy
Nanoparticles (NPs) are synthetic materials with dimensions
from 1 to 1000 nano-meters. NPs have large payloads, stability and the capacity for multiple, simultaneous applications
due to their unique size and high surface area:volume ratio
[60]. Despite these advantages, the major drawbacks associated with NP drug delivery system for clinical studies are
associated with short circulating half-life due to uptake by the
reticuloendothelial system (RES) for larger NPs, whereas smaller
NPs are subjects to tissue extravazations and renal clearance
[61]. Liposomes, solid lipids nanoparticles, dendrimers, polymers, silicon or carbon materials, and gold and magnetic
nanoparticles are examples of nano-carriers that have been
studied as drug delivery systems in cancer therapy. Therefore, surface modification of the nanoparticles with PEGs of
various chain length, shape, density, molecular weight and incorporation of different targeting moieties (ligands, antibodies,
etc.) is emerging as a more promising and technologically advanced drug delivery system in anti-cancer therapy [6264].
There are currently more than 35 US FDA-approved PEGylated
NPs, with a larger number in preclinical studies for both imaging
and therapy [8]. Among several PEGylated nanoparticle formulations for anticancer therapy, liposomes have been most
extensively studied.
5.1.
PEGylated liposomes in anticancer therapy
Liposomes are spherical, self-closed structures formed by one

or more concentric lipid bilayers with an encapsulated aqueous
phase in the center and between the bilayers composed of
natural or synthetic lipids [65]. The development of longcirculating liposomes with inclusion of the synthetic polymer
poly-(ethylene glycol) (PEG) in liposome composition could be
able to solve the issue of low serum half-life associated with
liposomes. PEG can be incorporated on the liposomal surface
in a number of ways. However, anchoring the polymer in
the liposomal membrane via a cross-linked lipid, PEGdistearoylphosphatidylethanolamine [DSPE], is reported to be
the most widely accepted method [66,67]. Preclinical studies
with PEGylated liposomes reported that the cytotoxic agents
entrapped in PEGylated liposomes tend to accumulate in tumors
[68]. However, recent preclinical studies of anti-cancer drug enclosed in PEGylated liposomes in rodents and dogs have shown
the rapid blood clearance of the pegylated drug carrier system
due to the increased anti-PEG-IgM production [69,70]. An
example of PEGylated liposomal formulations, PEGylated liposomal doxorubicin (PLD), and most extensively studied, is
discussed below:
5.1.1.
Doxil (PEGylated liposomal doxorubicin)
DOXIL is the trade name for PEGylated liposomal doxorubicin formulated to achieve better drug efficacy for cancer
chemotherapy. This product contains doxorubicin (Adriamycin)
enclosed in an 8090 nm size uni-lamellar liposome coated with
PEG. The modification increases the circulatory half-life of the
drug leading to its enhanced bioavailability at the tumor site
[71,72]. PEGylated liposomal doxorubicin has fewer side effects
on healthy cells than regular doxorubicin [73,74]. PLD has improved pharmacokinetic features, such as long circulation time
of about 6090 h for doses in the range of 3570 mg/m2 in patients with solid tumors. After PLD administration, nearly 100%
of the drug in the plasma remains in the encapsulated form.
Moreover, in comparison to free doxorubicin PLD, plasma clearance is dramatically slower and its volume of distribution
remains very small, which is roughly equivalent to the intravascular volume [7577]. After obtaining approval from FDA,
PEGylated liposomal doxorubicin (PLD) (DOXIL/Caelyx) is currently used to treat Kaposis sarcoma and recurrent ovarian
cancer (Table 2).
6.
PEGylated smart polymers in anticancer
therapy
Smart polymers are defined as polymers that undergo reversible large, physical or chemical changes in response to small
external changes in the environmental conditions, such as temperature, pH, light, magnetic or electric field, ionic factors,
biological molecules, etc. Smart polymers show promising applications in the biomedical field as delivery systems of
therapeutic agents [78]. Among various smart polymers currently in use in biomedical field of research, the temperature
sensitive systems are the most studied systems. The greater
therapeutic index of the targeted drug delivery systems can
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be achieved by adjusting the transition temperature (Tt) of thermally responsive polymers, i.e., between body temperature
(37 C) and the temperature approved for mild clinical hyperthermia (42 C) [79]. Within the temperature ranges, these
polymers facilitate tissue accumulation by localizing the aggregation of systemically delivered carriers to the heated tumor
volume [80,81]. For example, ThermoDox, a temperaturesensitive doxorubicin-loaded PEGylated liposome (DPPC),
releases encapsulated doxorubicin at elevated tissue temperature. DPPC has a transition temperature of 41.5 C, which makes
it suitable for temperature-sensitive technology [82]. The temperature can be achieved by radiofrequency ablation technique.
For ThermoDox, the concentration of the drug is up to 25 times
more in the treatment area than IV doxorubicin, and several
fold the concentration of other liposomally encapsulated doxorubicins [82,83]. Currently, it is under phase III clinical trial for
hepatocellular carcinoma (Table 2).
7.
PEGylated polymeric micelles in anticancer therapy
Polymeric micelles are colloidal dispersions prepared by blockcopolymers, consisting of hydrophilic and hydrophobic
monomer units. Self-assembling amphiphilic polymeric micelles represents an efficient drug delivery system for poorly
soluble or insoluble drugs [84]. Different varieties of amphiphilic polymeric micelles (i.e. diblock AB type, triblock ABA type
or graft copolymers) can be designed by arranging the monomeric units in different ways and orders [85,86]. The
hydrophobic block constitute the core and the hydrophilic block
makes the corona of the micelles. The water-soluble PEG blocks
with a molecular weight from 1 to 15 kDa are considered as
the most suitable hydrophilic corona-forming blocks [87]. Various
preclinical and clinical studies have shown the potential use
of PEGylated polymeric micelles with different hydrophobic
blocks such as PLGA poly(D,L-lactide-co-glycolide) [8890], poly
aspartate [91], -benzyl-L-glutamate [92], polyglutamate (Pglu)
[93], and poly(D,L-lactic acid) [94] in anti-cancer therapy. It is
to be noted that five different PEGylated polymeric micellar formulations, as enlisted in Table 3, are currently under clinical
trials for possible anticancer treatment [95,96].
8.
PEGylated nanoparticles for SiRNA delivery
in anticancer therapy
RNA interference is a natural phenomenon employed to selectively turn off the genes expressed in some diseases.
Molecular therapy using small interfering RNA (siRNA) has

shown great therapeutic potential for tumors and other diseases caused by abnormal gene over-expression or mutation.
It is a highly specific process for gene silencing. However, naked
molecules of siRNA are vulnerable to premature renal clearance and nuclease degradation. The negative charge and
hydrophilicity of siRNA also limit its permeability through cellular and endolysosomal membranes. Therefore, in order to
overcome these issues, siRNA requires a carrier system for effective delivery [97]. Modification of drug delivery systems with
PEGs of suitable chain length, molecular weight and percent
composition was proven to be efficient in overcoming intracellular and systemic siRNA delivery barriers [98]. CALLA 01,
a nanoparticle formulation (Calando Pharmaceuticals) formulated by using cyclodextrin nanoparticles conjugated to
transferrin and coated with PEG, is the first one to enter under
phase I clinical trials for solid tumors [44,99], in addition to few
more which are currently under development (Table 2).
9.
Conclusions
PEGylation offers a great advantage for bioactive molecules in

pharmaceutical and biological applications by way of reducing protein immunogenicity and increased serum half-life of
the drugs. This overview highlighted on the use of PEGylated
proteins, low molecular weight drugs and PEG micelles.
PEGylation improves the therapeutic efficacy of a drug by
passive targeting in a novel way. The process can also be combined effectively with active targeting and stimuli-responsive
targeted therapies for the development of new methodologies for the treatment of cancer. It is important to note that
the efficacy of PEGylated drugs depends on overall exposure
and its relationship to the pharmacodynamics of the drug. Molecular weight of PEG chain and its structural modifications
carries strategic importance for conjugation with drug molecule for effective PEGylation process. The research in this
direction shall be helpful in effective cancer treatment process
in near future.
Acknowledgements
The authors wish to acknowledge Dr. Rajakishore Mishra from
Central University Jharkhand, India, and Dr. Basabi Rana from
Loyola University Chicago, USA, for their valuable suggestions.
The grant in aid from DST, New Delhi (Project No. SR/S1/PC-24/
2009) is duly acknowledged. University fellowship to Prajna
Mishra for pursuing her research work is acknowledged.
Table 3 PEGylated polymeric micelles in clinical development as anticancer therapy.

Trade name for polymeric micelle
NK105
NK012
NC-6300
NC-6004
Genexol-PM
Block copolymer
PEG-P(aspartate) Paclitaxel
PEG-PGlu(SN-38)
PEG-P(aspartate) Epirubicin
PEG-PGlu(cisplatin)
PEG-P(D,L-lactide) Paclitaxel
Parent drug
Paclitaxel
SN-38
Epirubicin
Cisplatin
Paclitaxel
Clinical trial status

Phase II, advanced stomach cancer
Phase II, breast cancer
Phase I, breast cancer, stomach cancer, lymphoma
Phase I/II, solid tumors
Phase IV, breast cancer
Phase II, pancreatic cancer
doi: 10.1016/j.ajps.2015.08.011
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