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Synthetic Polymer-based Nanomaterials
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Chapter 1
Synthetic Polymer-based Nanomaterials

Swapnil S. Desale, Jinjin Zhang, and Tatiana K. Bronich
Abstract
Synthetic polymers play an essential role in the development of conventional pharmaceutical formulations
as well as devices for controlled drug delivery and represent the most commonly used “building blocks”
for engineering of various nanomedicines. In this chapter we review several classes of synthetic polymers
that are widely used for the design of drug delivery systems, synthetic methodologies to tailor their physi-
cochemical properties, and therapeutic applications and developments.
Key words Nanomedicines, Polymers, Polymerization, Nanoparticles, Drug delivery
1 Introduction
Nanomedicine is a rapidly developing area of biomedical research

that uses devices of nanoscale size to address urgent needs for effec-
tively detecting diseases and improving drug and gene delivery. Such
nanomaterial (NM)-based delivery vehicles have the ability to
improve drug pharmacokinetics, biodistribution, cell- or tissue-spe-
cific targeting, and drug exposure kinetics, resulting in enhanced
efficacy and improved tolerability [1–3]. The most sophisticated
nanocarriers can simultaneously deliver multiple therapeutic and/or
imaging agents and thus enable both diagnosis and therapy. Polymers
are playing an essential role in the development of conventional
pharmaceutical formulations as well as devices for controlled drug
delivery and represent the most commonly used “building blocks”
for engineering of the NM-based drug delivery systems. The
advances in synthetic polymer chemistry led to the exceptional diver-
sity and control over the composition, architecture and functionality
of the polymers, which in turn enables the building of NM with
tunable properties for various biomedical applications. This chapter
first highlights several classes of synthetic polymers, which are cur-
rently the most widely used for the design of NM-based drug deliv-
ery systems. The remainder of the chapter focuses on some examples
of polymeric NMs and their applications in drug and gene delivery.
Zheng-Rong Lu and Shinji Sakuma (eds.), Nanomaterials in Pharmacology, Methods in Pharmacology and Toxicology,
DOI 10.1007/978-1-4939-3121-7_1, © Springer Science+Business Media New York 2016
1
2 Swapnil S. Desale et al.
2 Synthetic Polymers
Polymers can be classified as homopolymers and copolymers based

on their composition. Homopolymer is defined as the polymer con-
taining a single type of repeating units, while copolymer is com-
posed of two or more different monomers. Both homopolymers
and copolymers have been used extensively for drug delivery appli-
cations. The development of these polymer-based drug delivery sys-
tems relies on novel polymeric architectures and appropriate
synthetic methodologies to tailor their physicochemical properties.
3 Polyesters
Among all degradable polymers, aliphatic polyester-based poly-

meric structures are receiving special attention because of their
compatibility with the natural environment and their ability to
undergo hydrolytic and biological degradation [4]. Among the
wide variety of aliphatic polyesters, poly(D,L-lactide-co-glycolide)
(PLGA), poly(lactic acid) (PLA), poly(caprolactone) (PCL) are
the most commonly used polymers for controlled drug release
applications. There are two methods of the synthesis of aliphatic
polyesters: polycondensation of diols and dicarboxylic acids or
hydroxycarboxylic acids and ring-opening polymerization (ROP)
of cyclic monomers (Scheme 1) [5, 6]. The polycondensation is
hampered by drawbacks such as typically required high tempera-
tures and long reaction times that favor side reactions, necessity of
continuous water removal to achieve high conversions and high
molecular weights. The polymers obtained in this process are char-
acterized by high polydispersity. ROP yields polymer products
with high molecular weight, lower polydispersity and, therefore, is
a preferred route to obtain aliphatic polyesters [7, 8]. Various
organometallic compounds, such as oxides, carboxylates, and
alkoxides are used as effective catalysts for the controlled synthesis
a
O O O O
+ n HO R2 OH C C R2 + 2n H2O
n HO R1 OH R1 O O n
b O O
Sn(Oct)2 O
O O
ROH + n + m Heating
RO
O
O
H
O O 2n 2m
O
O O
DL-lactide glycolide PLGA
Scheme 1 (a) Synthesis of polyesters by polycondensation of dicarboxylic acids and diols; (b) synthesis of
PLGA copolymer by ROP using alcohol as an initiator and stannous octoate as the catalyst
Synthetic Polymer-based Nanomaterials 3
of polyesters using ROP [9]. Alternately, polyesters without toxic

metallic residuals, which is an important requirement for biomedi-
cal and pharmaceutical applications, can be prepared by using
enzyme-catalyzed polymerizations [10]. Unlike chemical catalysts,
enzymes function under mild conditions, enable high enantiose-
lectivity and regioselectivity, and are recyclable. Extensive research
efforts have been expended in the past years to refine the ROP
technique for the synthesis of the polyesters with controlled archi-
tecture and tailor-made properties. To obtain a polymer with a par-
ticular combination of desirable properties, copolymerization
techniques have been extensively used. Controlling the
composition, morphology, glass transition temperature, and degra-
dation rate of the copolymers allows regulation of the drug release
behavior from such matrices. Nanoparticles formulated from bio-
degradable polyesters are of great interest for drug delivery pur-
poses. A wide variety of hydrophilic or hydrophobic drugs and
biological macromolecules can be encapsulated into biodegradable
polyesters-based nanoparticles and delivered to specific organs or
cells [11]. A number of techniques are available for the formula-
tion of polyester-based nanoparticles (or nanocapsules). The choice
of a particular approach mainly depends on the physicochemical
properties of the polymer (i.e., solubility and molecular weight)
and the drug physicochemical properties (i.e., hydrophobicity/
hydrophilicity, sensitivity to the solvent). Currently, the most pop-
ular methods are emulsion/solvent evaporation or diffusion, dou-
ble emulsion, nanoprecipitation, and the salting out procedure.
The emulsion/solvent evaporation method involves the prepara-
tion of an oil-in-water emulsion, where a small quantity of water-
immiscible organic solvent containing polymer and hydrophobic
drug (oil phase) is emulsified in an aqueous phase containing a
stabilizer [12, 13]. The most common stabilizers are hydrophilic
molecules such as polyvinyl alcohol (PVA), polysorbates
(TWEEN®), or sodium cholate. Stable nanoparticles are formed in
the aqueous phase by organic solvent evaporation under increased
temperature or reduced pressure. In the emulsion/diffusion
method, the oil phase containing polymer is dissolved in a partially
water-miscible solvent (e.g., ethyl acetate, propylene carbonate)
[14, 15]. The addition of a certain volume of water to the oil-in-
water emulsion induces a change in the equilibrium of the system
and causes the partially water-miscible solvent to diffuse from the
droplets into the aqueous phase. This reduces the polymer’s solu-
bility and results in particle formation. Another approach is the
double-emulsion, W/O/W, method [16, 17]. The main benefit of
the double-emulsion method is its ability to efficiently encapsulate
hydrophilic drugs and proteins. In this approach, the drug, dis-
solved in water, is added to an organic solvent containing polymer,
forming a water-in-oil emulsion. Then a small quantity of this ini-
tial emulsion is added to a second aqueous phase containing an
emulsifier, such as PVA, to stabilize the particles. Nanoparticles are

then obtained by evaporation of the organic solvent. Typically this
method yields nanoparticles with larger sizes than single emulsion
method with moderate drug loading and encapsulation efficiency.
Nanoprecipitation (or solvent displacement) method utilizes inter-
facial polymer deposition to form nanoparticles [18–20]. In this
simple process, polymer and a drug are dissolved in a water-miscible
solvent and this solution is then added dropwise to an aqueous
solution (non-solvent) with or without stabilizer. Solvent diffusion
results in polymer precipitation on the interface between the
aqueous phase and finely dispersed oil droplets, resulting in the
formation of solid particles. Depending on the solvent choice and
solvent–non-solvent ratio, this method is suitable for encapsulation
of both hydrophilic and hydrophobic drugs as well as protein-
based therapeutics. In general, nanoparticles of smaller sizes but
with lower entrapment efficiencies are obtained through this
method when compared to other methods. Finally, the salting out
method is an oil-in-water emulsion comprised of a primary aque-
ous phase containing stabilizer and a high concentration of salt
(e.g., magnesium chloride hexahydrate) and polymer dissolved in a
water-miscible solvent, such as acetone or tetrahydrofuran [21].
Due to the presence of a high concentration of salt, there is no dif-
fusion of the solvent into the aqueous phase. Fast addition of a
large amount of water to this oil-in-water emulsion reduces the
ionic strength and leads to the migration of the water-miscible
organic solvent into the aqueous phase, inducing formation of
solid particles. In this method, particles must be purified to remove
residual salt and solvent prior to use. A central challenge in the
development of drug-encapsulated polymeric nanoparticles is the
inability to control the mixing processes required for their synthe-
sis, which results in variable nanoparticle physicochemical proper-
ties (size, surface composition, and drug loading). To address this
challenge the Langer group [22] developed a rapid and tunable
mixing procedure utilizing hydrodynamic flow focusing in micro-
channels to control nanoprecipitation and prepare nanoparticles in
a reproducible manner. The microfluidic technique allows tuning
the size of the resulting particles by varying flow rates, polymer
composition, molecular weight or polymer concentration in
organic solution. Remarkably, higher drug encapsulation was also
reported for the polymeric nanoparticles prepared through micro-
fluidics [22]. Recently, DeSimone and colleagues have developed a
unique nanofabrication process called Particle Replication In
Nonwetting Templates (PRINT) [23]. Using soft-lithography
techniques adopted from the semiconductor industry, PRINT
enables the production of monodisperse polymeric nanoparticles
with well-defined control over particle size, shape, composition,
and surface chemistry, and permits the loading of a wide range of
cargoes with high loading efficiency [24, 25].
4 Polyanhydrides
Polyanhydrides, polymers containing hydrolytically labile anhy-

dride linkages in hydrophobic backbone, have been investigated
for more than three decades as important biomaterials used for
short-term release of drugs [26]. Polyanhydrides are characterized
by their fast degradation followed by rapid erosion of material, but
at the same time can be designed to release drugs that last from
days to weeks by suitable choice of monomers. Numerous poly-
mers have been synthesized in this class of material by various
polymerization techniques such as melt condensation, ROP, inter-
facial condensation, dehydrochlorination, and dehydrative cou-
pling agents [27]. The most convenient method of synthesizing
high molecular weight polyanhydride copolymer is by the melt
polycondensation of anhydride prepolymers (Scheme 2) [28, 29].
Solution polymerizations at ambient temperature are typically
utilized to prepare polyanhydrides from heat-sensitive monomers
and generally yield low molecular weight polymers. The degrada-
tion of polyanhydrides is a hydrolytically triggered process and
depends on the uptake of water into the polymer matrix and pH of
the medium. The rate of water uptake is dependent on factors such
as crystallinity, polymer composition, and molecular weight. It was
reported that polyanhydrides derived from monomers containing
aromatic moieties degrade much slower than aliphatic polyanhy-
drides [30]. Thus, the degradation rate can be tuned by control-
ling the composition of the corresponding copolymers. They
degrade in vitro as well as in vivo to the nontoxic consistent dicar-
boxylic acids. Importantly, the materials based on the polyanhy-
drides show no evidence of inflammatory reaction [31].
Polyanhydrides constitute the only class of surface eroding poly-
mers approved for clinical trial use by the Food and Drug
Administration (FDA). One of the commonly used techniques for
the preparation of polyanhydride-based nanoparticles is the solvent
displacement method followed by freeze or spray drying [32–34].
Another method known as an anti-solvent nanoprecipitation tech-
nique utilized by Ulery et al. [35] and others [36–38] allows fab-
rication of the nanoparticles with relatively uniform size and shape.
In biomedical research, polyanhydride-based nanoparticles have
been widely explored as a vaccine adjuvant because of their ability
to induce potent immune response in a pathogen-mimicking man-
ner without side effects [37, 39–42].
O O
O O O O O O O O O O
O Vacuum
HO R OH Reflux O R O Heating O R O n
Scheme 2 Synthesis of polyanhydride prepolymer and polymer from a dicarboxylic acid

5 N-(2-Hydroxypropyl) Methacrylamide (HPMA) Copolymers
Among synthetic polymeric drug carriers, the water-soluble HPMA

copolymers are the most studied for the last 40 years [43]. HPMA
polymer–drug conjugates have been developed as nanomedicines
for delivery of a number of therapeutics, including anticancer and
anti-inflammatory agents [44–46]. HPMA polymers and their drug
conjugates were initially synthesized by conventional free radical
polymerization techniques. Recent advances in living radical polym-
erization methods, including atom transfer radical polymerization
(ATRP) and reversible addition-fragmentation chain transfer
(RAFT), allowed for the controlled synthesis of well-defined HPMA
copolymers with narrow molecular weight distributions (Scheme 3)
[47, 48].
HPMA copolymers have many attributes that make them ide-
ally suited for the development as drug carriers. These polymers
are biocompatible, non-immunogenic and can be tailored to the
characteristics of the specific target. The molecular weight of
HPMA copolymers can be adjusted to alter biodistribution, tissue
localization and elimination from the body. The proper selection
of the spacer between the drug and HPMA carrier (e.g., oligopep-
tide sequence, hydrazone bond, cis-aconityl spacer) allowed for
controlled drug release within the tissue [49–52]. The HPMA
copolymer conjugates containing doxorubicin were the first syn-
thetic polymer-based therapeutics to enter clinical trials. Since
then, numerous conjugates have been synthesized to contain drug
or drug combinations, proteins and peptides, as well as targeting
moieties and/or imaging probes. In addition, HPMA polymers
were used for the modification of proteins, surface modification of
biomaterials, masking and retargeting of therapeutic viruses and as
macromolecular platforms for contrast agents.
O
CH2 C n
O O N Br
O O
HN HN
CuCl, bpy, 50 oC
80:20 IPA/H2O
OH OH
b
O S
HO CH2 Cn S
O
CTP, V501 O
HN CN
Acetic Buffer, pH 5.2,70 oC HN
OH
OH
Scheme 3 Synthesis of HPMA polymer by (a) ATRP and (b) RAFT polymerization methods
6 Polyethylenimine (PEI)
PEIs are synthetic cationic polymers that have been widely employed
as the most prominent polynucleotide delivery systems [53].
Depending on the linkage of the repeating ethylenimine units, PEI
possesses either branched or linear topology (Scheme 4). Branched
PEI is synthesized by polymerization of aziridine either in aqueous
or alcoholic solutions [54–56], where the reaction is controlled by
adjusting the temperature and initiator concentration, or in a rather
vigorous bulk polymerization of anhydrous aziridine at a lower tem-
perature [57]. Linear PEI has been synthesized via cationic ROP of
either N-(2-tetrahydropyranyl)azidirine [58] or unsubstituted and
2-substituted 2-oxazolines followed by acid or base-catalyzed hydro-
lysis of the corresponding N-substituted polymer [59, 60].
The efficiency of PEI as transfection agent as well as its cyto-
toxicity is closely linked to the polymer characteristics such as
molecular weight, the degree of branching, charge density and
buffering capacity. Generally, the low molecular weight linear or
branched PEIs have low cytotoxicity but display poor transfection
efficiency. In order to solve the efficiency versus toxicity problems,
cross-linked PEIs were synthesized to include biodegradable cross-
links that facilitate an increase in molecular weight but then follow-
ing cross-link degradation, allowing the release of lower molecular
weight components to reduce cytotoxicity [61]. Alternatively,
star-like PEI derivatives with high charge density have been
designed; these polymers utilize low molecular weight PEIs that
are conjugated to a central multivalent polymer core [62–64].
7 Amino Acid-based Polymers
Polymers based on natural L-amino acids are an attractive class of

materials given their biocompatibility, controlled biodegradability,
and metabolizable degradation products. Incorporation of amino
a
H2N NH
N NH2
H
N
N N
H2N N N
H H n
b
N MeOTs N Hydrolysis
n N
O n
O H
Scheme 4 Synthesis of (a) branched PEI by acid catalyzed polymerization of

aziridine and (b) linear PEI by ROP of 2-ethyl-2-oxazoline
H2N CO2H O O O O
Triphosgene R'-NH2
CH R' NH C CH NH n
HN
R R R
Scheme 5 Synthesis of polypeptides via α-amino acid N-carboxyanhydride ROP
acids as a building block into synthetic polymers not only allows

for adjusting hydrophilic/hydrophobic properties of the resulting
polymers and tune their degradability but also imparts chemical
functionalities to facilitate further modification with bioactive mol-
ecules (e.g., drugs, imaging probes, or targeting ligands). The
most common and efficient method to produce polypeptides of
sufficient molecular weight is ROP of N-carboxyanhydrides
(NCAs) [65]. NCAs are easily synthesized through a reaction
between amino acids and phosgene or a phosgene derivative (e.g.,
triphosgene), and the polymerization is commonly initiated using
amino-functional molecules (Scheme 5).
In recent years, the advances in NCA polymerizations, either
using metal initiators or improved conventional initiators, allowed
for the synthesis of broad range of block copolymers and side-chain
functionalized polypeptides with controlled characteristics (molec-
ular weight, sequence, composition, and molecular weight distri-
bution) [66]. In addition, the diversity of synthetic polymer
chemistries and “click” reactions offer the ability to covalently link
a variety of different polymers together and prepare hybrid materi-
als with functional macromolecular architectures and tunable phys-
icochemical properties to meet various requirements of biomedical
applications.
8 Dendrimers
Dendrimers are a unique class of polymeric materials most fre-

quently synthesized using divergent or convergent strategies by a
series of controlled polymerization reactions [67]. Divergent syn-
thesis grows outwards from a multifunctional core molecule and
comprises of two steps: first is the activation of functional surface
groups, and second is the addition of branching monomer units.
The process is repeated for several generations and a dendrimer is
built layer after layer. While this method is successful for the pro-
duction of relatively large quantities of dendrimers, problems
occur from side reactions and incomplete reactions of the end
groups that lead to structural defects. Convergent synthesis, on
the other hand, starts at the surface and proceeds inwards before
the attachment of the synthesized dendrons to the core [68]. In
the convergent growth, a small number of reactive sites are func-
tionalized in each step resulting in less number of side reactions
and more precise control over molecular weight of the dendrimer.
However, convergent synthesis strategy is generally limited to the

construction of lower-generation dendrimers due to steric difficul-
ties upon attachment of the dendrons to the core molecule. In
contrast to other synthetic polymers, dendrimers are nearly mono-
disperse in molecular weight and size. They are highly branched
macromolecules of nanoscale molecular size with multiple surface
group functionalities and practically perfect spherical topology in
case of higher generations. Functionalization of their terminal
groups provides an exceptional opportunity for the immobilization
of multiple bioactive molecules and solubilizing groups in a spe-
cific and controllable manner. Alternatively, the numerous internal
cavities in the dendrimer cores can be loaded with various drugs via
hydrophobic interaction, hydrogen bonds or chemical conjuga-
tion. Surface modification of the dendrimer by a modification with
polyethylene glycol (PEG), acetylation or esterification is often
used to improve the drug loading capacity of the resulting den-
drimers. It also renders them more biocompatible, less immuno-
genic, and less toxic, especially those decorated by free amino
functionalities [69–71]. Because of these characteristics, den-
drimers have been widely studied as nanoscale containers for deliv-
ery of therapeutic payloads. The flexibility to tailor both the core
and surface of these systems allows optimizing the properties of
drug carriers for the specific applications. Dendrimers of various
structure, amphiphilicity, and architecture were explored as carriers
for anticancer, antimalarial, antiviral, antitubercular, antimicrobial,
and antihypertensive drugs [72]. Their application as scaffolds of
prodrugs is particularly interesting [73–75]. Furthermore, several
groups addressed the strategies for the synthesis of the degradable
dendrimers that can achieve high accumulation and retention in
diseased tissues, but allow rapid and safe elimination of nontoxic
dendrimer fragments [76]. Biodegradable dendrimers are com-
monly prepared by inclusion of ester groups in the polymer back-
bone, which will be chemically hydrolyzed and/or enzymatically
cleaved by esterases in physiological solutions [77]. For example,
Frechet and colleagues reported efficient synthesis of robust and
biodegradable PEGylated dendrimer based on a polyester–polyam-
ide hybrid core. The architecture has been designed to avoid
destructive side reactions during the synthesis while maintaining
the dendrimer’s degradability [78]. Polycationic dendrimers can
be complexed with nucleic acids and used for gene therapy.
Applications of dendrimers as protein mimics [79], biomimetic
regeneration of hydroxyapatite [80], and mimicking in angiogenesis
[81] has also been reported. Furthermore, dendrimers can act as
“nano-drugs” themselves and their therapeutic potential has been
explored against various diseases [82]. As an example, dendrimer-
based nanomedicine mixed in carbomer gel (VivaGel®) is being
developed as a vaginal microbicide gel to prevent the transmission
of genital herpes and human immunodeficiency virus [83].
The active ingredient of this gel is a dendrimer comprising a divalent

benzhydrylamine core and four generations of lysine branches
capped with sulfonated naphthyl groups that impart hydrophobicity,
and a high anionic charge to the dendrimer surface. Initial human
trials have shown VivaGel to be safe and well-tolerated, and Phase II
clinical studies for its efficacy are ongoing. Despite the promise of
dendrimers-based drug delivery systems, their translation into actual
therapies is challenging due to their lengthy synthesis and the need
to develop nontoxic and biocompatible dendrimers.
9 Polymer Therapeutics
The term “Polymer Therapeutics” was coined by Prof. Ruth Duncan

to define a family of new chemical entities that comprises a variety of
complex macromolecular systems containing a water-soluble poly-
meric carrier covalently bound to the bioactive molecule(s). These
polymeric drugs include polymer–drug and polymer–protein conju-
gates, polymeric micelles where drug is covalently bound to the
polymer, and polyplexes (containing covalent linkers) developed as
nonviral vectors for the delivery of nucleic acids [84]. Polymer is an
integral and functional part of such multifunctional systems for
improved drug, protein and gene delivery [30, 85, 86]. The linkers
are typically sensitive to the conditions that are unique for the tar-
geted site (e.g., an acidic environment, presence of specific enzyme),
which increases the specificity of drug delivery and release. In addi-
tion, a targeting moiety may also be introduced into the conjugate
to increase its therapeutic index. PEGylation has become a well-
established technology for the use of proteins as drugs. When
attached to a protein, peptide and more recently to an aptamers,
typically via conjugation of a monomethoxylated PEG segment
bearing a reactive moiety at one of the polymer termini, PEG imparts
prolonged blood residency and diminished immunogenicity of the
bioconjugate. The most studied polymer–drug conjugates are based
on HPMA copolymer and PEG backbones and, initially, their design
was focused on cancer treatments and incorporated common che-
motherapeutic agents (e.g., doxorubicin, taxanes, camptothecin, or
platinates) [87]. Over the years, numerous conjugates have been
synthesized which contain drugs that act on the emerging targets for
cancer therapy such as angiogenesis, apoptotic pathways, kinases and
others. As an example, HPMA–fumagillol, the first antiangiogenic
conjugate, proved to be effective at inhibiting tumor growth and
exhibited a significantly better toxicity as compared to free drug
[88]. It was demonstrated that HPMA copolymer–wortmannin
conjugate retained the ability to inhibit type I PI3-kinase activity
[89], and HPMA–geldanamycin conjugate inhibited the capacity of
heat shock proteins such as HSP-90 to form complexes with client
oncoproteins [90, 91]. Therapies focusing on the activation of apop-
totic pathways are also promising anticancer strategies [92]. The

PEGylation of curcumin, a Jab1 inhibitor, and the conjugation of
Bcl2-inhibitor HA14 to HPMA, are two examples of this proapop-
totic approach [93, 94]. In addition, polymer–drug conjugates were
actively explored for the treatment of other diseases including infec-
tions [95], inflammation [96], rheumatoid arthritis [97] and diabe-
tes [98]. Several preclinical studies have already illustrated the
potential of conjugates in regenerative medicine, for example, for
wound healing [99], ischemia [100], or osteoporosis [101]. The
new concepts such as delivering drug combinations via one polymer
carrier [102], exploring new polymer architectures (branched,
grafted, and star polymers and dendrimers) or use of coiled-coil pep-
tides motifs as linkers [103] are the recent developments in the field
of polymer therapeutics. To address the concerns regarding the pos-
sible accumulation of the nondegradable polymers in the body, an
increasing number of biodegradable polymers such as poly(glutamic
acid) (PGA) [104], polyacetal Fleximer [105], poly(malic acid)
[106], dextrin [107] have been investigated as platforms for the
design of new polymer therapeutics. Translational research in poly-
mer therapeutics has yielded ten marketed PEG-protein/aptamer
conjugates [105, 108]. In the case of polymer–drug conjugates
progression to regulatory approval has been slower. The closest to
market is Opaxio™ (PGA-paclitaxel conjugate, also known as
Xyotax or CT-2103) developed by Cell Therapeutics Inc. [http://
www.celltherapeutics.com/opaxio], which is in advanced Phase III
clinical trials. Opaxio™ sister conjugate CT-2106, PGA-
camptothecin conjugate, is also in Phase II clinical trial. Promising
results are emerging from a number of ongoing clinical studies
involving anticancer conjugates such as ProLindac™, an HPMA
copolymer DACH-platinate from Access Pharmaceuticals that has
successfully completed a European Phase II clinical trial in patients
with ovarian cancer [109]. PEG-irinotecan conjugate (NKTR-
102) is undergoing Phase III evaluation in patients with metastatic
breast cancer and is also being studied in Phase II clinical trials in
ovarian and colorectal cancer [http://Nektar.com]. Mersana is
commercializing XMT1001 (Fleximer®-camptothecin conjugate)
as its lead candidate but has also a potent antiangiogenic conjugate
XMT1107 (Fleximer®-fumagillin) in Phase I studies. Overall, the
design and clinical development of new polymer therapeutics hold
a significant potential of this group of NMs for targeting a wide
range of the diseases.
10 Polymeric Micelles
Amphiphilic block or graft copolymers comprised of two or more

chains with different hydrophobicity have been used extensively
in pharmaceutical applications ranging from sustained-release
technologies to gene delivery. These copolymers are known to

spontaneously self-assemble in an aqueous solution into nano-
scopic polymeric micelles (10–100 nm) having fairly narrow size
distribution. The nature of the self-assembly process allows for sig-
nificant versatility in the chemical composition of the polymeric
micelles and thus permits fine tuning of the material properties,
morphology and sizes. These micelles have unique core–shell
architectures with hydrophobic polymer chains segregating into a
micelle core surrounded by a shell of hydrophilic chains.
Hydrophobic drugs can be entrapped into the micelle core non-
specifically through hydrophobic interactions or specifically by
chemical conjugation to the core-forming block of the copolymer
via a carefully designed pH- or enzyme-sensitive linker that can be
cleaved to release a drug in its active form. A variety of drugs with
diverse physicochemical properties can be incorporated into the
core by engineering the structure of the core-forming segment of
the copolymer to attain sufficiently strong interaction with drug
molecules. These polymeric micelle systems can also be used for
co-delivery of two or more drugs with similar or different proper-
ties for combination therapy, or to combine multiple modalities
within a single carrier [110, 111]. Hydrophilic shell serves as a
stabilizing interface between the hydrophobic core and external
milieu and most commonly consists of PEG chains with a molecu-
lar weight ranging from 2 to 15 kDa. In addition, shell can inhibit
protein binding and opsonization during systemic administration,
which allows them to remain in the circulation longer by evading
the mononuclear phagocytic system. Also, modification of the shell
with various ligands using different surface chemistries enables the
micelle to be targeted to a specific site. A much wider range of
hydrophobic blocks have been explored as drug loading cores.
Examples include polyesters, polyanhydrides, poly(L-amino acids),
poly(methyl methacrylate), phospholipids/long chain fatty acids,
polypropylene oxide (in Pluronics/poloxamers). The choice of
hydrophobic block is largely dictated by drug compatibility with
the hydrophobic core (when drug is physically loaded) and the
stability of the micelle. Micelles must be stable enough to retain
drug cargo upon administration and remain intact long enough to
accumulate in sufficient concentrations at the target site. The ther-
modynamic tendency for micelles to dissociate is primarily con-
trolled by the length of the hydrophobic block while the kinetic
(rate of dissociation) stability depends on many factors, including
the size of a hydrophobic block, the mass ratio of hydrophilic to
hydrophobic blocks, and physical state of the micelle core [112].
The incorporation of hydrophobic drugs may also further enhance
micelle stability. Among the different strategies to enhance the
kinetic stability of polymeric micelles, core- or shell-cross-linking
have been shown to limit the premature disassembly and slow
down the release of the encapsulated drug [113]. The resulting
cross-linked micelles are, in essence, nanoscale single molecules

that are stable upon dilution and can withstand environmental
challenges and shear forces without structural deterioration. For
example, Iijima et al. [114] have shown that core cross-linked
micelles of PEG-b-poly(D,L-lactide) possess high stability against
dilution, temperature change, and even dissolution of surfactants.
Wooley and coworkers [115, 116] cross-linked the micellar corona
and obtained the so-called shell-cross-linked knedel-like micelles—
robust nanostructures with a permeable cross-linked shell.
However, the reversible stabilization of the micellar structure will
be more desirable to achieve efficient intracellular drug release and
circumvent micelle accumulation in the body. To this end, the use
of degradable polymer components or the introduction of revers-
ible cross-links allowed development in situ degradable micelles
[117–119]. High loading capacity and controlled drug release
profile are key features for the potential drug delivery system. The
loading capacity and loading efficiency of the polymeric micelles is
influenced by several factors, including both structure of core-
forming block and a drug, molecular characteristics of the copoly-
mer, such as composition, molecular weight, and the solution
temperature. The maximum loading level is largely influenced by
the interaction between the drug and core-forming block, and
stronger interactions enable saturation to be reached at a lower
polymer concentration. The drug loading can also be improved by
enhancing the local environment of the micelle core through the
means of conjugation of small amount of drug [120] or conjuga-
tion of side chains with similar structure to the drug [121]. In
addition, the location of the incorporated molecules within poly-
meric micelles (micelle core or the core–shell interface) determines
the extent of solubilization as well as the rate of drug release [122,
123]. In general, for drugs physically incorporated in polymeric
micelles, release is controlled by the rate of diffusion of the drug
from the micellar core, stability of the micelles, and the rate of
biodegradation of the copolymer. If the micelle is stable and the
rate of polymer biodegradation is slow, the diffusion rate of the
drug will be mainly determined by the compatibility between the
drug and core-forming block of copolymer, amount of drug
loaded, the molecular volume of drug, length of the core forming
block, and physical state of the core. Moreover, external conditions
such as change in pH, temperature or application of ultrasound
[124] can also trigger drug release from polymeric micelles.
Another important but less investigated factor that can affect dif-
ferent characteristics of polymeric micelles is the morphology and
dimensions of micellar aggregates. Indeed, filamentous polymeric
micelles (“filomicelles,” also referred to as “worm micelles”) with
single dimensions as long as 18 μm (the diameter is ~57 nm) syn-
thesized from amphiphilic PEG-b-PCL copolymer were reported
to solubilize twice as much paclitaxel as spherical micelles [125].
Recently, Wooley’s group [126] demonstrated that shell-cross-

linked, rod-shaped micelles prepared from pH-sensitive poly(acrylic
acid)-b-poly(p-hydroxystyrene) block copolymer exhibited a
higher doxorubicin-loading capacity and rate of release compared
to their spherical counterparts derived from the same copolymer
precursor. Importantly, it was also demonstrated that rational
design of polymeric micelles and other NMs of a given geometry
(size and shape) offers an unprecedented control of their longevity
in circulation and targeting to selective cellular and subcellular
locations [127–129]. Further understanding of structure–activity
relationships of such complex multicomponent nanomedicines is
essential to determine the criteria for the successful development of
polymeric micelle therapeutics. Currently several micelle formula-
tions based on amphiphilic block copolymers are in clinical trials
for treating a variety of cancers [130–133]. In addition, the first
targeted micellar formulation (BIND-014) has recently reached
clinical development [134].
The field of polymeric micelles was significantly advanced by
employing charge-driven self-assembly of block copolymers con-
taining water-soluble ionic and nonionic block (double hydrophilic
block copolymers or block ionomers). The micellization of these
copolymers can be induced by adding oppositely charged molecules
such as synthetic [135, 136] or natural (DNA, proteins) [137–139]
polyelectrolytes, surfactants/lipids [140, 141], or metal ions [142,
143]. These molecules form electrostatic complexes with the
charged blocks of block ionomers, and prompt spontaneous segre-
gation of the resulting complexes into micelle-like structures with
electrostatically neutralized polyion cores and hydrophilic polymer
shells. Ionic block lengths, charge density, and ionic strength of a
solution affect the formation of stable block ionomer complexes
and, therefore, control the amount of the drug that can be incorpo-
rated within the micelles [139, 144]. As an example, the metal-
complex formation of ionic block copolymer, PEG-PGA, was
explored to prepare polymeric micelles incorporating anticancer
drug cisplatin. In preclinical studies, they exhibited remarkably pro-
longed blood circulation and effective accumulation in solid tumors
[145]. This formulation is currently being evaluated in Phase III
clinical trial as a treatment for pancreatic cancer under the name
NC-6004 (Nanoplatin; NanoCarrier Co., Ltd.; Japan) [146].
Since being proposed independently by Kabanov and Kataoka
[147, 148] in 1995, this approach has been widely used for devel-
oping nonviral gene delivery systems using cationic block or graft
copolymers. In this case, the neutralization of positive charges on
the polycation block by negatively charged DNA or siRNA leads to
the formation of polyion micelles. Advanced and tunable charac-
teristics of the cationic copolymers such as chemical structure and
length of the segments, rigidity, hydrophilicity, charge density, bio-
degradability allow to modulate gene-delivery properties such as
DNA binding, colloidal stability of the complexes, toxicity, endo-

somal escape, vector unpacking, and transfection efficiency [149–
151]. Similar to nucleic acid, charged proteins and peptides can be
entrapped into a polyion micelle core [137, 152–154]. Recently,
this strategy was successfully used for the delivery of antioxidant
enzymes to the central nervous system [155–157]. There has also
been a focus on the development of micellar carriers that are able
to deliver both a therapeutic drug and a nucleic acid [158]. As an
example, Wang and coworkers reported micelles composed of bio-
degradable PEG-poly(ε-caprolactone)-b-poly(2-aminoethylethylene
phosphate) triblock copolymers, PEG-PCL-PPEEA, with the capac-
ity to encapsulate hydrophobic paclitaxel into PCL core and com-
plex siRNA against polo-like kinase 1 to the cationic PPEEA block.
These micelles simultaneously delivered two payloads into the same
tumor cells both in vitro and in vivo, and inhibited tumor growth in
a synergistic manner following systemic administration [159].
11 Polymersomes
Polymersomes (polymeric vesicles) is another class of supramolecu-

lar assemblies formed by amphiphilic block copolymers in diluted
aqueous solutions. Typically the formation of vesicular structures is
favored for the copolymers with relatively low weight fraction of
hydrophilic block (~20–40 %) [160]. Polymersome sizes vary from
50 nm to 10 μm depending on the chemical composition and the
length of polymer blocks, the preparation method, as well as reac-
tion conditions [161]. The copolymers of various architectures
(diblock, triblock, graft, and dendritic) have been utilized as build-
ing blocks for design and preparation of polymersomes [162–165].
Nonbiodegradable poly(ethyl ethylene), poly(butadiene),
poly(dimethylsiloxane), poly(propylene oxide), polystyrene as well
as biodegradable PLA, PCL, and poly(trimethylene carbonate)
have been used as a hydrophobic part of the block copolymers
[166–171]. PEG, PGA and poly(acrylic acid) have been frequently
selected as water-soluble blocks. More recently, so-called PICsomes
(polyion complex vesicles) have been developed by electrostatic
self-assembly of oppositely charged block- and homoionomers
[172]. The key distinction between polymersomes and spherical
micelles is that the former have an interior aqueous cavity sur-
rounded by a wall that consists of entangled chains [173]. Due to
the higher molecular weight of the polymers, polymersome mem-
branes are generally thicker (8–22 nm), stronger, and hence,
intrinsically more stable and less permeable than conventional lipo-
somes. The thickness of the membrane is determined by the length
of the hydrophobic block and can be tuned through fine control of
the polymer chemical composition [167, 174–176]. The enhanced
structural integrity and much denser hydrophilic polymer brush on
the surface of the polymersomes lead to their more persistent cir-

culation in the bloodstream [177]. Polymersomes are able to
encapsulate hydrophilic, hydrophobic and amphiphilic molecules
like any other vesicular structure, but their membrane tunability
and superior stability are unique and undoubtedly beneficial for
potential applications in drug delivery as well as medical diagnos-
tics. Examples of drug-loaded polymersomes are increasingly broad
and now include anticancer drugs, oligonucleotides, therapeutic
proteins, diagnostic probes, or their combinations [178–182]. In
addition, targetability of the polymersomes with various ligands
attached to the surface has been demonstrated [183–187]. Recently,
modulation of the membrane stability or permeability in response
to specific stimulus has received a lot of attention as a strategy for
controlled drug release from polymersomes. Numerous stimuli
(e.g., pH, redox potential, temperature, magnetic field, light, and
ultrasound) have been exploited in the design of stimuli-responsive
polymersomes [188]. While these systems are still at the level of
research and development, their structural versatility and improved
properties in terms of stability and multifunctionality make them
excellent candidates for potential biomedical applications.
12 Polymeric Nanogels
The term “nanogels” usually defines hydrogel particles of nanoscale

size formed by physically or chemically cross-linked polymer net-
works [85]. Polymeric nanogels can be prepared by physical self-
assembly of interactive polymers [189] or by cross-linking reaction
of preformed polymers [190]. Nanoemulsion or microemulsion
polymerization methods are often used to obtain nanogels with
well-controlled sizes [191–193]. Another attractive set of synthetic
techniques for preparation of nanogel particles is based on a
template-assisted nanofabrication and exploit the internal water
phase of liposomes [194], cross-linking of polymeric micelles [195,
196] or lithographic PRINT process [24]. Various chemical cross-
linking reactions have now been developed, including photocross-
linking, carbodiimide-mediated amide bond cross-linking,
quaternization of amino groups, and “click” chemistry [143, 197–
199]. Labile bonds are frequently introduced into nanogels during
their synthesis to make them degradable and facilitate drug release.
Dispersed in the water, the nanogels are highly swollen and can
incorporate 30 % wt. and more of biological molecules and drugs
through electrostatic, van der Waals and/or hydrophobic interac-
tions or covalent bonding with the nanogel chains. These loading
capacities are unusually high and exceed those of liposomes and
polymeric micelles [85, 200]. As a result of drug loading, the
nanogels collapse forming stable nanoparticles, in which biological
agent becomes entrapped. Introducing dispersing hydrophilic
polymers (e.g., PEG) in a nanogel structure can prevent their

aggregation. During the collapse of the drug-nanogel complex
hydrophilic polymer chains become exposed at the surface and
form a protective layer around the nanogel. The control and versa-
tility of polymer chemistry allows designing a broad range of drug
formulations and inclusion of multiple therapeutic cargos within
the same nanogel carrier [85, 196, 201]. Stimuli-responsive drug
release via temperature or pH-induced volume collapse can also be
very attractive for drug delivery applications. The functionalization
of the nanogel surface can further facilitate their selective accumu-
lation in the target tissue or cells [202–204]. Development of
nanogels that can carry, protect, target and release therapeutic
agents in spatially and temporally controlled manner is actively
ongoing and their rational design can provide a platform for mul-
tiple applications.
Over the last decade, the field of polymer-based biomaterials
for delivery of low molecular drugs, proteins and nucleic acids has
seen exponential growth. Only selected examples were reviewed
here due to the large number of contributions on this topic. Indeed,
the recent advances in polymer chemistry have allowed the develop-
ment of a diverse range of NMs of various sizes, shapes, surface
chemistries, and targeting properties. Polymer composition also
plays an essential role in function and application of such macromo-
lecular carriers. There is growing evidence that some synthetic poly-
mers can display biological response-modifying activity and can
influence the molecular mechanism of action of a drug. Several of
the polymer-based nanocarriers are already in clinical use and
numerous of the others are undergoing various stages of preclinical
and clinical evaluation. Although considerable progress has been
made, further synthetic improvements are needed to design safe,
more “intelligent” and efficient drug delivery platforms.
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Synthetic Polymer-based Nanomaterials

Chapter · November 2015

Swapnil Desale Jinjin Zhang

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Synthetic Polymer-based Nanomaterials

Key words Nanomedicines, Polymers, Polymerization, Nanoparticles, Drug delivery

Nanomedicine is a rapidly developing area of biomedical research

Polymers can be classified as homopolymers and copolymers based

Among all degradable polymers, aliphatic polyester-based poly-

of polyesters using ROP [9]. Alternately, polyesters without toxic

emulsifier, such as PVA, to stabilize the particles. Nanoparticles are

Polyanhydrides, polymers containing hydrolytically labile anhy-

Scheme 2 Synthesis of polyanhydride prepolymer and polymer from a dicarboxylic acid

5 N-(2-Hydroxypropyl) Methacrylamide (HPMA) Copolymers

Among synthetic polymeric drug carriers, the water-soluble HPMA

7 Amino Acid-based Polymers

Polymers based on natural L-amino acids are an attractive class of

Scheme 4 Synthesis of (a) branched PEI by acid catalyzed polymerization of

Scheme 5 Synthesis of polypeptides via α-amino acid N-carboxyanhydride ROP

acids as a building block into synthetic polymers not only allows

Dendrimers are a unique class of polymeric materials most fre-

However, convergent synthesis strategy is generally limited to the

The active ingredient of this gel is a dendrimer comprising a divalent

The term “Polymer Therapeutics” was coined by Prof. Ruth Duncan

totic pathways are also promising anticancer strategies [92]. The

Amphiphilic block or graft copolymers comprised of two or more

technologies to gene delivery. These copolymers are known to

cross-linked micelles are, in essence, nanoscale single molecules

Recently, Wooley’s group [126] demonstrated that shell-cross-

DNA binding, colloidal stability of the complexes, toxicity, endo-

Polymersomes (polymeric vesicles) is another class of supramolecu-

the surface of the polymersomes lead to their more persistent cir-

The term “nanogels” usually defines hydrogel particles of nanoscale

polymers (e.g., PEG) in a nanogel structure can prevent their

1. Brigger I, Dubernet C, Couvreur P (2002) 6. Labet M, Thielemans W (2009) Synthesis of

condensation polymerizations. Trends platform for controlled synthesis of polymeric

branched polyethylenimine: effect of molecu- 69. Jevprasesphant R, Penny J, Jalal R, Attwood

DL et al (2006) Polycefin, a new prototype of delivery of chemotherapeutic agents.

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