Yang 2017

REVIEW
Star Polymers www.mrc-journal.de
Nano-Star-Shaped Polymers for Drug Delivery Applications

Da-Peng Yang, Ma Nwe Nwe Linn Oo, Gulam Roshan Deen, Zibiao Li,* and Xian Jun Loh*
heterogeneous star-shaped polymers.

With the advancement of polymer engineering, complex star-shaped polymer Research interest in star-shaped and other
architectures can be synthesized with ease, bringing about a host of unique forms of polymers has been bolstered by
properties and applications. The polymer arms can be functionalized with dif- the fact that they are able to self-assemble
into supramolecular structures with addi-
ferent chemical groups to fine-tune the response behavior or be endowed with tional properties that can be designed
targeting ligands or stimuli responsive moieties to control its physicochemical using their functionalizable arms.[5,6]
behavior and self-organization in solution. Rheological properties of these These unique properties unattainable by
solutions can be modulated, which also facilitates the control of the diffusion their linear counterparts has found many
of the drug from these star-based nanocarriers. However, these star-shaped applications in fields from materials sci-
ence to medicine and pharmaceutics[7]
polymers designed for drug delivery are still in a very early stage of develop-
With the unique supramolecular archi-
ment. Due to the sheer diversity of macromolecules that can take on the star tectures, they possess a combination of
architectures and the various combinations of functional groups that can be many preferential properties in the same
cross-linked together, there remain many structure–property relationships system, granting the potential to be used
which have yet to be fully established. This review aims to provide an intro- for diverse requirements with a single
ductory perspective on the basic synthetic methods of star-shaped polymers, application.[8,9] The linear branching
chains in star-shaped polymers, for
the properties which can be controlled by the unique architecture, and also example, can be chemically modulated
recent advances in drug delivery applications related to these star candidates. to fabricate stimuli-responsive materials.
Stimuli-responsive moieties that are
capable of automatically undergoing con-
1. Introduction formational or chemical changes upon receiving signals from
the external environment[10,11] are ideal for applications such
Star-shaped polymers are a class of branched macromole- as drug delivery where temporal and spatial release of thera-
cules with more than three linear arms radiating from a cen- peutics are crucial.[12–17] Some typical signals include changes
tral core.[1–4] When the arms are equivalent in both structure in temperature, irradiation with light, application of mechan-
and chain length, they are considered to be homogeneous ical force, exposure to alternating electric or magnetic fields,
star-shaped polymers. Otherwise, they are considered to be and changes in chemical composition or pH of the external
environment.[18,19] In a parallel manner, recent advances in
biomedicine have led to an increased interest toward con-
Prof. D.-P. Yang
College of Chemical Engineering & Materials Science trolled drug release which can be achieved with these star-
Quanzhou Normal University shaped polymer systems.[20,21] Conventional methods of drug
Quanzhou 362000, China administration are nonspecific and they usually involve peri-
M. N. N. L. Oo odic application to the patients, raising the concentration of
School of Chemical and Biomedical Engineering drug levels throughout the entire biological system. This is
Nanyang Technological University not ideal as it leads to a transient fluctuation of drug levels
62 Nanyang Drive Singapore, Singapore 637459, Singapore
within the body. Controlled release of drugs, on the other
Prof. G. R. Deen
Soft Materials Laboratory hand, allows active drugs or chemicals to be released at
Natural Sciences and Science Education specific rate and targeted site so as to achieve the intended
National Institute of Education effect of the drugs.[15,16,22–27] This allows for the conveni-
Nanyang Technological University ence of fewer drug administrations, and reduced likelihood
Singapore 637459, Singapore
of side effects as the dose does not exceed toxic levels. Star-
Dr. Z. Li, Prof. X. J. Loh
Institute of Materials Research and Engineering (IMRE)
shaped polymers, with their functionalizable branch arms
A*STAR, 2 Fusionopolis Way, Innovis, #08-03 can be chemically modified to control the biodegradation
Singapore 138634, Singapore rates inside the body, incorporated stimuli-responsive moie-
E-mail: lizb@imre.a-star.edu.sg; lohxj@imre.a-star.edu.sg ties to allow spatial and temporal control for drug delivery,
Prof. X. J. Loh or synthesized with specific biomarkers to target the delivery
Department of Materials Science and Engineering of these star-shaped drug delivery polymers to the desired
National University of Singapore
9 Engineering Drive 1, Singapore 117576, Singapore physiological environments such as cancer cells.[28,29] It is
especially useful in delivering hydrophobic drugs in aqueous
DOI: 10.1002/marc.201700410 environments.[30]
Macromol. Rapid Commun. 2017, 1700410 1700410 (1 of 25) © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.advancedsciencenews.com www.mrc-journal.de
Polymer, in general, has been one of the go-to classes of

materials to be used as controlled drug delivery vehicles due to Zibiao Li obtained his Ph.D.
its myriad of properties including biocompatibility, the ability in 2014 from the National
to functionalize, and ease of synthesis.[31–35] With newer poly University of Singapore.
merization techniques developed over the years, we now Currently, he is working
have improved control over the structures of synthesized as a research scientist at
macromolecules, especially those of the star-shaped polymers, the Institute of Materials
which has allowed us to functionalize and recombine various Research and Engineering,
arm architectures to suit various needs.[36,37] Star polymers have A*STAR, Singapore. His
garnered immense interest for researchers who are looking research interests are focused
for more compact and complex architectures with well-defined on biodegradable and func-
properties. Star-shaped polymers with more arms meant that tional polymeric material
they can carry more drug molecules than their linear counter- design, structural property
parts and also be functionalized with targeted molecules for investigations, and their hybrid fabrications for biomedical
more targeted delivery.[38,39] Compact structure also meant that and consumer care applications.
they are not easily removed from blood owing to their smaller
hydrodynamic volumes and radii of gyration, strengthening
Xian Jun Loh is a polymer
their bioavailability.[40] For such a complex system with abun-
chemist working in the
dant desirable properties, much more need to be understood
interdisciplinary field of
on the current synthesis, properties, and applications to bring
biomaterials. He is the
the utilization of these star-shaped polymer architectures to
Programme Manager of the
the next level.[41] Hence, this review places a focus on the most
Consumer Care Programme
recent advances in the synthesis and functionalization of star-
at the Institute of Materials
shaped polymers for various drug delivery applications, and
Research and Engineering
provides a contemporary perspective on the innovation in this
(IMRE). His main research
area that can expedite the development of star-shaped polymers
interests are the design of
for therapeutic purposes.
supramolecular hydrogels for
biomedical and personal care
applications.
2. Star Architectures
Delving deeper into the study of star-shaped polymers, we
note that instead of the simple definition of homogeneous and in terms of which of the polymeric blocks are directly attached
heterogeneous star-shaped polymers, there are many more to the star-shaped polymer’s core.
complex architectures (Figure 1). This necessitates the need
for a more diverse series of classification systems to catego-
rize these star-shaped polymers to comprehensively embrace 3. Synthesis of Star-Shaped Polymers
the unique features that they possess. The section below sum-
marizes some common categories that can be used to describe The three usual synthetic routes for star-shaped polymers are:
them in more detail according to their monomer composition, the “arm-first”, “core-first”, and the grafting-onto approaches, as
sequence distribution of arms, and chemical or molecular presented in Figure 2.[45–47]
nature of core. However, it has to be noted that these categori-
zation criteria are not exclusive to each other.
With reference to Figure 1A, the arms of the star polymers 3.1. “Arm-First” Method
with diblock or triblock copolymers are called star-block copoly-
mers,[2,3,42–44] where the properties of both block copolymers The “arm-first” method is also known as the “arm-in” or con-
and star-shaped polymers are amalgamated. In functionalized vergent approach. This method forms the stars by cross-linking
star-shaped polymers or functionalized stars as in Figure 1D, linear arm precursors to first form macromolecular chains,
functional groups may be present on the arms, or at the ends which are then linked to the core via covalent, supramolecular,
of each of the arms. In the former, they are known as in-chain and coordination bond linking agent that is multifunctional.
functionalized stars, while in the latter, as end-functionalized It has been employed in the synthesis of hyperbranched star-
star polymers. Molecular weight asymmetry is present in star- shaped poly-l-lactic acid (PLLA) polymers which marry both
shaped polymers that possess arms with different molecular the fluorescent and bioabsorbable properties.[48] The utility of
weights but identical chemistry. Subdividing the functionalized this method lies in the control it gives over all the synthesis
stars, for functional group asymmetry, the arms are similar steps, and that by forming the arms first, we can isolate and
chemically, and have equivalent molecular weights, but they characterize them. This allows preparation of controlled poly
possess different functional groups. Whereas in topological merization with a highly customized control over its structure,
asymmetry, the star-shaped polymers’ arms all possess the composition, and functionality. In this method, the arm poly-
same chemical composition and molecular weights, but differ mers can be predesigned and characterized prior to the star
number distribution is broader compared

to similar architecture produced from other
synthesis method, low yield due to low arm
to star conversions, and requires rigorous
purifications. On an industrial scale, this
may make the manufacturing process more
complicated, with very narrow margins for
error to synthesize well-defined structures.
3.2. “Core-First” Method
Other names for this approach are the “arm-

out” or divergent approach. Suitable multi
functional linkers that have the ability to
initiate the polymerization of multiple arms,
radiating out from the cores, are utilized in
this process. A close example being that of
Tao et al. where they first synthesized man-
nitol core linked with poly(d,l-lactide-co-
glycolide)-d-α-tocopheryl polyethylene glycol
1000 succinate. This novel star architecture
with nanoparticle polymer has been reported
to have the highest antitumor efficacy, paving
the road for future breast cancer chemo-
therapy.[49] To synthesize well-defined star
macromolecules with arms that are similar
in molecular weights, the rate of initiation
of chain extension must be greater than that
of propagation and the different initiation
sites must all have a similar degree of reac-
tivity. Most importantly, it gives a high yield
of the purest form of synthesized polymer
which can be conveniently separated from
its starting reagents. However, the linking
reaction may be extremely time-consuming,
and the products usually tend to have low
arm numbers. To circumvent this, many
groups have started the synthesis process
with functionalized hyperbranched[50,51] and
dendritic[52,53] polymers, polysaccharides,[54,55]
nanogels,[56] and nanoparticles[57–59] to pro-
duce a product with larger core with more
arms. Another limitation of this method is
that the arms of the synthesized stars cannot
be directly characterized, so indirect methods
have to be employed to determine the exact
characteristics, complicating the synthesis
and characterization processes. Furthermore,
Figure 1. Overview of various star architectures according to A) composition and sequence
distribution of arms, B) different arms, C) different cores, and D) functional placement. during the radical polymerization of the arms,
star–star coupling may also result, giving rise
to ill-defined and uneven star structures.[60]
formation, allowing greater control over the exact arm structure
required, ideal for synthesizing miktoarm stars. This method
also avoids the complication of low molecular weight cores that 3.3. Grafting-Onto Approach
is further explained in the “core-first” approach later. Another
benefit is that the number of branches can easily be assessed This method allows the most precise structural control among
by knowing the functionality of the linking agent. These advan- all the star synthesis approaches since the core and the arms
tages are, however, coupled with the limitation that the arm can be synthesized separately before forming the final star
Figure 2. Synthetic approaches for star-shaped polymers: A) “arm-first”, B) “core-first”, and C) the grafting-onto approach.
architecture. Usually, this method is used to synthesize stars The usage of LRP is of great convenience as it reduces the need
with low arm numbers (4–8 arms) since a higher arm number for strict purification of the reactants and allows the utiliza-
makes the process more challenging due to steric hindrance tion and presence of different functional groups during and
around the core, which can lead to incomplete linking of arms after the polymerization process.[69] The major techniques of
to the core. A hybrid synthesis method of grafting-onto and LRP available are atom transfer radical polymerization, revers-
core-first has been hailed as a useful technique for building ible addition–fragmentation chain-transfer polymerization,
miktoarm star polymers,[61–64] where multifunctional cores can and nitroxide mediated free-radical polymerization.[70–72] The
first be synthesized and arm polymers can be grafted onto via various techniques of LRP have been adopted to grow the arms
polymerization. of the star-shaped polymers. Alternatively, ring opening poly
merization (ROP) can also be used to synthesize star-shaped
polymers.[73,74] These techniques are described briefly below.
4. Polymerization Techniques
About half of the global production of polymers is based upon 4.1. Atom Transfer Radical Polymerization (ATRP) Technique
free-radical polymerization, a proven process that is extremely
flexible in its application.[65,66] In free-radical polymerization, ATRP is an example of a technique used to attain living poly
the propagating species is the long-chain free radical that is merization, and it functions on the formation of radicals from
generated by the attack of free radicals from initiators. These dormant alkyl halides by halogen abstraction with transition
unstable initiators make the process very unpredictable and metal complexes.[24,75–83] This method hinges on the fact that
uncontrollable.[67] Hence, living radical polymerization (LRP) the equilibrium in this reaction lies largely on the side of the
was adopted in a bid to circumvent the existing limitations.[68] dormant alkyl halides, meaning that the number of radicals
produced is few. This translates into a lower radical concentra- was modified to be octasubstituted amine-terminated POSS
tion, and reduces the possibility of radical termination reac- by click reaction, followed by an arm extension reaction with
tions to maintain the living polymerization of the arms of these succinic anhydride to generate eight carboxyl acid groups. The
star-shaped polymers, or other polymers for that matter.[84,85] disulfide-containing ATRP initiator was introduced through
The most desirable factor for using ATRP is its ability to pre- esterification to obtain the POSS–(SS-Br)8 for subsequent
pare well-defined polymers to produce definite polymerization polymerization. Due to the presence of disulfide linkage, this
products. Li et al., for example, used ATRP to graft a polyhedral structure is bioreducible into low-molecular weight polycations
oligomeric silsesquioxane (POSS)-based initiator with block pol- with higher transfection efficiency. ATRP has even been used
ymers from cationic poly[2-(dimethylamino) ethyl methacrylate] to synthesize star-shaped zwitterionic polymers made of poly
(PDMAEMA) and zwitterionic poly[N-(3-methacryloylamino) amidoamine-graft-poly [3-dimethyl (methacryloyloxyethyl)
propyl)-N,N-dimethyl-N-(3-sulfopropyl) ammonium hydroxide] ammonium propanesulfonate] (PAMAM-g-PDMAPS).[89] To
(PMPDSAH).[86] In this study, the POSS-based octafunctional facilitate the ATRP reaction, the second generation PAMAM
ATRP initiator was prepared by one step reaction consisting of dendrimers were first prepared and then converted into the
complex processes of hydrolysis, dehydration, condensation, PAMAM–Br macroinitiator by the reaction with 2-bromoisobu-
and structure reforming, which is different from the transes- tyryl bromide. Then, dendritic star-shaped polymers PAMAM-
terification reaction reported in previously reported POSS– g-PDMAPS with different PDMAPS chain lengths can be
PDMAEMA star polymers.[87] These star-shaped structures prepared through a typical ATRP process in the presence of
were shown to self-assemble with the POSS hydrophobic core zwitterionic DMAPS as monomer. With this system, the drug
inside, PDMAEMA as the cationic shell, and the PMPDSAH adriamycin can be loaded not only within the PAMAM core,
as the hydrophilic nonfouling corona. This amphiphilic hybrid but also in the PDMAPS layers, which adds additional control
copolymer system was used to codeliver tumor suppressing over the release profile by adjustment to the PDMAPS chain
gene p53 and doxorubicin (DOX) in vivo and showed good drug lengths in addition to its pH-controlled release. Dai et al. have
loading capacity, strong DNA condensation ability, reduced also synthesized biodegradable and biomimetic star-shaped
protein adsorption, and good biocompatibility while reducing porphyrin core poly(ε-caprolactone)-b-poly(gluconamidoethyl
the side effects. In a similar approach, POSS core and eight methacrylate) (SPCCL-b-PGAMA) block copolymers by direct
disulfide-linked PDMAEMA with different molecular weights ATRP of unprotected d-gluconamidoethyl methacrylate gly-
were synthesized (Figure 3).[88] In this work, vinyl-POSS comonomer (GAMA) in a three-step reaction.[90] First, the
Figure 3. Synthesis of POSS–(SS-PDMAEMA)8 star-shaped polymers using ATRP. Adapted with permission.[88] Copyright 2014, American Chemical
Society.
well-defined star-shaped polycaprolactone (PCL) with four detached from the core.[99] Using these methods, we can apply
hydroxyl end groups (SPPCL) was synthesized by the controlled either the “arm-first” or “core-first” approaches described ear-
ROP of ε-caprolactone monomer using porphyrin as initiator. lier. Since termination cannot be fully eliminated from the LRP
By converting SPPCL precursor into the SPPCL–Br in an ter- processes, this translates into the possibility of radical termina-
minal acylated reaction with 2-bromo-2-methylpropionate end tion of these species to form unwanted products like star–star
groups, the subsequent ATRP of GAMA was successfully car- coupled products, nonlinear arms, or dead arms. Whereas, in
ried out to produce the designed star-shaped polymers. The the latter process, the arms of the star-shaped polymer are at all
resulting polymers display self-assembly and act as nanosized times dormant. This generally means that the products will be
photosensitizing agents which are able to encapsulate hydro- cleaner and there will be the absence of the above-mentioned
phobic drugs for controlled and targeted delivery. unwanted species.
ATRP may be used for both “arm-first” and “core-first” In one study, Zhao and co-workers reported a facile syn-
methods, depending on the choice of functional initiators, thesis of star polymers on the basis of S-(4-vinyl)benzyl
mono mers, and most critically, the timing and sequence of S′-propyltrithiocarbonate using RAFT copolymerization with
addition of the comonomers.[91] A caveat is that addition of the vinyl monomers. It showed that the approach based on two
cross-linker should only happen strictly before or after poly successive RAFT processes is general and versatile to synthe-
merization, otherwise, the reaction might result in random size multiarm star polymers with controllable arm length.[100]
branching of polymers or random cross-linking of gel net- In a recent report, a new tetrafunctional RAFT agent,
works.[92] This has been among the most favored approaches tetrabenzyl(1,3-dithietane-2,2,4,4-tetrayl)-tetracarbanotrithioate,
used in synthesizing core cross-linked star (CCS) polymers, and was developed to synthesize star-shaped polystyrene (PS) poly-
its success has been furthered with the creation of an ATRP mers.[101] The Z-group constitutes the core and the R-group is
system where electron transfer is used to regenerate the acti- made of benzyl moiety in the designed tetrafunctional RAFT
vators by Matyjaszewski et al., where ATRP can be performed agent, where propagating radicals grow away from the core site
even in conditions with limited air, which makes the fabrication and show good ability to control the molecular weight.
of star polymers more economically attractive.[93] Amphiphilic miktoarm star polymers are especially useful in
that they have lower critical micelle concentration as compared
to the liner block copolymers, with the added ability to tailor the
4.2. Reversible Addition–Fragmentation Chain-Transfer (RAFT) structure–morphology relationships for various applications by
Polymerization making use of the functionalizable arms. An important aspect
of these miktoarm star polymers is that they can also be effec-
RAFT polymerization utilizes chain-transfer agents. It then tively synthesized by RAFT and further decorated with more
proceeds by a degenerative transfer process, with the chain- features.[102] For example, Qiao and co-workers recently devel-
transfer agents being compounds that contain thiocarbonylthio oped a visible light mediated RAFT polymerization technique
moieties.[2,44,94–97] Among all the LRP techniques mentioned, in the presence of trithiocarbonates (TTC) as the control agent
RAFT polymerization is the most versatile, being able to tole (Figure 4).[103] Interestingly, the “living” core can be further
rate a myriad of reaction conditions.[98] Depending on the chain extended upon the addition of another fresh monomer
RAFT agent used, the leaving group may either be bound to to generate additional arms for each stars as well as pseudo-
the core of the star-shaped polymer, or generate a radical that is miktoarm star polymers. The high retention of TTC groups in
Figure 4. Schematic illustration showing the synthesis of miktoarm star-shaped polymers by photocontrolled RAFT polymerization in the presence of
trithiocarbonate (TTC) under visible light. Reproduced with permission.[103] Copyright 2015, American Chemical Society.
the star core potentially provides an avenue for postfunction-

alization reactions using other coupling chemistries to afford
multifunctional nanocarriers for specific applications.
4.3. Nitroxide-Mediated Free-Radical Polymerization (NMRP)

Technique
NMRP utilizes alkoxyamines as the initiators for polymeriza-

tion.[104–109] These compounds undergo homolysis at the CO
bond under certain conditions, producing two radicals, a
nitroxide radical and a carbon radical.[110] NMRP then functions
on the basis of the persistent radical effect (PRE), observable
in some radical systems where the formation of one product
is highly favored because of the stability of one of the radical
species, nitroxide.[111,112] A critical point to note is that the coup
ling between these persistent radicals is reversible, hence, the
persistent radicals still form a majority even as their concen-
tration increases over an extended period of time. The other
radical is transient, and reacts spontaneously with monomers
to lengthen the macromolecular chain, or with other transient
radicals or the persistent radical to result in a termination
step.[113] However, as mentioned earlier, because of the huge
availability of the persistent radicals, the transient radicals tend
to couple with the persistent radicals rather than with them-
selves, allowing the polymerization to proceed until the feed Figure 5. A) The synthetic approach of polypeptide-based core cross-
depletes.[114] The effectiveness of the polymerization process linked star (CCS) polymers by NMRP. B) pH responsiveness of the
depends much on the choice of nitroxide species.[110] To achieve core–shell nanoparticles formed from the as-synthesized star polymers.
Reproduced with permission.[120] Copyright 2010, American Chemical
rapid chain growth and uniform chain lengths, we will require
Society.
initiators that enable fast homolysis of the CO bond, with
relatively few side reactions.
At any point during the polymerization process, the huge an amine-functionalized alkoxyamine via N-carboxyanhydride
majority of the persistent radicals due to the PRE ensures (NCA)-ROP followed by chain extension with styrene. A series
that the ends of the growing chains are “capped” by the medi- of CCS polymers were then synthesized through NMRP at dif-
ating nitroxide.[115] This prevents the termination of arms of ferent feed ratios (Figure 5). Interestingly, it showed that the
the star polymers via the coupling of active chain ends, and conversion efficiency increased at higher content of DVB,
affords us greater control over the polymerization process probably due to the reduced spatial constraints which could
to create arms of equal chain length and structure. In addi- allow for more complete accommodation incorporation of the
tion, compared to ATRP and RAFT, NMRP possesses many PBLGA-b-PS into the star structure. Due to the presence of the
advantages such as the metal free process and is more toler- polypeptide, the yielded nanoparticles from the CCS also dem-
able to amine and carboxylic acid groups during polymeriza- onstrated stimuli-responsiveness at different pH values.[120]
tion. The first report on the synthesis of star-shaped polymers
using NMRP can be dated back to 1997 by Solomon and co-
workers.[116] Since then, several research groups have reported 4.4. ROP Technique
the preparation of star polymers by NMRP.[117,118] For instance,
Kuo and co-workers reported the synthesis of a series of star The ring opening polymerization technique is usually com-
block copolymers from POSS by core-first NMRP.[119] To facili- bined with other processes in order to synthesize star-shaped
tate the reaction, eight N-alkoxyamine groups were attached polymers, typically, with arms developed by the living polymeri-
onto the eight corners of POSS cube through quantitative zation techniques explained earlier.[121] Miktoarm stars can also
hydrosilylation. The obtained octa-N-alkoxyamines POSS be made by incorporating mixed arms during the cross-linking
can be used as a platform to further prepare star POSS–(PS)8 stage.[122] ROP produces stars that are characterized by ester
homopolymers and POSS–(PS-P4VP)8 diblock copolymers linkages which are desirable biomedical because of the ease of
through NMRP, showing narrow distribution in molecular hydrolysis at physiological conditions (Figure 6).[33,123,124] ROP
weight control. Recently, Heise and co-workers demonstrated is a two-step one-pot process where ROP is done with the addi-
the a facile preparation of well-defined polypeptide-based CCS tion of a catalyst and an initiator to produce living arms in a
polymers by reaction of 2,2,5-trimethyl-4-phenyl-3-azahexane-3- bulk polymerization process. With ROP, higher molecular
nitroxide-derived alkoxyamine end groups with divinyl benzene weight stars can be achieved more quickly, and the stars that
(DVB) (Figure 4).[120] In this study, poly(γ-benzyl-l-glutamate-b- are synthesized can be fully degraded, causing them to find
styrene) (PBLGA-b-PS) in linear structure was first made from huge applications in the biomedical field.[125]
The double hydrophilic miktoarm amphi-

philic PS(PNIPAAM-b-P4VP)2 copolymer
was obtained using PS(PNIPAAM)2-2Br
as macroinitiator and 4-vinyl pyridine as
the monomer via consecutive ATRP chain
extension (Figure 7). In addition, the self-
assembly behaviors of the resultant miktoarm
amphiphilic block copolymers were also
investigated. It showed that the aggregate
morphology changed from sphere-shaped
micelles to a mixture of spheres and rods, and
Figure 6. The use of ROP in synthesizing star-shaped polymers. Reproduced with permis- eventually rod-shaped nanorods when the pH
sion.[126] Copyright 2003, American Chemical Society. value changed from 4.7 to below 1.0.[129]
In addition, sequential RAFT and ATRP
Chen et al., for example, have used ROP to synthesize 6-arm from a multi-initiator-functionalized hyperbranched polyg-
star-shaped poly(lactic-co-glycolic acid) (6-s-PLGA) loaded with lycerol (MI-HPG) core were also reported to prepare a mixed
paclitaxel (PTX) which has been used for antiproliferative arm star copolymers of poly(N,N-dimethylacrylamide) (PDMA)
therapy.[40] Although PLGA has been long approved by the US and PNIPAAM.[130] The MI-HPG core was synthesized from
Food and Drug Administration, much research is still required an amine-functionalized polyglycerol, followed by modifica-
to develop previous linear PLGA into different architectures that tion with 2-chloropropionamide groups (ATRP initiator) and
can effectively meet a wide range of application requirements 4,4′-azobis(4-cyanovaleric acid) (azo initiator). By using this ini-
and this group has demonstrated that this highly stable 6-arm tiator, the dimethylacrylamide was polymerized from MI-HPG
polyplex can be formed using ROP. ROP has also been used to core by the RAFT method in the presence of S,S′-bis(α,α′-
synthesize fluorescent star-shaped polymers from s-poly(methyl dimethyl-α″-acetic acid) trithiocarbonate as a chain-transfer
methacrylate-co-glycidyl methacrylate) (P(MMA-co-GMA)) by agent. The subsequent controlled synthesis of mixed arm star
modifying oxirane with ethylenediamine and attaching fluo- copolymers was achieved by cografting PNIPAAM onto the
rescein iso-thiocyanate covalently to the amine groups.[127] HPG-g-PDMA macroinitiator by ATRP.[130] Emerging click
This system was not only able to induce apoptosis of cancer chemistry has been demonstrated to be an efficient and fast
cells but the fluorescently labeled drug carrier allowed real- ligation technology for preparation of star polymers with com-
time monitoring of the cellular uptake and localization, fur- plex structure and functionalities.[128,131] Satoh and co-workers
ther improving the drug carrier studies in vivo. Yang et al. has reported an innovative method to synthesize stereo-miktoarm
also found that cholic acid, a natural bile acid can be used as star poly(lactic acid) (PLA) by click coupling of azido-functional-
a cheap and readily available platform to synthesize branched ized poly-d-lactic acids (PDLAs) and the ethynyl-functionalized
degradable polymers.[127] In their system, they use ROP to syn- PLLAs possessing different branches (Figure 8).[132] The parent
thesize 3-arm amphiphilic block copolymer from trimethylene polymers azido-functionalized PDLAs and ethynyl-function-
carbonate from methyl cholate and conjugated with functional- alized PLLA possessing linear and two- and three-branched
ized poly(ethylene glycol) (PEG) containing vinyl sulfone group structures were prepared by the ROP of d-lactide and l-lactide
which can be used to install biological ligands for better speci- using azido- or ethynyl-functionalized initiators. The click reac-
ficity during delivery. This serves as a simpler and cheaper syn- tion of the azido-functionalized PDLAs and the ethynyl-func-
thesis route using metal-free organocatalytic living ROP which tionalized PLLAs using the copper(I) bromide/N,N,N′,N″,N″-
has the potential to be scaled up for mass manufacturing of pentamethyldiethylenetriamine catalyst afforded 3-, 4-, 5-,
hydrophobic drug delivery systems. and 6-armed stereo-miktoarm star-shaped PLAs. The unique
structure allowed these stereo-miktoarm star-shaped PLAs
formed stereocomplex crystals without any trace of homochiral
4.5. Star Polymers Prepared by Combined Techniques crystallization.[132]
The combination of different polymerization techniques has also

been previously explored to develop star-shaped polymers with 5. Properties of Star-Shaped Polymers
complex architectures.[128] In one example, Zhang et al. reported
5.1. Bulk Properties
the synthesis of miktoarm star amphiphilic block copoly
mers poly(styrene)–(poly(N-isopropylacrylamide)-4-vinylpyri- Any polymers which have multiple domains, or with multiple
dine)2 (PS–(PNIPAAM-P4VP)2) via a combination of NMRP blocks or are made from multiple components generally have
and ATRP (Figure 7).[129] In this work, a novel nitroxide free the ability to generate controlled or well-defined multi phase
radical, 1-(4-methyleneoxy-2,2,6,6-tetramethylpiperidinoxyl)- morphologies. These could go through order–disorder transi-
3,5-bi(bromo-methyl)-2,4,6-trim-ethylbenzene (TEMPO-2Br) tions and order–order transitions to result in other morphologies
was designed and first used to mediate styrene polymeriza- which may be utilized for specialized applications. As inves-
tion. Furthermore, the precursor linear PS–TEMPO-2Br was tigated by Olvera de la Cruz and Sanchez, the static structure
Q (q) 
factor can be represented functionally as S(q)−1 = 
utilized as macroinitiator to prepare the miktoarm amphi-
− 2χ ,
philic copolymers, PS(PNIPAAM)2, by ATRP of NIPAAM.  N 
Figure 7. Synthesis of miktoarm star amphiphilic block copolymers poly(styrene)–(poly(N-isopropylacrylamide)-4-vinylpyridine)2 (PS–(PNIPAAM-

P4VP)2) via a combination of NMRP and ATRP. Reproduced with permission.[130] Copyright 2009, John Wiley and Sons.
where Q is a copolymer-dependent function, N refers to the plotted, they managed to determine that it is easier for linear
number of repeat units in each polymeric chain, and χ refers to diblock copolymers to phase separate as compared to sym-
the Flory interaction parameter. From the spinodal curves they metrically grafted A2B miktoarm star-shaped polymers. They
Figure 8. Synthesis of stereo-miktoarm PLA star polymers by click coupling of azido-functionalized PDLA and the ethynyl-functionalized PLLA. Repro-
duced with permission.[133] Copyright 2013, American Chemical Society.
also concluded that for nearly symmetrical AnBn miktoarm the body, most designs are structured toward attaining slower
star-shaped polymers, microphase separation was solely influ- drug release rates for efficient and targeted drug delivery.
enced by the molecular weight of the diblock copolymer, Over the years, the most studied classes of soft materials
instead of the molecular weight of the whole star.[133] are linear polymers and colloids, and they differ significantly
in terms of dynamics and rheological behavior. Linear poly-
mers tend to be involved in short range interaction, which in
5.2. Properties and Rheological Behavior in Solution turn means that high concentrations are required for them
to attain ordering in solutions. Conversely, colloidal solu-
The thermodynamics and kinetics of micellization, and the tions display strong long range interactions and ordering
micellar structural parameters – namely aggregation number, in the solution phase. Both these structures represent nag-
micellar size, dimensions of the core and the shell, and critical ging extremes of behaviors in solution, and complex macro-
micelle concentration (CMC) have been studied extensively in molecular structures like the star-shaped polymers are the
the past (Figure 9).[134] In general, polymer or macromolecule means to achieve something in between. Like typical micellar
architecture plays a key role in manipulating micellar proper- structures of diblock copolymers, star-shaped polymers show
ties, and provides a new avenue for tuning micelle behavior for a nonuniform mono mer density distribution. Star-shaped
specific applications.[135–137] In the recent past, a few studies polymers that are dissolved in good solvents at concentra-
dealt directly with the complex star-shaped architectures, and tions higher than the coil overlap concentration – where steric
the major takeaway is that star-shaped polymers tend to show and frictional interactions with neighboring coils are non-
reduced aggregation numbers with larger CMC values than negligible,[138] exhibit liquid-like order. This is a consequence
similar polymers taking up the linear form.[102] However, the of the augmented osmotic pressure that compensates for the
CMC values between star polymers and linear polymers also stored deformation energy of the outstretched arms (because
varied when the factors are different, such as the molecule of entropic gain) of the star. Above the coil overlap concen-
weight, topological structure, chain length, etc. tration, cooperative diffusion, self-diffusion, and structure
Polymeric micelles are also able to provide sustained release relaxation controlled density fluctuations and the relaxation of
of the entrapped drugs over periods ranging from hours to days concentration.
in most cases. In these, the drugs are released from the micelle In general, star-shaped polymers often differ in terms of
core via outward drug diffusion, or through the disintegration thermal properties as compared to similar polymers with the
of the micelle. If the glass transition temperatures of the com- linear form because of their complex molecular architecture,
ponents forming the core are above the average body tempera- and they usually possess lower glass transition temperatures,
ture of 37 °C, these cores are in the glassy or frozen state, and melting points, crystallinities, and decomposition temperatures
they cause a slower rate of drug release. Also, the strength of versus their linear counterparts, as is the case for star-shaped
the interaction between the drugs and the segments forming up versus linear polylactides.[139] These properties are, however,
the core can influence the rate at which outward diffusion of the heavily dependent on the type and number of the end or ter-
drug occurs. It is also worthy to note that the amount of drug minal groups.[140]
loaded can also take on a determining role in the drug release
rates. When the drug loading of hydrophobic drugs like clon-
azepam is too high, there is a great likelihood of drug crystal- 5.3. Viscoelastic Properties of Star-Shaped Polymers
lization within the core of the micelle, which reduces the drug
release rates. In general, given the aggressive environment in Person and Helfand put forth a theory in 1983 describing the
viscoelastic properties of star polymers, by predicting how the
viscosity, μ0, and the steady-state shear compliance, J e0, depend
on molecular weights. Included was also how the dynamic
moduli, G′(ω) and G′′(ω), depended on frequency. This is based
on star-shaped polymers having f number of arms. The rela-
tions are as follows
1
M 2  M  (1)
µ0 ∝  a  exp  v ′ a 
 Me   Me 

where Ma is the molecular weight of the arm, Me is the mole

cular weight between entanglements and v′ is a constant associ-
ated with the potential function, and
2
∞
∞ 
J e0 = ∫ tG ( t ) dt /  ∫ G ( t ) dt  (2)
0 0 
Figure 9. Possible micellar structure of star-shaped polymers. Repro-
duced with permission.[135] Copyright 2005, American Chemical Society. where G(t) is the stress relaxation modulus, and
G * (ω ) ≡ G′(ω ) + iG ″(ω ), with G ( t ) = G0 (1 − ξ ( t )) + O (α −1 ) (3) In addition to the micelle and vesicle, the self-assembly of
star polymers to form intelligent hydrogel formation has also
been widely exploited.[144] In one recent study, Li et al devel-
where Fourier transform of the stress relaxation modulus oped a novel star–star supramolecular hydrogel from the self-
allows us to obtain the dynamic modulus, with ξ(t) being the assembly between a star-shaped adamantyl-terminated 8-arm
fraction of the tube that has undergone relaxation due to the poly(ethylene glycol) and a star-shaped poly(N-isopropylacryla-
movement of the end of the an arm passing through. These mide) with a β-cyclodextrin (β-CD) core (Figure 11).[145] The
equations were developed based on the theory of concentrated strong ability to form inclusion complexation between the two
solutions of linear polymers.[141] parent star polymers would subsequently self-aggregate into a
Polymer materials with highly elastic mechanical properties 3D network that induced thermoresponsive hydrogel forma-
are especially important for bone tissue regeneration and drug tion. The star–star supramolecular architecture was formed
delivery applications because they match the innate elastic and via self-assembling host–guest interaction, in which the star-
ductile properties of many tissues in the body, making them an shaped PNIPAAM with one β-CD core is the macromolecular
ideal drug delivery medium. Hence, Xie et al. has developed a host, and the adamantyl-terminated 8-arm PEG star polymer
biocompatible and elastomeric star-shaped polymer via photo- is the macromolecular guest. At low temperature of 25 °C, the
crosslinking from inositol-based PLLA and PEG.[142] They have star–star pseudo-block copolymer dissolved in water to form
proven this the star-shaped polymer showed desirable elasticity clear solution and this host–guest mixture transited into a
of 18 MPa in tensile strength, 200 MPa in modulus, and 200% white stable hydrogel when the temperature increased to 37 °C.
in elongation, which are all comparable to the values of most Interestingly, this sol–gel transition was completely thermor-
human tissues. eversible, making it unique and different from the previously
reported irreversible supramolecular gel-forming system.[146]
5.4. Self-Assembly Behavior in Solution

5.5. Drug Encapsulation Properties
The self-assembling of star-shaped polymers in solution can
be enabled by attaching functional groups along or at the end Amphiphilc star polymers with their hydrophobic cores are
of the star’s arms for homogeneous stars, or by using selective especially useful in encapsulating hydrophobic drugs to deliver
solvents for miktoarm and star–block copolymers. These will into aqueous in vivo environments, which otherwise would
cause the star-shaped polymers to form micellar structures in be unachievable with free drug delivery alone.[147] There are
solution, and in this state, they can be utilized for numerous two primary methods for encapsulating hydrophobic drugs in
applications. An example of stimuli-responsive self-assembly in micelles of star polymers, or micelles of any other polymers
solutions is evident in the miktoarm stars synthesized by Ge for that matter; the dialysis and the oil in water (o/w) emul-
et al., comprising a temperature responsive PNIPAAM arm and sion methods. In the first method, the drug and the star-shaped
four pH-sensitive PDMAEMA arms.[143] These stars self-assem- polymers are simultaneously dissolved in a good solvent fol-
bled into micellar structures with PNIPAAM and PDMAEMA lowing which they are to be dialyzed against selective solvents.
cores in acidic environments (at elevated temperatures) and In this dialysis process, the micelles begin to form, and as
slightly alkaline environments, respectively. they do, they simultaneously incorporate the drugs into their
Recently, Tsukruk and co-workers reported a complexed micelle cores. Conversely, in the o/w emulsion method, the
hierarchical self-assembly of vesicle formation from a cationic drugs are first dissolved into a suitable organic solvent (take, for
miktoarm star polymer, poly(ethylene oxide)113-(quaternized instance, dichloromethane), and they are then added to a solu-
poly(2-(dimethylamino)ethyl methacrylate)60)4 and a linear tion of micelles in the aqueous condition dropwise. The (hydro-
anionic polyelectrolyte, (poly(styrenesulfonate)20) through phobic) cores of these micelles would then trap the emulsion
electrostatic interactions (Figure 10).[9] Due to the presence containing the drug, thus the drug gets incorporated into the
of bis-hydrophilic phase from cationic miktoarm star polymer micelle core as the organic solvent is evaporated. The structure
and linear anionic polymer, the resultant vesicles possessed of the macromolecule involved can greatly affect the drug car-
unilamellar formation, with inter-polyelectrolyte complexe rying ability of the polymeric micelles, and is a core factor influ-
wall sandwiched between poly(ethylene oxide) brushes, as encing the stability, size, size distributions, kinetics of release,
illustrated in Figure 10A. The obtained vesicles can be further and the biodistribution of the micelles. In star-shaped poly-
used to fabricate microcapsules with tannic acid via facile layer- mers with hydrophobic cores, the cores serve as a nanosized
by-layer (LBL) assembly (Figure 10B). The hydrogen bonding reservoir for the storage of the drugs. Thus, the composition
between tannic acid (TA) and polymersomes provided the of the core blocks can influence the efficacy of drug loading
main driving force for the LBL self-assembly which is highly and drug release behaviors.[148] It also has to be noted that the
sensitive to external pH. Through the combination of the compatibility between the drugs to be loaded and the micelle
star polymer based vesicles and LBL with TA, a dual-respon- core-forming blocks is one of the crucial factors that should be
sive behavior with the programmable release of two different accounted for when designing the star-shaped polymers. The
types of encapsulated molecules from the multicompartmental biodegradability of the core segments also has to be consid-
microcapsules was obtained (Figure 10C), showing vast poten- ered, to ensure that there is no accumulation of drug carriers
tial applications in self-healing materials, smart coatings, and in the body that remain there for the long term. Knop et al.
microreactors.[9] have demonstrated the fabrication of unimolecular micelles
Figure 10. A) Self-assembly of vesicle formation from a cationic miktoarm star polymer and anionic linear polyelectrolytes. B) Scheme illustration
showing the LBL assembly process of microcapsules from vesicles and tannic acid. C) Demonstration of the sequential release of two types of mole
cules from the as-fabricated microcapsules. Reproduced with permission.[9] Copyright 2016, American Chemical Society.
from amphiphilic star-shaped [PCL18-b-POEGMA]4 and [PCL18- in vitro gene transfection to MCF-7 breast cancer cells[153] and
b-poly(oligo(2-ethyl-2-oxazoline)methacrylate)s (POEtOxMA)]4 docetaxel (DOC) and siRNA target plasmid MMP-9 (pMR3) to
which showed greater stability of the DOX-encapsulating hydro- HNE-1 cells.[152]
phobic core than free drug in aqueous environments with no
short term cytotoxicity.[149] The presence of both hydrophobic
and hydrophilic parts in amphiphilic stars not only acts as a 6. Functionalization of Star-Shaped Polymers
driving force to self-assemble in water, but also encapsulates
a poorly soluble molecule, proving its worth as a drug nano- Another important aspect of star-shaped polymers is the
carrier. This can be accomplished by synthesizing star-shaped ability to functionalize them well with the different poly
polymers that contain poly(tert-butyl acrylate) arms which were merization methods that have been developed. Using special
subsequently deprotected to produce hydrophilic poly(acrylic functional groups, we can allow for drugs to achieve more
acid) (PAA) arms.[150] Alonso-Cristobal et al. have also achieved targeted deliveries, for drugs to be imaged, for incorporating
similar results by using branched poly(ε-caprolactone) as hydro- other biocompatible functionalities, and for dealing with sol-
phobic core and branched PEG as the hydrophilic arms.[151] vent incompatibility issues. To elaborate more on targeting
Recently, star-shaped polymers with CD core and cationic functionalities, by attaching specific ligands that can recognize
arms have also raised much interest in drug delivery research as cancerous cells or tumors (or any other disease-related physi-
they can coload both hydrophobic drugs and genes from stable ological sites), one can significantly increase the efficacy of
polymer complexes in vivo, without much trouble with micel- drug delivery systems. Closely related to this is the imaging
lization requirements.[152] This system has been successful in functionality where attached functional groups may allow
Figure 11. Formation of the star–star supramolecular architecture induced by the self-assembly of star-shaped polymers and the temperature induced
supramolecular hydrogel formation. Reproduced with permission.[146] Copyright 2013, Wiley-VCH Verlag GmbH & Co. KGaA.
medical practitioners to identify diseased tissues that the stars Disulfide groups can be degraded to thiol groups in the
have latched on to. Moreover, biocompatible functionalities presence of a variety of reducing agents. In previous study,
like lengthening the duration of which a particular drug circu- Matyjaszewski and co-workers reported the synthesis of thiol-/
lates in the body can be made possible through incorporating disulfide-functionalized star polymers and their redox response
certain functional groups. To this end, surface functional- behavior (Figure 12).[156] In their report, a poly(n-butyl acrylate)-
izing star-shaped polymers with PEG has seemingly achieved based star polymer, poly(ethylene glycol diacrylate)-poly(n-
success, allowing a “passive targeting” of tumors by virtue of butyl acrylate) (polyEGDA–(polyBA)n), was first synthesized by
having the drug circulate for longer periods within the body.[154] ATRP, followed by a further polymerization of a disulfide (SS)
This is described as the “enhanced permeability and retention” cross-linking agent bis(2-methacryloyloxyethyl) disulfide to from
effect.[155] the arm end SS cross-linked star polymer. It showed that the
Figure 12. Reduction and oxidation of SH-/SS-functionalized star polymers. Reproduced with permission.[157] Copyright 2010, American Chemical
Society.
disulfide functionality could be cleaved via reducing reactions, shrinkage of PNIPAAM corona would concomitantly decrease
generating individual stars containing SH groups at the chain the average distance between gold nanoparticles on the micelle
ends. Interestingly, the transformation between SS cross-linked surfaces. This would further induce a dramatic redshift of the
star and SH-star was reversible via repetitive reduction and oxi- maximum of the surface plasmon band from 524 to 535 nm by
dation. As a consequence of this reversible reaction, disulfide the enhanced interparticle coupling effect.[158]
cross-linked star polymer gels were also obtained. Dynamic The uniqueness of star-shaped polymers is the fact that it
mechanical study showed that SS-functionalized star poly- is possible to achieve a high local density of active functional
mers respond to reduction–oxidation conditions, indicating the groups which can be modulated according to various require-
cleavage and the reformation of the disulfide bonds, indicating ments. Various stimuli-responsive moieties such as pH respon-
high potential of utilizing this intelligent polymeric materials sive DMAEMA and temperature responsive NIPAAM can
in self-healing applications.[156] now be linked onto the drug encapsulating cores such that the
In addition to functionalizing star polymers by organic release profile can be externally controlled precisely. This opens
compound, utilization of inorganic nanoparticles to tune the up the window to many potential applications, namely advanced
material features star polymer has also been explored. Liu and coatings, nanostructured thin films, and drug delivery.[159]
co-workers recently reported the functionalization of Au nano More details on this controlled delivery will be discussed in the
particles onto the surface of thiol-functionalized H40-PNI- next section.
PAAM star polymers in a two-step reaction in aqueous solution
(Figure 13).[157] Thermoresponse H40-PNIPAAM star polymers
were first prepared by modification of H40 dendrimer into 7. Applications of Star-Shaped Polymers
H40-based macroRAFT agent, followed by the polymerization
of NIPAAM monomer in a typical RAFT process. In aqueous 7.1. Star-Shaped Polymers for Use in Drug Delivery
solution, H40-PNIPAAM star polymer dissolved and self-
assembled into unimolecular micelles with H40 as the core with In this review, we are mainly focused on using star-shaped
surrounding PNIPAAM grafts as the corona. The dithioester polymers for drug delivery. In this regard, amphiphilic star-
groups conjugated at the surface of unimolecular micelles shaped polymers seem to be the prominent candidate owing
could be transformed to thiol groups upon addition of excess to their abilities to encapsulate and contain molecules. There
sodium borohydride (NaBH4). The gold nanoparticle deco- are several reports on using star polymers for drug delivery. For
rated hybrid star polymers were obtained after addition of the instance, the usage of star-shaped polymers with PS or poly(n-
thiol-terminated H40-PNIPAAM into the citrate-capped gold butyl acrylate) hydrophobic cores as initiators in the polym-
nanoparticle solutions. Due to the covalent linkage between erization of cationic DMAEMA. Here, the star polymer existed
surface thiol groups and gold nanoparticles, the obtained hybrid in the glassy state, resulting in reduced DNA transfection as
system is extremely stable, and exhibited reversible swelling compared to when rubbery polymers were utilized.[160] Tra-
and shrinkage in response to external temperatures. The ditional methods of polymeric drug delivery simply encapsu-
Figure 13. A) Scheme showing the decoration of Au nanoparticles on to the surface of unimolecular micelle self-assembled from H40-PNIPAAM star
polymer. B) Demonstration of the thermotunable spatial distance between Au nanoparticles attached at the unimolecular micelle surface. Reproduced
with permission.[158] Copyright 2007, American Chemical Society.
lates drugs to the hydrophobic cores, but this is often PTX by 10 000-fold. Following this, solubilized PTX could then
plagued by problems of early release or poor delivery as the be unloaded into the body from the dendriPGs – this was also
micelles may start to degrade and unload the drugs before tested with the star-shaped graft polymers in an aqueous envi-
reaching their targets.[35,158,161–167] This method is also usually ronment. The release rates were determined to be a function
characterized by low drug loading capacities. To deal with this of the star and dendrimer generation.[171] This new architecture
problem, newer methods involve the conjugation of drugs to utilizing the star-shaped polymer structure signals the poten-
the polymer chains through covalent chemical bonding. This tial introduction of new methods of drug delivery in the future,
leads to improvements in both drug loading capacities and especially in the case of drugs with low water solubility.
it also affords better control over the release profiles of the Instead of using PEG as the hydrophilic segments, Cheng
drug.[168] Also, for cancer drug delivery, where the optimum size et al. developed 4-arm star block copolymers (with biodegra-
for accumulation at tumor sites is in the range of tens of nano dability) using poly(ethyl ethylene phosphate) (PEEP) as the
meters, Liu et al. polymerized monodisperse poly(oligoethylene hydrophilic shell instead. This was done by ROP of 2-ethoxy-
glycol) methyl ether acrylate (POEGMA) based stars via RAFT. 2-oxo-1,3,2-dioxaphospholane with hydroxyl terminated four
Aldehyde groups at the core of the stars were utilized for the arm star poly(ɛ-caprolactone) with stannous octoate (Sn(Oct)2)
attachment of doxorubicin – a bacterial antibiotic used pri- as a coinitiator. These stars had low CMC values in the range of
marily in the treatment of leukemia and other forms of cancer. 5.74 × 10−4 to 3.87 × 10−3 g L−1, and they spontaneously assem-
The in vitro studies showed that the stars with attached doxo- bled into micelles with sizes ranging from 45 to 110 nm. They
rubicin had similar levels of cell toxicity as compared to free were also shown to load between 1.6% and 3.5% (wt/wt) of PTX
doxorubicin,[169] and this presents a method of cancer treatment with drug loading efficiencies of 16–35% that were roughly two
that might serve as a more targeted approach in drug delivery. times higher than their linear counterparts. The drug release
In a similar manner, Wei et al. managed to synthesize a observed showed a spike at the initial phase, following a sta-
star block copolymer with four arms, comprising, on average, bilization of the release rate with a sustained release of up to
a single hydrophobic poly(methyl methacrylate) (PMMA) arm, two weeks (slower rate as compared to linear counterparts),
with three hydrophilic PNIPAAM arms.[170] This required with an eventual release 45–85% of the initially loaded PTX in
careful design and molecular level synthesis. The carboxylic the 25 d test duration. It was also shown that polymer structure
acid-functionalized PMMA (PMMA-COOH) were first prepared correlates significantly to the drug release kinetics, with faster
via radical polymerization with 3-mercaptopropionic acid as the release with an increasing fraction of PEEP, and conversely
chain-transfer agent, while PNIPAAM blocks were prepared slower release rates were obtained with longer hydrophobic
by making amino-terminated PNIPAAM (PNIPAAM-NH2) via blocks. Finally, in vitro cytotoxicity assays were ran, which
radical polymerization with 2-amino ethanethiol hydrochlo- exhibited the biocompatibility of these star-shaped block copoly-
ride being used as the chain-transfer agent. The functionalized mers comprising PEEP and PCL as they showed no apparent
PNIPAAM-NH2 was attached to longer PNIPAAM macromers cytotoxicity.[172] Also, another example of an approach to
via a condensation polymerization method involving the amino improve the solubility of hydrophobic drugs are the star-shaped
groups of PNIPAAM and N-acroyloxysuccinimide. These polymers synthesized by Deng et al. with poly(amidoamine)
were extended by attaching to larger PNIPAAM blocks, and (PAMAM) dendron arms and β-CD cores. These stars were
were eventually connected to the PMMA block to produce the cationic under the correct conditions, and they proved to be
star-shaped polymer. The star-shaped block copolymers were good buffering agents, possess good small interfering RNA
amphiphilic in nature, and they underwent self-assembly (siRNA) loading capabilities, had high siRNA transfection effi-
to form micelles in aqueous environments, into spherically ciencies in fibroblasts, and also showed good biocompatibility
shaped nanoparticles. By measuring the optical absorbance of with low cytotoxicity. The structure of the core also meant that
the samples, it was determined that the micelles formed were it possessed vacant internal hydrophobic cavities which could
able to show reversible aggregation and dispersion in response be used to encapsulate poorly water soluble drugs.[146] To test
to the thermal cycles they were exposed to. This was due to this, methotrexate (MTX), which is well-known to be poorly sol-
the fact that the outer polymer layer, which mainly comprised uble in aqueous conditions, was used to be loaded into one of
PNIPAAM, had a lower critical solution temperature (LCST) the variants of these stars via the dialysis method. The dendron
of 34 °C. This star-shaped polymer was able to exhibit good arms played a vital role in helping achieve sustained release, by
entrapment efficiency of prednisone acetate due to its unique hindering the outward diffusion of the entrapped MTX. Thus,
structure, and it also had good drug release behavior.[170] In the these stars could see potential multifunctional applications in
latter, it aims to achieve high densities or concentrations of the drug delivery as well as efficient siRNA delivery.[173]
ethylene glycol chains, and yet at the same time, we wish to
remove the tendency of the dilution of ethylene glycol following
injection. Both of this can be achieved simultaneously with the 7.2. Controlled Drug Release Using Star-Shaped Polymers
adoption of a star-shaped polymer architecture. Ooya et al. suc-
cessfully improved PTX solubility in water by about four orders In recent times, the self-assembly of micelles from amphiphilic
with the synthesis of star and dendrimer architectures of eth- copolymers for the delivery of drugs has risen in popularity.[174]
ylene glycol units.[171] Dendrimers of polyglycerol (dendriPGs) Further improvements to these delivery systems in recent years
were miscible and soluble in water at high concentrations, with include equipping them with the ability to respond to external
no sizable effect on raising the viscosity of the resulting solu- signals, for instance, a change in pH or temperature. These
tion. Moreover, at 80 wt%, dendriPGs improve the solubility of bestow the micelles with controlled drug release abilities. The
release kinetics of drugs is arguably the most critical aspect of on the drug release kinetics as once the cores degrade, all the
drug delivery systems that needs to be discussed. The architec- encapsulated drug molecules are dispersed instantly. Some
ture of the star-shaped macromolecules significantly affects the examples involve the inclusion of acid degradable ester linkages
rate at which encapsulated molecules and drugs diffuse out of within the core,[179] the usage of acid-labile di(methacryloyloxy-
their cores, in addition to the other major factors – core to shell 1-ethoxy)methane cross-linker to obtain cores that can
size ratios, polymer hydrodynamic volumes, degree of amphi- degrade,[180] the incorporation of cleavable disulfide linkages
philicity, and density of arms. Another way of influencing drug (which unfortunately produces stars with broad polydispersi-
release is to functionalize the drugs with stimuli-responsive ties using ATRP),[181] or the usage of bislactone cross-linkers to
behavior. One example of this is to incorporate pH-sensitive make polyester-based cores.[178]
degradation to stars, which may allow targeted drug release as In another approach, a semi-interpenetrating network con-
the body comprises many different environments with different sisting of poly(vinyl alcohol) (PVA) and star PDMAEMA was
localized pH values. Degradation of these star-shaped polymers used as a drug delivery vehicle. This method of drug delivery
is also critical in any biomedical applications as we should represents a departure from the drug delivery methods that
always try to reduce the accumulation of polymeric materials in have been discussed thus far. This semi-interpenetrating
the body as much as possible, by allowing them to degrade into hydrogel network was able to swell in aqueous conditions, and
smaller or metabolizable fragments. developed a porous structure after treatment in acid by virtue
As emphasized earlier, the two critical components of star- of the presence of the star PDMAEMAs. These pores and the
shaped polymers are the cores and the arms, and these have swollen structure provided greater volume and exposed sur-
different degradation behaviors. With the methods explained face area for drug storage, and also numerous other avenues
above, we can potentially attach cores with arms of virtually any for the release of drugs. Under different pH conditions, these
chemical composition to design the desirable physical proper- composite hydrogels comprising star PDMAEMAs exhib-
ties. For example, it has been reported that higher branching ited different drug release behaviors. These stars take on
resulted in faster degradation rate.[175] Also, as water is present more extended conformations at lower pH, creating more
in huge amounts in the body, hydrolysis is typically looked at pores, resulting in quicker drug release.[182] The section below
as one of the ways to degrade the arms, and this explains why will detail the different forms of external stimuli that can be
polyester-based structures are typically utilized in the arms of employed for a wide variety of drug delivery applications.
CCS polymers. For instance, similar to PLA, PCL is also gen-
erally considered to be a biocompatible and biodegradable
(although it takes some time) polymer[31,137,174,176,177] and this 7.2.1. Thermoresponsive Star-Shaped Polymers
is incorporated into the arms of star-shaped polymers by using
alkyl halide functionalized PCL chains in the synthesis process. The first example of thermoresponsive stars is the ther-
These are then cross-linked to the core with monomeric divinyl moresponsive core–shell nanoparticles from miktoarm
species such as DVB so that the arms can be easily removed by stars comprising hydrophobic PS, PCL, and PNIPAAM syn-
hydrolysis, without disturbing the functionality of the star’s core thesized by Zhang et al.[183] These stars then form micelles
(Figure 14).[178] In miktoarm star polymers, one can design stars through self-assembly in aqueous environments with PS
with only a fraction of degradable arms, allowing us greater and PCL at their cores, and a corona comprising PNIPAAM.
control over the rate at which the drug is being released as the Upon hitting the PINIPAAM segment’s LCST, the micelles
density of the stars’ coronas influence how easily drugs can dif- shrink spontaneously in response to the temperature change.
fuse out of the cores. In this respect, stars with more degradable By altering the amount of PNIPAAM in these stars, the nano-
arms typically show increased drug release kinetics as compared particle size can be controlled.[183] Chen et al. utilized ther-
to their counterparts with a smaller ratio of degradable arms. mosensitive PNIPAAM and PCL blocks as arm segments for
As opposed to influencing the rates of diffusion, by tweaking fabricating thermoresponsive star-shaped copolymers that
the degradability of the cores, we can have a more direct effect were able to form micelles for drug delivery. These were syn-
thesized by ROP of ε-caprolactone with cholic acid functional-
ized PNIPAAM macroinitiators, and the resulting stars had
an LCST of 37 °C, and cytotoxicity tests revealed no obvious
cytotoxicity. These stars undergo self-assembly into spher-
ical micelles at room temperature in aqueous environments
with relatively low CMCs, and they had diameters ranging
between 30 and 75 nm. The drug loading ability of the stars
was tested with MTX, an anticancer drug, with which they
exhibited effective loading and a temperature triggered drug
release rate. This was possible due to the temperature-sen-
sitive micelles which could undergo phase transitions that
corresponded with significant thermosensitive size changes
at different temperatures.[184] In another type of thermosensi-
Figure 14. Schematic illustration showing the selectively degradable core tive star polymers, Zhang et al. have used β-CD as a core for
cross-linked star polymers. Reproduced with permission.[179] Copyright drug encapsulation with hydrophilic PDMA blocks and tem-
2006, American Chemical Society. perature-responsive PNIPAAM blocks.[185] Below the LCST,
both blocks are water soluble but above the LCST, PNIPAAM Another example of pH-responsive nanofilms developed
blocks become insoluble aggregates. These aggregations from star-shaped polymers can be seen in the work of Kim
interact together with the hydrophilic blocks to form a 3D et al., where PDMAEMA stars and PAA star-shaped polymers
hydrogel which has unique properties of biocompatibility, are both incorporated into thin films with multiple layers via
convenient gel formation, and thermal responsibility as a a LBL assembly.[189] This was executed by using the electro-
potential drug delivery medium. static interactions between the polyelectrolyte arms of these
stars. Because of the unique structure of star-shaped polymers,
the films that were made were nonuniform and nanoporous,
7.2.2. pH-Responsive Star-Shaped Polymers however, the thickness and porosity of the multilayer star films
could be tuned by adjusting the pH during assembly. During
Schramm et al. synthesized water soluble star-shaped polymers post-treatment, different pH environments would result in
with PCL and various methoxy polyethyleneglycol methacrylate extensive structural change in the films, which was not possible
monomers (Figure 15).[186] These produced stars with biode- with their linear counterparts. The pH responsive behavior of
gradable hydrophobic cores which can release the encapsulated these nanofilms opens up many potential applications in their
drugs or molecules under acidic conditions.[186] use as drug delivery vehicles.[189]
In another study in 2009, Kul et al. synthesized star-shaped Jones et al. prepared pH-sensitive star-shaped polymers with
block polymers with 5 poly(t-butyl acrylate) arms attached to ethyl methacrylate and tert-butyl methacrylate to make up the
a poly(ethylene oxide) core via ATRP to use as unimolecular hydrophobic segments, and poly(ethylene glycol)methacrylate
nanocontainers. The arms were hydrophobic and the core was for the hydrophilic segment. They form unimolecular micelles
hydrophilic. In acidic media, the t-butyl acrylate groups hydro- that may be used to encapsulate drugs. The greater the amount
lyzed to form acrylic acids for the unloading of the encapsu- of hydrophobic monomers, the higher the molecular weights
lated drugs.[187] Another interesting use of pH-responsive of the aggregates they formed in water. Upon hydrolysis, the
star-shaped polymers involves the development of a hydrogel tert-butyl methacrylate groups introduced acid functions, and
for drug delivery from an interpenetrating network of poly[2- the stars exhibited two main sizes at both low and high pH.
(dimethylamino)ethyl methacrylate] stars of 21 arms and PVA By increasing pH, more of the acid functions along the arms
by Wu et al. which will be further elaborated in a following sec- will get ionized, and this is associated with an increased proges-
tion.[182] Connal et al. prepared PAA-based core CSS by using terone in vitro release rate.[190]
acid-protected poly(tert-butyl acrylate) via ATRP, and reacting it In a similar manner, Lidicky et al. have proposed the use
with divinyl benzene before deprotection.[188] These PAA star of star-shaped polymer–doxorubicin conjugates synthesized
polyelectrolytes had fully charged acrylic acid groups in the pH as long-circulating high molecular weight polymer prodrugs
range of 8–10, and they adopted a more “open” conformation with a dendrimer core and target-specific antibody attached
with larger diameters (about 30 nm). At lower pH, protonating at a single point to form star architecture.[191] The anticancer
the acrylic acid groups cause the polymers to return to a more drug doxorubicin encapsulated in this system was attached
coiled conformation, with smaller diameters in the region to the N-(2-hydroxypropyl)methacrylamide (HPMA)-based
of 23 nm. In this study, pH-responsive multilayer films were copolymer chain via a pH-labile hydrazone linkage. This make
developed from these PAA-based core stars and poly(allylamine the system stable at pH 7.4 but the drug was readily released
hydrochloride) (PAH). These films could be utilized for bio- in pH5-5.5 acidic environments via the hydrolysis of the hydra-
medical applications, and in drug delivery, where each of the zone bonds, demonstrating its efficacy in antilymphoma prop-
individual CCS polymers that are coated onto the thin film erties for large B-cell lymphoma. DOX has also been released
may serve as a nanocontainer for drug loading and release via pH control by Gao et al. where the star-shaped polymer
(Figure 16).[188] micelles synthesized from poly (ε-caprolactone)/PEG effec-
tively induced more tumor cell apotosis at pH 5.5 than the free
drug itself.[192]
7.2.3. Enzyme-Responsive Star-Shaped Polymers
Byrne et al. synthesized well-defined star-shaped polypeptides

with poly(g-benzyl-l-glutamate) (PBLG) arms from dendrimers
of polypropylene imine by using g-benzyl-l-glutamate NCA
initiators. Deprotecting these PBLG arms converted the stars
into poly(l-glutamic acid) (PGA) star polypeptides. Different
concentrations of drugs can be loaded into these star-shaped
polymers depending on the length of the grafted chains as
well as the number of PGA arms. Moreover, the PGA grafts,
being polypeptidic in nature, were susceptible to the enzyme
Figure 15. Schematic illustratration of the release of drugs via biodeg- thermolysin, and bestowed enzyme-responsiveness and a
radation of the star-shaped polymers. Reproduced with permission.[187] means of controlled degradation to these star polypeptides[193]
Copyright 2009, The Royal Society of Chemistry. (Figure 17).
Figure 16. Schematic representation of morphology changes in hybrid star PAA/PAH multilayer films. Reproduced with permission.[189] Copyright
2008, American Chemical Society.
7.2.4. Reduction-Responsive Star-Shaped Polymers 7.2.5. Light-Responsive Star-Shaped Polymers
A deviation from the above-mentioned methods involves the Ability to control the release of drugs at targeted sites with con-
shedding of the shells of micelles of star-shaped polymers when trolled rate, from an external source is a novel advantage in
placed in reductive environments. This was successfully dis- the realm of gene delivery as it makes remote control possible.
played by Ren et al. when they developed star-shaped polymers Light, especially, is an easily available and easily controllable
based on PCL and PEG[194] (Figure 18). These micelles could source of external stimulus. Xue and co-workers have used
first be internalized by tumors, following which the reductive porphyrin core, an organic compound with macrocycle con-
environment would cause the shedding of the micelles’ shells, jugated structure, with poly(l-lysine) dendron arms to deliver
resulting in rapid drug release. This approach shows potential pEGFP to 3T3 cells in vitro via the photodynamic therapy.[195]
in intracellular drug delivery. Porphyrins are well known for their photochemical internali-
In a similar manner, redox stimulus responsive miktoarm zation capabilities to release highly reactive oxygen species that
star micelles synthesized from mPEG–SS–PMMA has been induces an effective and selective destruction of diseased tis-
demonstrated to show rapid release of drug methotrexate in sues.[196] However, its use has been dampened due to its self-
response to the reductive conditions, resulting in anitumor quenching characteristics, hydrophobicity, and nonselectivity
activity toward HeLa cells.[102] The drug was released in the in in vivo applications. Star-shaped polymers with porphyrin
presence of dithiothreitol (DTT) when the disulfide linkages in cores have immense potential owing to their flexible architec-
the polymers were broken and this observation adds as a new ture, controllable surface functionality, and low hydrodynamic
frontier in the cytoplasmic drug delivery. radius. Dai et al., for example, have prepared star-shaped
porphyrin-core poly(l-lactide)-b-poly (gluconamidoethyl meth-
acrylate) block copolymers for targeted killing of diseased
cells.[197] To improve this system, arginine was added onto the
surface to improve the gene transfection efficiency, and was
proven that this system was able to deliver both the hydro-
phobic DOC and MMP-9 plasmid simultaneously, escalating
the nanomedicine delivery for cancer. Another star-shaped
polymeric system that displays photodynamic capabilities was
developed by Singh and co-workers where they used 4-arm
PEG with biotin and coumarin chromophore to deliver chemo-
therapeutic drugs.[198] Coumarin can be activated to release the
anticancer drug chlorambucil in a photocontrolled manner and
the innate fluorescence properties offer the added advantage of
photoguided therapy to deliver the drug to a more specific site
(Figure 19).[199] Such synergistic behavior of single component
organic polymer system demonstrates a strong potential plat-
form for photoguided therapy.
7.2.6. Dual-Responsive Star-Shaped Polymers

Figure 17. Enzymatic release of drugs from star-shaped polymers.
Reproduced with permission.[194] Copyright 2012, The Royal Society of Among all the stimuli, temperature and pH are two impor-
Chemistry. tant environmental factors in in vivo environment and also
Figure 18. Schematic illustration of destabilization of star-shaped polymer micelle in reductive environment. Reproduced with permission.[195]
Copyright 2011, The Royal Society of Chemistry.
can be designed easily in many applications.[25] Liu et al. at pH 9, pH 7.4, and pH 5. When utilized in drug delivery
synthesized an amphiphilic star block copolymer combining at physiological conditions, the release profiles depended
the temperature sensitive PNIPAAM and the pH sensitive on both parameters, and they demonstrated pH-triggered
PDMAEMA to form the hydrophilic arms of a star-shaped accelerated drug release at fixed temperatures, and temper-
polymer with a hydrophobic core of PMMA. These stars ature-triggered accelerated drug release at fixed pH.[200] Xue
formed stable micelles which had sizes in the range of 120 et al. have used the same materials to deliver similar results,
and 80 nm when they were loaded with drugs and unloaded, where their cationic 8-arm star polymers has thermo-, pH-,
respectively. As both temperature and pH sensitive groups and ionic strength sensitivities.[201] Thus, these dual-respon-
are present in the stars, they exhibited a pH-dependent ther- sive star-shaped polymers promise wide-ranging applications
moresponse, with LCSTs of 39.5, 36.6, and 32 °C, respectively, in drug delivery.
Another example of such thermo- and pH-responsive stars
are those synthesized by Jackson and Fulton, which are water-
soluble CCS prepared from cross-linking polymer chains
containing amino and aldehyde functional groups to form
dynamic imine bonds. The imine bond formation here is revers-
ible, and its equilibrium is dependent on the pH of the environ-
ment, with high pH conditions favoring imine formation and
low pH acidic environments doing the contrary. Release of any
hydrophobic molecules that are complexed within the polymer
cores can simply be triggered by altering the pH of the aqueous
or physiological environment (Figure 20).[202] Moreover, the
thermoresponsive cores allow these stars to reversibly switch
between hydrophilic and hydrophobic character, which can also
be utilized to trigger the release of the complexed hydrophobic
molecules.[202]
Schmalz et al. synthesized a dual-responsive star-shaped
polymer based off poly(N,N-diethylaminoethyl methacrylate)
(PDEA) to try to exhibit dual responsiveness to temperature
and pH. The synthetic process was performed via ATRP in
a “core-first” approach. PDEA stars respond to both tem-
perature and pH variations, but the temperature-respon-
sive behavior is independent of molecular weight and star
architecture.[203]
Apart from the dual control of temperature and pH, cross-
Figure 19. A–D) Illustration of various types of light responsive polymer linked star polymers have also been designed to respond to
micelles. Reproduced with permission.[200] Copyright 2012, American both pH change and reduction environments. An example
Chemical Society. is that of Wang et al. where star-shaped polymers based
Figure 20. Schematic illustrating the functioning of a dual-responsive CCS. Reproduced with permission.[203] Copyright 2011, Royal Society of
Chemistry.
on poly(l-glutamic acid)-poly(l-phenylalanine-co-l-cystine) and the results were comparable to that found for free doxo-
(PLG-P(LP-co-LC)) was used to deliver DOX and trans-3,5,4′- rubicin, confirming the viability of using star polymer–drug
trihydroxystilbene (RES). In this architecture, the PLG inter- conjugates for therapeutic applications.[169] Recently, Sumerlin
acts via strong electrostatic interaction with cationic DOX and and co-workers reported in a facile and efficient method for the
the poly(l-phenylalanine) (PLP) interacts with the hydrophobic attachment of anticancer drug methotrexate onto poly(N-(2-hy-
RES. The stable self-assembled structure dissociated with droxypropyl) methacrylamide) (PHPMA)-based star shape poly-
10 × 10−3 m DTT and at low pH.[204] mers (Figure 21).[205] MTX is a folic acid antagonist which has
been widely used in the treatment of a number of cancers. The
carboxylic acid functional group in MTX provides a straightfor-
7.2.7. Star Polymer–Drug Conjugates ward approach for direct conjugation to the hydroxyl group of
HPMA. To demonstrate the versatility of the designed strategy,
It is well known that disulfides degrade in a fast rate in the cyto- HPMA–MTX was used in the preparation of core cross-linked
plasm because of the presence of reducing agents such as glu- star polymer in a RAFT process. It showed that the drug could
tathione. Therefore, the conjugation of drugs onto star polymers be directly polymerized without altering the integrity of the star
through disulfide linkages could be utilized to achieve the con- polymer. Because of the nature of direct polymerization of drug-
trol release of the interested cargo. Following the cell internali- conjugated monomers, the amount of drug in the star polymers
zation of the star polymer–drug conjugates and disassociation could be tuned by controlling the degree of polymerization of
of the star polymer core, the drug release should be followed by the drug–monomer. By choosing a proper cross-linker in the
efficient removal of the lower molecular weight star fragments core, the conjugated drugs in the star polymers could be more
from the body, which is expected to avoid the systemic toxic accu- susceptible to release under specific conditions.[205]
mulation problems. In one recent study, Davisand co-workers In addition to the attachment of drug molecules, Liu
designed star polymers with PEG grafts in the coronas and vinyl et al. recently reported a multi-biomolecule conjugation onto
benzaldehyde (VBA) in the cores.[169] Due to the presence of the β-CD-based star copolymers, including DOX, folic acid (FA),
aldehyde functional groups in the cores, doxorubicin was able to and gadolinium-tetraazacyclododecanetetraacetic acid (DOTA-
be conjugated via a pH-sensitive imine bond and the pay loads Gd) moieties for integrated cancer cell-targeted drug delivery
of the star polymers were adjustable and can be controlled by and magnetic resonance (MR) imaging contrast enhance-
manipulating the VBA composition in the cores. Interestingly, it ment (Figure 22).[206] During the synthesis, asymmetrically
showed that the imine bonds were easy to break at pH value of functionalized β-CD consisting of 7 azide functionalities and
5.5, which is comparable to the pH found in endosomes or lyso- 14 α-bromopropionate groups at the respective upper and
zomes in cells. Further biological evaluation revealed that the lower rims of the rigid toroidal β-CD core, (N3)7-CD-(Br)14, was
doxorubicin-conjugated star polymers had a level of cytotoxicity first prepared. The subsequent ATRP of HPMA, conjugated
Figure 21. Synthetic route of poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA) macro-chain-transfer agents and its copolymerization with HPMA–
MTX to prepare the drug-loaded star polymers. Reproduced with permission.[206] Copyright 2015, The Royal Society of Chemistry.
Figure 22. Schematic illustration for the fabrication of multifunctional micellar nanoparticles integrated with targeted drug delivery and magnetic
resonance (MR) imaging contrast enhancement functions from β-CD-based star copolymers, (DOTA-Gd)7–CD–(PHPMA–FA–DOX)14, covalently con-
jugated with doxorubicin (DOX), folic acid (FA), and DOTA-Gd (Gd) moieties, and pH-induced DOX release via the cleavage of acid-labile carbamate
linkages between DOX and HPMA arms. Reproduced with permission.[207] Copyright 2012, Elsevier B.V.
with DOX and FA, and click reaction with alkynyl-(DOTA-Gd) of multifunctional pH-disintegrable star polymers augurs well
complex afforded the (DOTA-Gd)7-CD-(PHPMA-FA-DOX)14 for potential applications in the field of image-guided cancer
star polymer. The resultant star polymers possess 7 DOTA-Gd chemotherapy.[206]
complex moieties and 14 PHPMA arms which are covalently
anchored with DOX and FA via acid-labile carbamate linkages
and ester bonds, respectively. In vitro drug release investiga- 7.3. In Vivo Studies of Star Polymers
tion showed a highly pH-dependent release of DOX. In a time
period of 42 h, the cumulative releases of DOX was 10%, 53%, Many of the earlier described work have evaluated the utility
and 89% conjugated DOX at pH 7.4, 5.0, and 4.0, respectively. of the polymers in vitro, investigation of these star polymers
Together with the targeting effect and enhanced T1 relaxivity, in vivo has been limited. The pharmacokinetics of a 64 kDa
the integrated design of diagnostic and therapeutic functions tritiated PEG-based star polymer after subcutaneous and
pulmonary administration in rats were evaluated.[207] Upon reaching the target site since the arms structure aggregates
administration subcutaneously, there was almost complete prevent the direct contact with the in vivo degradation mecha-
bioavailability of the polymers as well as a similar organ bio- nisms. Moreover, the polymer arms can be functionalized with
distribution profile to the polymer after intravenous admin- different chemical groups to influence the response behavior,
istration. From the results, it was noted that star polymers resulting in more controlled and targeted delivery of the drug
displayed similar pharmacokinetic behavior to PEGylated den- carried. The polymers can also be made to vary in terms of mor-
drimers. Another paper reports behavior of poly[(oligoethylene phology by the simple tweaking of arm lengths and chemical
glycol) acrylate] (POEGA) star polymers synthesized via a ver- compositions, making the synthesis of various star-shaped poly-
satile arm-first RAFT polymerization approach in vivo. Three mers easily achievable without raising the manufacturing cost.
different molecular weight (49, 64, and 94 kDa) POEGA star Finally, since star-shaped polymers are still in the nascent
polymers were assessed in rats and nude mice bearing human stages of development, and because of the sheer diversity of
MDA MB-231 tumors after intravenous administration.[208] The macromolecules that can take on the star architectures (which
largest star polymer showed a longer plasma exposure time is also made possible by the flexible synthesis and polymeriza-
than the smaller star polymers due to different polymer biodeg- tion techniques), many structure–property relationships have
radation and urinary excretion rates. Tumor biodistribution was yet to be fully established. Thus, it requires further explora-
greatest for the longest circulating 94 kDa star. Biodegradable tion into the potential influence of the number of arms, their
RAFT synthesized PDMAEMA stars was synthesized via chain lengths, the functionalities of the blocks, arms and cores, and
extended in the presence of N,N-bis(acryloyl)cystamine and their self-assembly and stimuli-responsive properties, and how
DMAEMA.[209] The star polymers were able to self-assemble these correlate to their loading capacities and drug release pro-
with siRNA and form small uniform nanoparticle complexes. files. The special architecture, together with the highly active
The star polymers appeared nontoxic to cells and treatment functional group density puts star-shaped polymers in the
with star polymer–siRNA complexes resulted in uptake of prime position to be utilized for future developments in drug
siRNA into cells as well as a significant decrease in target gene delivery.
mRNA and protein levels. In addition, delivery of clinically rele-
vant amounts of siRNA complexed to the star polymer silenced
target gene expression by 50% in an in vivo tumor setting. Conflict of Interest
RAFT synthesized star polymers were designed to contain dif-
ferent lengths of cationic PDMAEMA side arms and varied The authors declare no conflict of interest.
amounts of POEGMA.[210] The star-POEGMA polymers formed
polyplexes with siRNA. These polyplexes delivered siRNA
with to pancreatic cancer cells to silence a gene (TUBB3/βIII- Keywords
tubulin) which is currently undruggable using chemical agents, biomaterials, drug delivery, polymers
and is involved in regulating tumor growth and metastases. The
systemic administration of the polyplexes resulted in high accu-
Received: June 20, 2017
mulation of siRNA to orthotopic pancreatic tumors in mice and Revised: June 28, 2017
silenced βIII-tubulin expression by 80% at the gene and protein Published online:
levels in pancreatic tumors. The same group has also studied
the influence of the structure of star macromolecular ligands
on the relaxivity of gadolinium contrast agents constructed as
nanoparticle systems.[211] Further development could look at [1] J. L. Schultz, E. S. Wilks, J. Chem. Inf. Model. 1998, 38, 85.
the precise control of biological cues in a star polymer and trig- [2] S. Cosson, M. Danial, J. R. Saint-Amans, J. J. Cooper-White,
gered release and breakdown of such structures in an in vivo Macromol. Rapid Commun. 2017, 38, 1600780.
[3] F. Hild, N. T. Nguyen, E. Deng, J. Katrib, G. Dimitrakis, P. L. Lau,
system.[212]
D. J. Irvine, Macromol. Rapid Commun. 2016, 37, 1295.
[4] K. Ma, Z. S. An, Macromol. Rapid Commun. 2016, 37, 1593.
[5] R. d’Arcy, A. Gennari, R. Donno, N. Tirelli, Macromol. Rapid
8. Conclusion Commun. 2016, 37, 1918.
[6] E. Ye, X. J. Loh, Aust. J. Chem. 2013, 66, 997.
As mentioned earlier, the improvements in the techniques and [7] J. G. Tirrell, M. J. Fournier, T. L. Mason, D. A. Tirrel, Chem. Eng.
development of new methods for polymerization has been a News Arch. 1994, 72, 40.
great boon to the advancement of polymer engineering. One of [8] A. W. Jackson, D. A. Fulton, Polym. Chem. 2013, 4, 31.
the results of these developments is the introduction of complex [9] W. Xu, A. A. Steinschulte, F. A. Plamper, V. F. Korolovych,
star-shaped polymer architectures, which bring about a host V. V. Tsukruk, Chem. Mater. 2016, 28, 975.
[10] Y.-L. Wu, X. Chen, W. Wang, X. J. Loh, Macromol. Chem. Phys.
of unique properties and applications. Upon modulating the
2016, 217, 175.
starting materials compositions and conditions, these polymers [11] S. S. Liow, Q. Dou, D. Kai, A. A. Karim, K. Zhang, F. Xu, X. J. Loh,
are able to self-organize, leading to the formation of micellar ACS Biomater. Sci. Eng. 2016, 2, 295.
aggregates, nanoparticles, and core–shell structures with prop- [12] X. J. Loh, J. Appl. Polym. Sci. 2013, 127, 2046.
erties that are different from the linear versions of themselves. [13] X. J. Loh, J. Appl. Polym. Sci. 2013, 127, 992.
These self-assembled structures have the added advantage of [14] X. J. Loh, M.-H. Tsai, J. del Barrio, E. A. Appel, T.-C. Lee,
avoiding premature degradation by the host system before O. A. Scherman, Polym. Chem. 2012, 3, 3180.
[15] V. P. N. Nguyen, N. Kuo, X. J. Loh, Soft Matter 2011, 7, 2150. [48] S. Nagarajan, B. S. R. Reddy, J. Tsibouklis, Eur. Polym. J. 2012, 48,
[16] X. J. Loh, V. P. N. Nguyen, N. Kuo, J. Li, J. Mater. Chem. 2011, 21, 1357.
2246. [49] W. Tao, X. W. Zeng, T. Liu, Z. Y. Wang, Q. Q. Xiong, C. P. Ouyang,
[17] E. Ye, P. L. Chee, A. Prasad, X. Fang, C. Owh, V. J. J. Yeo, X. J. Loh, L. Q. Huang, L. Mei, Acta Biomater. 2013, 9, 8910.
Mater. Today 2014, 17, 194. [50] M. Jesberger, L. Barner, M. H. Stenzel, E. Malmstrom, T. P. Davis,
[18] X. An, A. Zhu, H. Luo, H. Ke, H. Chen, Y. Zhao, ACS Nano C. Barner-Kowollik, J. Polym. Sci., Part A: Polym. Chem. 2003, 41,
2016. 3847.
[19] Q. Yang, L. Li, W. Sun, Z. Zhou, Y. Huang, ACS Appl. Mater. Inter- [51] G. Kreutzer, C. Ternat, T. Q. Nguyen, C. J. G. Plummer,
faces 2016, 8, 13251. J. A. E. Manson, V. Castelletto, I. W. Hamley, F. Sun, S. S. Sheiko,
[20] W. Lin, N. Yao, H. Li, S. Hanson, W. Han, C. Wang, L. Zhang, Poly- A. Herrmann, L. Ouali, H. Sommer, W. Fieber, M. I. Velazco,
mers 2016, 8, 397. H. A. Klok, Macromolecules 2006, 39, 4507.
[21] X. Song, Y. Wen, J.-l. Zhu, F. Zhao, Z.-X. Zhang, J. Li, [52] X. J. Hao, C. Nilsson, M. Jesberger, M. H. Stenzel, E. Malmstrom,
Biomacromolecules 2016, 17, 3957. T. P. Davis, E. Ostmark, C. Barner-Kowollik, J. Polym. Sci., Part A:
[22] A. A. Hwang, J. Lu, F. Tamanoi, J. I. Zink, Small 2015, 11, 319. Polym. Chem. 2004, 42, 5877.
[23] S. S. Liow, Q. Dou, D. Kai, Z. Li, S. Sugiarto, C. Y. Yu, R. T. Kwok, [53] J. L. Hedrick, M. Trollsas, C. J. Hawker, B. Atthoff, H. Claesson,
X. Chen, Y. L. Wu, S. T. Ong, A. Kizhakeyil, N. K. Verma, B. Z. Tang, A. Heise, R. D. Miller, D. Mecerreyes, R. Jerome, P. Dubois,
X. J. Loh, Small 2017, 13, 1603404. Macromolecules 1998, 31, 8691.
[24] Z. Li, D. Yuan, G. Jin, B. H. Tan, C. He, ACS Appl. Mater. Interfaces [54] D. M. Haddleton, K. Ohno, Biomacromolecules 2000, 1, 152.
2016, 8, 1842. [55] M. H. Stenzel-Rosenbaum, T. P. Davis, V. K. Chen, A. G. Fane,
[25] Z. Li, E. Ye, David, R. Lakshminarayanan, X. J. Loh, Small 2016, 35, Macromolecules 2001, 34, 5433.
4782. [56] H. F. Gao, K. Matyjaszewski, Macromolecules 2008, 41, 1118.
[26] X. J. Loh, B. J. H. Yee, F. S. Chia, J. Biomed. Mater. Res., Part A [57] S. Angot, N. Ayres, S. A. F. Bon, D. M. Haddleton, Macromolecules
2012, 100, 2686. 2001, 34, 768.
[27] X. J. Loh, W. Guerin, S. M. Guillaume, J. Mater. Chem. 2012, 22, [58] L. Barner, C. Li, X. J. Hao, M. H. Stenzel, C. Barner-Kowollik,
21249. T. P. Davis, J. Polym. Sci., Part A: Polym. Chem. 2004, 42, 5067.
[28] A. C. Fonseca, A. C. Serra, J. F. J. Coelho, EPMA J. 2015, 6, 22. [59] S. Muthukrishnan, F. Plamper, H. Mori, A. H. E. Muller,
[29] Z. Tang, L. Zhang, Y. Wang, D. Li, Z. Zhong, S. Zhou, Acta Bio- Macromolecules 2005, 38, 10631.
mater. 2016, 42, 232. [60] K. Ohno, B. Wong, D. M. Haddleton, J. Polym. Sci., Part A: Polym.
[30] X. Zhou, Q. Zheng, C. Wang, J. Xu, J. Wu, T. B. Kirk, D. Ma, Chem. 2001, 39, 2206.
W. Xue, ACS Appl. Mater. Interfaces 2016, 8, 12609. [61] Q. Zhang, G. Z. Li, C. R. Becer, D. M. Haddleton, Chem. Commun.
[31] X. Fan, B. H. Tan, Z. Li, X. J. Loh, ACS Sustainable Chem. Eng. 2012, 48, 8063.
2017, 5, 1217. [62] J. L. Bender, P. S. Corbin, C. L. Fraser, D. H. Metcalf,
[32] Z. Li, B. H. Tan, T. Lin, C. He, Prog. Polym. Sci. 2016, 62, 22. F. S. Richardson, E. L. Thomas, A. M. Urbas, J. Am. Chem. Soc.
[33] Z. Li, X. J. Loh, Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol. 2002, 124, 8526.
2016, 9, e1429. [63] O. Altintas, A. P. Vogt, C. Barner-Kowollik, U. Tunca, Polym. Chem.
[34] X. D. Chi, X. F. Ji, L. Shao, F. H. Huang, Macromol. Rapid Commun. 2012, 3, 34.
2017, 38, 1600626. [64] J. Zhu, Y. Y. Liu, L. Q. Xiao, P. Zhou, Macromol. Chem. Phys. 2016,
[35] H. Henke, O. Bruggemann, I. Teasdale, Macromol. Rapid Commun. 217, 773.
2017, 38, 1600644. [65] W.-M. Wan, A. W. Baggett, F. Cheng, H. Lin, S.-Y. Liu, F. Jäkle,
[36] R. Aksakal, M. Resmini, C. Becer, Polym. Chem. 2016, 7, 171. Chem. Commun. 2016, 52, 13616.
[37] S. Kikuchi, Y. Chen, E. Ichinohe, K. Kitano, S.-i. Sato, Q. Duan, [66] F. Khelifa, S. Ershov, Y. Habibi, R. Snyders, P. Dubois, Chem. Rev.
X. Shen, T. Kakuchi, Macromolecules 2016, 49, 4828. 2016, 116, 3975.
[38] Y. Pan, P. Cai, M. Farmahini-Farahani, Y. Li, X. Hou, H. Xiao, Appl. [67] J. Merna, P. Vlček, V. Volkis, J. Michl, Chem. Rev. 2016, 116, 771.
Surf. Sci. 2016, 385, 333. [68] S. Beyazit, B. T. S. Bui, K. Haupt, C. Gonzato, Prog. Polym. Sci.
[39] Y. Azuma, T. Terashima, M. Sawamoto, Macromolecules 2017, 50, 2016, 62, 1.
587. [69] M. Semsarilar, S. Perrier, Nat. Chem. 2010, 2, 811.
[40] Y. X. Chen, Z. Y. Yang, C. Liu, C. W. Wang, S. X. Zhao, J. Yang, [70] J. Jennings, G. He, S. M. Howdle, P. B. Zetterlund, Chem. Soc. Rev.
H. F. Sun, Z. P. Zhang, D. L. Kong, C. X. Song, Int. J. Nanomed. 2016, 45, 5055.
2013, 8, 4315. [71] Z. Zhang, P. Zhang, Y. Wang, W. Zhang, Polym. Chem. 2016, 7, 3950.
[41] J. M. Ren, T. G. McKenzie, Q. Fu, E. H. Wong, J. Xu, Z. An, [72] Z. Li, D. Yuan, X. Fan, B. H. Tan, C. He, Langmuir 2015, 31, 2321.
S. Shanmugam, T. P. Davis, C. Boyer, G. G. Qiao, Chem. Rev. 2016, [73] U. U. Ozkose, C. Altinkok, O. Yilmaz, O. Alpturk, M. A. Tasdelen,
116, 6743. Eur. Polym. J. 2017, 88, 586.
[42] A. P. Narrainen, S. Pascual, D. M. Haddleton, J. Polym. Sci., Part [74] M. Bednarek, Prog. Polym. Sci. 2016, 58, 27.
A: Polym. Chem. 2002, 40, 439. [75] Z. Li, H. Yin, Z. Zhang, K. L. Liu, J. Li, Biomacromolecules 2012, 13,
[43] C. F. Huang, J. Aimi, K. Y. Lai, Macromol. Rapid Commun. 2017, 38, 3162.
1600607. [76] Z. Li, P. L. Chee, C. Owh, R. Lakshminarayanan, X. J. Loh, RSC
[44] X. Y. Zhang, D. M. Liu, X. H. Lv, M. Sun, X. L. Sun, W. M. Wan, Adv. 2016, 6, 28947.
Macromol. Rapid Commun. 2016, 37, 1735. [77] J. Collins, S. J. Wallis, A. Simula, M. R. Whittaker, M. P. McIntosh,
[45] D. Kuckling, A. Wycisk, J. Polym. Sci., Part A: Polym. Chem. 2013, P. Wilson, T. P. Davis, D. M. Haddleton, K. Kempe, Macromol.
51, 2980. Rapid Commun. 2017, 38, 1600534.
[46] G. R. J. Artus, S. Olveira, D. Patra, S. Seeger, Macromol. Rapid [78] M. Fantin, F. Lorandi, A. A. Isse, A. Gennaro, Macromol. Rapid
Commun. 2017, 38, 1600616. Commun. 2016, 37, 1318.
[47] H. Henke, S. Posch, O. Bruggemann, I. Teasdale, Macromol. Rapid [79] X. W. Jiang, L. F. Zhang, Z. P. Cheng, X. L. Zhu, Macromol. Rapid
Commun. 2016, 37, 769. Commun. 2016, 37, 1337.
[80] D. C. McLeod, N. V. Tsarevsky, Macromol. Rapid Commun. 2016, [114] N. Alkayal, H. Durmaz, U. Tunca, N. Hadjichristidis, Polym. Chem.
37, 1694. 2016, 7, 2986.
[81] Y. Sha, D. L. Qi, S. C. Luo, X. H. Sun, X. L. Wang, G. Xue, [115] C. J. Hawker, A. W. Bosman, E. Harth, Chem. Rev. 2001, 101,
D. S. Zhou, Macromol. Rapid Commun. 2017, 38, 1600568. 3661.
[82] K. E. Styan, C. D. Easton, L. G. Weaver, L. Meagher, Macromol. [116] S. Abrol, P. A. Kambouris, M. G. Looney, D. H. Solomon,
Rapid Commun. 2016, 37, 1079. Macromol. Rapid Commun. 1997, 18, 755.
[83] L. Wu, U. Glebe, A. Boker, Macromol. Rapid Commun. 2017, 38, [117] A. J. Pasquale, T. E. Long, J. Polym. Sci., Part A: Polym. Chem. 2001,
1600475. 39, 216.
[84] J. Xia, X. Zhang, K. Matyjaszewski, Macromolecules 1999, 32, 4482. [118] T. Tsoukatos, S. Pispas, N. Hadjichristidis, J. Polym. Sci., Part A:
[85] P. Chmielarz, S. Park, A. Sobkowiak, K. Matyjaszewski, Polymer Polym. Chem. 2001, 39, 320.
2016, 88, 36. [119] C.-H. Lu, J.-H. Wang, F.-C. Chang, S.-W. Kuo, Macromol. Chem.
[86] Y. M. Li, B. Xu, T. Bai, W. G. Liu, Biomaterials 2015, 55, 12. Phys. 2010, 211, 1339.
[87] X. J. Loh, Z.-X. Zhang, K. Y. Mya, Y.-l. Wu, C. B. He, J. Li, J. Mater. [120] R. J. I. Knoop, M. de Geus, G. J. M. Habraken, C. E. Koning,
Chem. 2010, 20, 10634. H. Menzel, A. Heise, Macromolecules 2010, 43, 4126.
[88] Y. Y. Yang, X. Wang, Y. Hu, H. Hu, D. C. Wu, F. J. Xu, ACS Appl. [121] Y. Satoh, K. Miyachi, H. Matsuno, T. Isono, K. Tajima, T. Kakuchi,
Mater. Interfaces 2014, 6, 1044. T. Satoh, Macromolecules 2016, 49, 499.
[89] L. N. Li, Y. Wang, F. Ji, Y. Wen, J. J. Li, B. G. Yang, F. L. Yao, J. Bio- [122] S. Cui, X. Pan, H. Gebru, X. Wang, J. Liu, J. Liu, Z. Li, K. Guo,
mater. Sci., Polym. Ed. 2014, 25, 1641. J. Mater. Chem. B 2017, 5, 679.
[90] X. H. Dai, Z. M. Wang, Y. F. Huang, J. M. Pan, Y. S. Yan, D. M. Liu, [123] Z. Li, J. Yang, X. J. Loh, NPG Asia Mater. 2016, 8, e265.
L. Sun, RSC Adv. 2014, 4, 42486. [124] Z. Li, B. H. Tan, Mater. Sci. Eng., C 2014, 45, 620.
[91] S. Li, H. S. Chung, A. Simakova, Z. Wang, S. Park, L. Fu, [125] J. T. Wiltshire, G. G. Qiao, Macromolecules 2006, 39, 4282.
D. Cohen-Karni, S. Averick, K. Matyjaszewski, Biomacromolecules [126] A. Mielanczyk, M. Skonieczna, K. Bernaczek, D. Neugebauer, RSC
2017, 18, 475. Adv. 2014, 4, 31904.
[92] H. Gao, K. Matyjaszewski, Macromol. Symp. 2010, 291–292, 12. [127] C. Yang, S. Q. Liu, S. Venkataraman, S. J. Gao, X. Y. Ke, X. T. Chia,
[93] K. Matyjaszewski, H. Dong, W. Jakubowski, J. Pietrasik, J. L. Hedrick, Y. Y. Yang, J. Controlled Release 2015, 208, 93.
A. Kusumo, Langmuir 2007, 23, 4528. [128] Z. Wu, H. Liang, J. Lu, Macromolecules 2010, 43, 5699.
[94] D. J. Keddie, Chem. Soc. Rev. 2014, 43, 496. [129] W. Zhang, W. Zhang, N. Zhou, J. Zhu, Z. Cheng, X. Zhu, J. Polym.
[95] H. T. Ho, M. Le Bohec, J. Fremaux, S. Pioge, N. Casse, L. Fontaine, Sci., Part A: Polym. Chem. 2009, 47, 6304.
S. Pascual, Macromol. Rapid Commun. 2017, 38, 1600641. [130] K. Ranganathan, R. Deng, R. K. Kainthan, C. Wu, D. E. Brooks,
[96] L. Peng, Z. Y. Li, X. H. Li, H. Xue, W. D. Zhang, G. J. Chen, J. N. Kizhakkedathu, Macromolecules 2008, 41, 4226.
Macromol. Rapid Commun. 2017, 38, 1600548. [131] J. Han, D. Zhu, C. Gao, Polym. Chem. 2013, 4, 542.
[97] W. T. Xue, J. Wang, M. Wen, G. J. Chen, W. D. Zhang, Macromol. [132] T. Isono, Y. Kondo, I. Otsuka, Y. Nishiyama, R. Borsali, T. Kakuchi,
Rapid Commun. 2017, 38, 1600733. T. Satoh, Macromolecules 2013, 46, 8509.
[98] C. Boyer, V. Bulmus, T. P. Davis, V. Ladmiral, J. Liu, S. Perrier, [133] M. Olvera de La Cruz, I. C. Sanchez, Macromolecules 1986, 19,
Chem. Rev. 2009, 109, 5402. 2501.
[99] R. T. Mayadunne, J. Jeffery, G. Moad, E. Rizzardo, Macromolecules [134] F. Wang, T. K. Bronich, A. V. Kabanov, R. D. Rauh, J. Roovers, Bio-
2003, 36, 1505. conjugate Chem. 2005, 16, 397.
[100] C. Zhang, Y. Zhou, Q. Liu, S. Li, S. B. Perrier, Y. Zhao, Macro [135] Z. Li, Z. Zhang, K. L. Liu, X. Ni, J. Li, Biomacromolecules 2012, 13,
molecules 2011, 44, 2034. 3977.
[101] T. G. Wright, W. Weber, H. Pfukwa, H. Pasch, Macromol. Chem. [136] Z. Li, B. H. Tan, G. Jin, K. Li, C. He, Polym. Chem. 2014, 5, 6740.
Phys. 2015, 216, 1562. [137] X. Fan, Z. Wang, D. Yuan, Y. Sun, Z. Li, C. He, Polym. Chem. 2014,
[102] Q. H. Zhou, J. Lin, L. D. Li, L. Shang, Colloid Polym. Sci. 2015, 293, 5, 4069.
2291. [138] C. Clasen, J. Plog, W.-M. Kulicke, M. Owens, C. Macosko,
[103] T. G. McKenzie, E. H. H. Wong, Q. Fu, A. Sulistio, D. E. Dunstan, L. Scriven, M. Verani, G. H. McKinley, J. Rheol. 2006, 50, 849.
G. G. Qiao, ACS Macro Lett. 2015, 4, 1012. [139] Y.-L. Zhao, Q. Cai, J. Jiang, X.-T. Shuai, J.-Z. Bei, C.-F. Chen, F. Xi,
[104] O. Garcia-Valdez, R. Ledezma-Rodriguez, R. Torres-Lubian, L. Yate, Polymer 2002, 43, 5819.
E. Saldivar-Guerra, R. F. Ziolo, Macromol. Chem. Phys. 2016, 217, [140] S. H. Lee, S. Hyun Kim, Y. K. Han, Y. H. Kim, J. Polym. Sci., Part A:
2099. Polym. Chem. 2001, 39, 973.
[105] N. B. Kannan, B. H. Lessard, Macromol. React. Eng. 2016, 10, [141] D. S. Pearson, E. Helfand, Macromolecules 1984, 17, 888.
600. [142] M. H. Xie, J. Ge, Y. M. Xue, Y. Z. Du, B. Lei, P. X. Ma, J. Mech.
[106] B. King, B. H. Lessard, Macromol. React. Eng. 2017, 11, 1600073. Behav. Biomed. Mater. 2015, 51, 163.
[107] D. D. Ozcam, F. Teymour, Macromol. React. Eng. 2017, 11, [143] Z. Ge, Y. Cai, J. Yin, Z. Zhu, J. Rao, S. Liu, Langmuir 2007, 23,
1600042. 1114.
[108] R. Schroot, T. Schlotthauer, M. Jager, U. S. Schubert, Macromol. [144] J. Wang, F. Zhang, W. P. Tsang, C. Wan, C. Wu, Biomaterials 2017,
Chem. Phys. 2017, 218, 1600534. 120, 11.
[109] Y. N. Zhou, Z. H. Luo, Macromol. React. Eng. 2016, 10, 516. [145] Z.-X. Zhang, K. L. Liu, J. Li, Angew. Chem., Int. Ed. 2013, 52,
[110] D. Le, T. N. Phan, L. Autissier, L. Charles, D. Gigmes, Polym. 6180.
Chem. 2016, 7, 1659. [146] A. A. Karim, Q. Dou, Z. Li, X. J. Loh, Chem. - Asian J. 2016, 11,
[111] T. Junkers, C. Barner-Kowollik, J. Lalevée, in RSC Polymer Chemistry 1300.
Series (Eds: D. Gigmes), Royal Society of Chemistry, London 2016. [147] X. Fan, J. Y. Chung, Y. X. Lim, Z. Li, X. J. Loh, ACS Appl. Mater.
[112] T. N. Phan, A. Ferrand, L. Liénafa, M. Rollet, S. Maria, R. Bouchet, Interfaces 2016, 8, 33351.
D. Gigmes, Polym. Chem. 2016, 7, 6901. [148] R. Satchi-Fainaro, R. Duncan, Polymer Therapeutics II: Polymers as
[113] A. Darabi, O. García-Valdez, P. Champagne, M. F. Cunningham, Drugs, Conjugates and Gene Delivery Sytems, Springer Science &
Macromol. React. Eng. 2016, 10, 82. Business Media, New York, USA 2006.
[149] K. Knop, D. Pretzel, A. Urbanek, T. Rudolph, D. H. Scharf, [184] W.-Q. Chen, H. Wei, S.-L. Li, J. Feng, J. Nie, X.-Z. Zhang,
A. Schallon, M. Wagner, S. Schubert, M. Kiehntopf, A. A. Brakhage, R.-X. Zhuo, Polymer 2008, 49, 3965.
F. H. Schacher, U. S. Schubert, Biomacromolecules 2013, 14, 2536. [185] H. J. Zhang, Q. Yan, Y. Kang, L. L. Zhou, H. Zhou, J. Y. Yuan,
[150] F. A. Plamper, H. Becker, M. Lanzendörfer, M. Patel, A. Wittemann, S. Z. Wu, Polymer 2012, 53, 3719.
M. Ballauff, A. H. Müller, Macromol. Chem. Phys. 2005, 206, 1813. [186] O. G. Schramm, M. A. Meier, R. Hoogenboom, H. P. van Erp,
[151] P. Alonso-Cristobal, M. Laurenti, F. J. Sanchez-Muniz, J.-F. Gohy, U. S. Schubert, Soft Matter 2009, 5, 1662.
E. Lopez-Cabarcos, J. Rubio-Retama, Polymer 2012, 53, 4569. [187] D. Kul, L. M. Van Renterghem, M. A. Meier, S. Strandman,
[152] T. Liu, W. Xue, B. Ke, M. Q. Xie, D. Ma, Biomaterials 2014, 35, H. Tenhu, S. S. Yilmaz, U. S. Schubert, F. E. Du Prez, J. Polym. Sci.,
3865. Part A: Polym. Chem. 2008, 46, 650.
[153] D. Ma, H. B. Zhang, Y. Y. Chen, J. T. Lin, L. M. Zhang, J. Colloid [188] L. A. Connal, Q. Li, J. F. Quinn, E. Tjipto, F. Caruso, G. G. Qiao,
Interface Sci. 2013, 405, 305. Macromolecules 2008, 41, 2620.
[154] P. J. Photos, L. Bacakova, B. Discher, F. S. Bates, D. E. Discher, [189] B.-S. Kim, H. Gao, A. A. Argun, K. Matyjaszewski, P. T. Hammond,
J. Controlled Release 2003, 90, 323. Macromolecules 2008, 42, 368.
[155] Y. Matsumura, H. Maeda, Cancer Res. 1986, 46, 6387. [190] M.-C. Jones, M. Ranger, J.-C. Leroux, Bioconjugate Chem. 2003, 14,
[156] J. Kamada, K. Koynov, C. Corten, A. Juhari, J. A. Yoon, M. W. Urban, 774.
A. C. Balazs, K. Matyjaszewski, Macromolecules 2010, 43, 4133. [191] O. Lidicky, O. Janouskova, J. Strohalm, M. Alam, P. Klener,
[157] H. Xu, J. Xu, X. Jiang, Z. Zhu, J. Rao, J. Yin, T. Wu, H. Liu, S. Liu, T. Etrych, Molecules 2015, 20, 19849.
Chem. Mater. 2007, 19, 2489. [192] X. Gao, B. L. Wang, X. W. Wei, W. Rao, F. Ai, F. Zhao, K. Men,
[158] X. Fan, Z. Li, X. J. Loh, Polym. Chem. 2016, 7, 5898. B. W. Yang, X. Y. Liu, M. J. Huang, M. L. Gou, Z. Y. Qian,
[159] R. S. Navath, B. Wang, S. Kannan, R. Romero, R. M. Kannan, N. Huang, Y. Q. Wei, Int. J. Nanomed. 2013, 8, 971.
J. Controlled Release 2010, 142, 447. [193] M. Byrne, P. D. Thornton, S.-A. Cryan, A. Heise, Polym. Chem.
[160] A. M. Alhoranta, J. K. Lehtinen, A. O. Urtti, S. J. Butcher, 2012, 3, 2825.
V. O. Aseyev, H. J. Tenhu, Biomacromolecules 2011, 12, 3213. [194] T.-B. Ren, Y. Feng, Z.-H. Zhang, L. Li, Y.-Y. Li, Soft Matter 2011, 7,
[161] S. Banskota, P. Yousefpour, A. Chilkoti, Macromol. Biosci. 2017, 17, 2329.
1600361. [195] D. Ma, Q. M. Lin, L. M. Zhang, Y. Y. Liang, W. Xue, Biomaterials
[162] M. Y. Liu, P. Gao, Q. Wan, F. J. Deng, Y. Wei, X. Y. Zhang, 2014, 35, 4357.
Macromol. Rapid Commun. 2017, 38, 1600575. [196] J. W. Snyder, W. R. Greco, D. A. Bellnier, L. Vaughan,
[163] A. Polomska, J. C. Leroux, D. Brambilla, Macromol. Biosci. 2017, B. W. Henderson, Cancer Res. 2003, 63, 8126.
17, 1600228. [197] X. H. Dai, Z. M. Wang, W. Liu, C. M. Dong, J. M. Pan, S. S. Yuan,
[164] T. Rhim, K. Y. Lee, Macromol. Res. 2016, 24, 577. Y. S. Yan, D. M. Liu, L. Sun, Colloid Polym. Sci. 2014, 292,
[165] R. Suntornnond, J. An, C. K. Chua, Macromol. Mater. Eng. 2017, 2111.
302, 1600266. [198] M. Gangopadhyay, T. Singh, K. K. Behara, S. Karwa, S. K. Ghosh,
[166] T. Thambi, V. H. G. Phan, D. S. Lee, Macromol. Rapid Commun. N. D. P. Singh, Photochem. Photobiol. Sci. 2015, 14, 1329.
2016, 37, 1881. [199] Y. Zhao, Macromolecules 2012, 45, 3647.
[167] O. Zagorodko, J. J. Arroyo-Crespo, V. J. Nebot, M. J. Vicent, [200] Y. Liu, X. Cao, M. Luo, Z. Le, W. Xu, J. Colloid Interface Sci. 2009,
Macromol. Biosci. 2017, 17, 1600316. 329, 244.
[168] P.-F. Gou, W.-P. Zhu, Z.-Q. Shen, Biomacromolecules 2010, 11, 934. [201] Y. Xue, D. F. Wei, A. N. Zheng, Y. Guan, H. N. Xiao, J. Macromol.
[169] J. Liu, H. Duong, M. R. Whittaker, T. P. Davis, C. Boyer, Macromol. Sci., Part A: Pure Appl. Chem. 2014, 51, 898.
Rapid Commun. 2012, 33, 760. [202] A. W. Jackson, D. A. Fulton, Chem. Commun. 2011, 47, 6807.
[170] H. Wei, X. Zhang, C. Cheng, S.-X. Cheng, R.-X. Zhuo, Biomaterials [203] A. Schmalz, M. Hanisch, H. Schmalz, A. H. E. Müller, Polymer
2007, 28, 99. 2010, 51, 1213.
[171] T. Ooya, J. Lee, K. Park, J. Controlled Release 2003, 93, 121. [204] W. L. Wang, L. Zhang, M. T. Liu, Y. Le, S. S. Lv, J. X. Wang,
[172] J. Cheng, J.-X. Ding, Y.-C. Wang, J. Wang, Polymer 2008, 49, 4784. J. F. Chen, RSC Adv. 2016, 6, 6368.
[173] J. Deng, N. Li, K. Mai, C. Yang, L. Yan, L.-M. Zhang, J. Mater. [205] B. S. Tucker, S. G. Getchell, M. R. Hill, B. S. Sumerlin, Polym.
Chem. 2011, 21, 5273. Chem. 2015, 6, 4258.
[174] X. Fan, S. Jiang, Z. Li, X. J. Loh, Mater. Sci. Eng., C 2017, 73, 275. [206] T. Liu, X. Li, Y. Qian, X. Hu, S. Liu, Biomaterials 2012, 33, 2521.
[175] B. Jeong, Y. K. Choi, Y. H. Bae, G. Zentner, S. W. Kim, J. Controlled [207] S. Y. Khor, J. Hu, V. M. McLeod, J. F. Quinn, C. J. H. Porter,
Release 1999, 62, 109. M. R. Whittaker, L. M. Kaminskas, T. P. Davis, J. Pharm. Sci. 2016,
[176] Z. Li, J. Li, J. Phys. Chem. B 2013, 117, 14763. 105, 293.
[177] B. H. Tan, J. K. Muiruri, Z. Li, C. He, ACS Sustainable Chem. Eng. [208] S. Y. Khor, J. Hu, V. M. McLeod, J. F. Quinn, M. Williamson,
2016, 4, 5370. C. J. H. Porter, M. R. Whittaker, L. M. Kaminskas, T. P. Davis,
[178] J. T. Wiltshire, G. G. Qiao, Macromolecules 2006, 39, 9018. Nanomedicine 2015, 11, 2099.
[179] L. Kilian, Z. H. Wang, T. E. Long, J. Polym. Sci., Part A: Polym. [209] C. Boyer, J. Teo, P. Phillips, R. B. Erlich, S. Sagnella, G. Sharbeen,
Chem. 2003, 41, 3083. T. Dwarte, H. T. T. Duong, D. Goldstein, T. P. Davis, M. Kavallaris,
[180] E. Themistou, C. S. Patrickios, Macromolecules 2004, 37, 6734. J. McCarroll, Mol. Pharmaceutics 2013, 10, 2435.
[181] H. Gao, N. V. Tsarevsky, K. Matyjaszewski, Macromolecules 2005, [210] J. Teo, J. A. McCarroll, C. Boyer, J. Youkhana, S. M. Sagnella,
38, 5995. H. T. T. Duong, J. Liu, G. Sharbeen, D. Goldstein, T. P. Davis,
[182] W. Wu, J. Liu, S. Cao, H. Tan, J. Li, F. Xu, X. Zhang, Int. J. Pharm. M. Kavallaris, P. A. Phillips, Biomacromolecules 2016, 17, 2337.
2011, 416, 104. [211] Y. Li, S. Laurent, L. Esser, L. V. Elst, R. N. Muller, A. B. Lowe,
[183] Y. Zhang, H. Liu, H. Dong, C. Li, S. Liu, J. Polym. Sci., Part A: C. Boyer, T. P. Davis, Polym. Chem. 2014, 5, 2592.
Polym. Chem. 2009, 47, 1636. [212] J. F. Quinn, M. R. Whittaker, T. P. Davis, Polym. Chem. 2017, 8, 97.

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REVIEW

Star Polymers www.mrc-journal.de

Nano-Star-Shaped Polymers for Drug Delivery Applications

heterogeneous star-shaped polymers.

Polymer, in general, has been one of the go-to classes of

number distribution is broader compared

3.2. “Core-First” Method

Other names for this approach are the “arm-

the star core potentially provides an avenue for postfunction-

4.3. Nitroxide-Mediated Free-Radical Polymerization (NMRP)

NMRP utilizes alkoxyamines as the initiators for polymeriza-

The double hydrophilic miktoarm amphi-

The combination of different polymerization techniques has also

Figure 7. Synthesis of miktoarm star amphiphilic block copolymers poly(styrene)–(poly(N-isopropylacrylamide)-4-vinylpyridine)2 (PS–(PNIPAAM-

where Ma is the molecular weight of the arm, Me is the mole

5.4. Self-Assembly Behavior in Solution

7.2.3. Enzyme-Responsive Star-Shaped Polymers

Byrne et al. synthesized well-defined star-shaped polypeptides

7.2.4. Reduction-Responsive Star-Shaped Polymers 7.2.5. Light-Responsive Star-Shaped Polymers

7.2.6. Dual-Responsive Star-Shaped Polymers

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Yang 2017

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Yang 2017

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REVIEW

Star Polymers www.mrc-journal.de

Nano-Star-Shaped Polymers for Drug Delivery Applications

heterogeneous star-shaped polymers.

Polymer, in general, has been one of the go-to classes of

number distribution is broader compared

3.2. “Core-First” Method

Other names for this approach are the “arm-

the star core potentially provides an avenue for postfunction-

4.3. Nitroxide-Mediated Free-Radical Polymerization (NMRP)

NMRP utilizes alkoxyamines as the initiators for polymeriza-

The double hydrophilic miktoarm amphi-

The combination of different polymerization techniques has also

Figure 7. Synthesis of miktoarm star amphiphilic block copolymers poly(styrene)–(poly(N-isopropylacrylamide)-4-vinylpyridine)2 (PS–(PNIPAAM-

where Ma is the molecular weight of the arm, Me is the mole­

5.4. Self-Assembly Behavior in Solution

7.2.3. Enzyme-Responsive Star-Shaped Polymers

Byrne et al. synthesized well-defined star-shaped polypeptides

7.2.4. Reduction-Responsive Star-Shaped Polymers 7.2.5. Light-Responsive Star-Shaped Polymers

7.2.6. Dual-Responsive Star-Shaped Polymers

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where Ma is the molecular weight of the arm, Me is the mole