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Aust. J. Chem. 2012, 65, 978–984 http://dx.doi.org/10.1071/CH12251
Peptide-Based Star Polymers: The Rising Star in Functional Polymers Adrian Sulistio,A Paul A. Gurr,A Anton Blencowe,A and Greg G. QiaoA,B A
Department of Chemical and Biomolecular Engineering, The University of Melbourne, Parkville, Vic. 3010, Australia. B Corresponding author. Email:
[email protected]
Peptide-based star polymers show great potential as the next-generation of functional polymers due to their structurerelated properties. The peptide component augments the polymer’s properties by introducing biocompatible and biodegradable segments, and enhancing their functionalities and structural ordering, which make peptide-based star polymers an attractive candidate in the field of nanomedicine. This article provides a brief summary of the recent developments of peptide-based star polymers synthesised from 2009 onwards. It is evident that the studies conducted so far have only started to uncover the true potential of what these polymers can achieve, and with continued research it is anticipated that peptide-based star polymers will be realised as versatile platforms applicable to broader fields of study, including drug delivery, tissue engineering, biocoatings, bioimaging, and self-directing templating agents. Manuscript received: 21 May 2012. Manuscript accepted: 2 July 2012. Published online: 30 July 2012.
Introduction Star polymers are a type of complex macromolecular architecture having three-dimensional (3D) globular structures where multiple linear ‘arms’ are connected to a central core.[1,2] They have long been studied for their unique properties, including low solution viscosities,[3,4] encapsulation capabilities,[1,2,5] large number of internal and peripheral functionalities, as well as enhanced and compartmentalized functionalities.[1,2,6–10] In the past two decades, advances in controlled polymerization techniques including nitroxide mediated polymerisation (NMP), atom transfer radical polymerisation (ATRP), reversible addition-fragmentation chain-transfer (RAFT) polymerisation, ring-opening metathesis polymerisation (ROMP), and ringopening polymerisation (ROP) have led to a rapid growth in the development of star polymers bearing a wide selection of functionalities. Previously, such development was hampered by the lack of available techniques (mainly anionic and cationic polymerisation) and their poor functional group tolerance.[1] The unique properties of star polymers coupled with their ease of synthesis have opened up a plethora of possible advanced materials applications, such as the formation of honeycomb films for membrane technologies,[11–15] homogeneous catalysts,[10,16] rheological modifiers,[3,4] and more recently, polymer therapeutics.[17–20] The increased interest in polymer therapeutics within the nanomedicine field, particularly in targeted drug delivery, drugeluting implants, (bio)imaging, and tissue regeneration presents a new challenge for polymer chemists. As a result of strict requirements imposed by regulatory agencies (e.g. European Medicines Agency (EMEA) and the U.S. Food and Drug Administration (FDA)) careful consideration must be given to the types of building blocks that are used to prepare biocompatible and biodegradable polymers targeted towards clinical Journal compilation Ó CSIRO 2012
applications. In general, polymers derived from synthetic building blocks do not satisfy one or both of these conditions and therefore, restricts progress in this field of research. In order to overcome these limitations, the search for new materials that have high functionalities, good processability and more importantly, are biologically benign have prompted polymer chemists to investigate the use of naturally occurring materials (e.g. amino acids) as building blocks to create hybrid polymeric systems with various macromolecular architectures. In this regard, the selection of amino acid building blocks and polypeptide structural features is a very important step forward, since many of these materials are already present in the body and are continually being created and destroyed. Furthermore, there is a wide selection of naturally occurring and synthetic amino acids bearing different side-chain functional groups, which provides a facile approach to introduce functionalities into the resulting macromolecular architectures, including star polymers.[21] However, some homopeptides (e.g. polyglutamine, polyalanine, and polyleucine) and peptides with specific sequences can act as signalling molecules or aggregate in vivo, resulting in the onset of neurodegenerative diseases such as Huntington’s, Alzheimer’s, and Parkinson’s disease.[22] Therefore, careful consideration should be given to the selection of amino acids, particular amino acid sequences, and the degree of polymerisation of peptides, particularly for in vivo applications where precise control of the amino acid composition and sequence in the macromolecular architectures is crucial. In order to control the composition, configuration, and morphology of complex polymeric systems synthesised from simple amino acid building blocks, a controlled polymerization strategy or peptide sequencing approach needs to be established. Although solid-phase peptide synthesis provides excellent structural control, it is not practical for the preparation of large www.publish.csiro.au/journals/ajc
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polypeptides (.100 residues) as a result of unavoidable deletions and truncations from incomplete deprotection and coupling steps.[23] Scale-up of the process is also time consuming and expensive. The seminal work of Deming describing the controlled ROP of amino acid N-carboxyanhydride (NCA) derivatives using transition metal catalysts[24] has been credited for the rapid development of peptide-based polymeric materials. This method is ideal for the large scale synthesis of peptides, however, affords no control over the specific amino acid sequence of peptides prepared from copolymerization of several different NCA derivatives. This work has also inspired others to develop controlled ROP systems for NCA derivatives. For example, the application of silazane derivatives[25,26] or primary O
(a)
R O HN O
Multifunctional initiator ≡ NH2
NCA monomer
(b)
End-functionalized Multifunctional Iinking agent peptide
O
(c)
O O
NH
O HN
O O
Macroinitiator ≡ NH2
di-NCA cross-linker
Scheme 1. Synthetic approaches for the preparation of peptide-based star polymers via (a) core-first (or grafting-from), (b) grafting-to, and (c) armfirst approaches, adapted from Blencowe et al.[1]
amine hydrochloride salts[27] as initiators, and high vacuum[28] or low temperature techniques,[29] which have laid the foundations to produce well defined peptide-based polymers having various architectures.[30,31] In recent years the renewed interest in well defined peptide architectures, brought about by the introduction of controlled NCA polymerisation methodologies, has led to extensive research in this field. Due to the large amount of literature available on this topic, this highlight article will only focus on the recent development of peptide containing star polymers synthesised via ROP of NCA derivatives, or a combination of ROP and other polymerization techniques, after 2009. For developments before 2009, the reader is referred to comprehensive reviews by Kricheldorf[30] and Hadjichristidis et al.[31] which provide summaries of the different polymeric architectures that have been synthesised from amino acid NCA derivatives. The star polymers discussed in this highlight article will be divided into two parts; hybrid star polymers composed of a combination of amino acid and synthetic building blocks, and peptide-based star polymers that are derived entirely from amino acid building blocks. There are three prevalent methods for constructing star polymers, namely the core-first (or grafting-from), grafting-to, and arm-first approaches; for a detailed description of each of these approaches the reader is referred to the recent review on star polymers by Blencowe et al.[1] With reference to the synthesis of peptide-based stars, the core-first approach involves the use of multifunctional amine initiators as the core, which can concurrently initiate the ROP of amino acid NCA derivatives to form several arms (Scheme 1a). The use of preformed peptides and multifunctional coupling agents to form stars can be categorized as a grafting-to approach, whereby the peptides form the arms and the coupling agent acts as the core (Scheme 1b). The arm-first approach on the other hand, involves the reaction of living macroinitiators (MI) (or macromonomers) with a multifunctional cross-linker to afford stars, whereby the former become the arms and the latter the core (Scheme 1c).[1] This type of star polymer is also referred to as a core cross-linked star (CCS) polymer or large-core star polymer in order to distinguish it from star polymers prepared via other approaches.[1,32–35] Table 1 provides a summary of the peptide-based star polymers that were synthesised via these
Table 1. Peptide-based star polymers synthesised via the core-first, grafting-to and arm-first approaches after 2009 Synthetic approach Core-first Core-first Core-first Grafting-to Grafting-to Arm-first Arm-first Arm-first Arm-first Arm-first
Arm compositionA
Core compositionB
Polymerization methodC
fD
Ref.
PS, PIP, PBLL PS, PBLL, PLLHCl, PLL(DS) PBLG PLGA, octadecane, cholesterol, POSS PBLG PZLL, PBLG PLL PEG-PLL PBLG PEG
N/A N/A PPO (Jeffamine) N/A Octafunctional POSS DVB PLC PLC PLC PBLG and PLC
Anionic and ROP Anionic and ROP ROP Thiol-alkyne chemistry Copper-click chemistry ROP, FRP, RAFT ROP ROP ROP ROP
3 3, 4 3 3 8 N/A 3–349 36 17–152 9700
41 42 43 46 47 48 49, 51 50 51 52
PS ¼ polystyrene; PIP ¼ polyisoprene; PBLL ¼ poly(tert-butoxycarbonyl-L-lysine); PLLHCl ¼ poly(L-lysine) hydrochloride; PLL(DS) ¼ poly-(L-lysine) dodecyl sulfate; PBLG ¼ poly(benzyl-L-glutamate); PLGA ¼ poly(L-glutamic acid); POSS ¼ polyhedral oligomeric silsesquioxane; PZLL ¼ poly(carboxybenzyloxy-L-lysine); PEG ¼ poly(ethylene glycol). B PPO ¼ poly(propylene oxide); DVB ¼ divinyl benzene; PLC ¼ poly(L-cystine). C ROP ¼ ring-opening polymerisation; FRP ¼ free radical polymerisation; RAFT ¼ reversible addition-fragmentation chain-transfer. D f is the average number of arms per star polymer. A
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(a) H N 4 HN
NH2 NH2
Deprotection
BLL NCA
PS-(NH2)2-PS
PS2-PBLL2
SDS
PS2-PLLHCI2
(b)
PS2-(PLL(DS))2
(c)
100 nm
(d)
100 nm
PS
50 nm
Fig. 1. (a) Synthesis of A2B2-type 4-armed star polymer consisting of PS (A) and poly(tert-butoxycarbonyl-L-lysine) (PBLL) (B), which was then deprotected to give poly(L-lysine) hydrochloride (PLLHCl) arms. Subsequent complexation with sodium dodecyl sulfate (SDS) gave poly-(L-lysine) dodecyl sulfate (PLL(DS)). TEM images and respective schematic illustration of packing of (b) PS2PBLL2, (c) PS2PLLHCl2, and (d) PS2(PLL(DS))2.[42] (Reproduced with permission from the ACS.)
approaches after 2009 and will be discussed in further detail in the subsequent sections. Peptide-Based Star Polymers via the Core-First Approach The majority of star-shaped polymers synthesised via the corefirst approach utilise 3, 4, or 6 amino-functionalized initiators to polymerize benzyl-L-glutamate or carboxybenzyloxy-L-lysine NCA derivatives.[36] In addition, Aoi et al.[37,38] and Applehans[39] have described the use of dendritic macroinitiators with the core-first approach to afford low polydispersity stars. A star polymer having an uncharacteristically high number of arms for the core-first approach was produced using a poly(trimethyleneimine) dendrimer as the macroinitiator to produce a 64-arm star of polysarcosine.[38] In more recent times further development of the core-first approach to synthesise hybrid stars has been reported. As a continuation of earlier studies,[40] Hadjichristidis and co-workers reported the self-assembly of ABC-type miktoarm star polymers consisting of two random coil-like arms of polystyrene (PS) and polyisoprene (PIP) coupled to an a-helical polypeptide, poly(tert-butoxycarbonyl-L-lysine) (PBLL).[41] These three arm stars were found to form smectic layers of rods (PBLL) and coils (PS and PIP) typical of rod-coil block copolymers. Secondary ordering of the hydrophobic coil layers resulted in an inner structure consisting of rectangular cylinders. In a subsequent paper, Junnila et al. deprotected A2B- and A2B2-type 3- and 4-armed star polymers consisting of PS (A) and PBLL (B) arms to form PS2-poly(L-lysine) hydrochloride (PS2PLLHCl) and PS2-PLLHCl2 stars, respectively (Fig. 1a).[42] TEM studies of the protected PS2PBLL and PS2PBLL2 stars revealed that the a-helical conformation of the polypeptide arms promoted lamellar self-assembly with the 4-armed star providing a more uniform packing of the a-helical polypeptide chains (Fig. 1b). Upon deprotection the PS2PLLHCl and PS2-PLLHCl2 stars formed micelles in a non-ordered lattice comprised of PLLHCl cores surrounded by PS chains (Fig. 1c). Complexation of the deprotected stars with sodium dodecyl sulfate (SDS) afford
supramolecular structures, which induced polypeptidesurfactant self-assembly to form b-sheets (Fig. 1d). Sa´nchez-Ferrer et al.[43] synthesised a series of rod-coil block copolymers via ROP of benzyl glutamate (BLG) NCA using a triamino poly(propylene oxide) (PPO) macroinitiator (Scheme 2). Four examples were given with 3-arm stars consisting of PPO cores and PBLG arms of varying arm and core molecular weights. Self-assembly studies revealed that control over the lamellar phase in this system was dependent on the degree of polymerization (DP) of the PBLG arms. Stars with more than 20 amino acid residues per arm led to a lamellar phase in which the a-helical peptide chains were closely packed into a hexagonal lattice. Peptide-Based Star Polymers via Grafting-to Approach For the grafting-to approach only one example has been published before 2009, which reported a combination of ATRP and ROP to form 3-armed stars with a PS-b-PBLG arm configuration.[44] Recent examples of stars prepared by the grafting-to approach have taken advantage of highly efficient coupling methods of peptide-polymer conjugation, including thiol-ene and conventional copper click chemistries.[45] Ray et al. reported the synthesis of A2B-type star-like polymers consisting of either octadecane, cholesterol, or polyhedral oligomeric silsesquioxane (POSS) groups coupled to an alkyne terminated PBLG via thiol-alkyne chemistry (Fig. 2).[46] Whereas the bulky POSS structure resulted in a 1 : 1 mixture of mono- and disubstituted products, the efficiency of the cholesterol coupling could not be conclusively determined due to the absence of clearly resolved peaks in the 1H NMR spectrum of the product. Furthermore, the lack of evidence for mono-substituted cholesterol and POSS products by 13C NMR appear to make determination of the coupling efficiency inconclusive. Despite being less like stars and more like end-group functionalized polypeptides, these polymers were shown to self-assemble in aqueous solutions to form vesicles (size dependent on pH) after deprotection of the benzyl protecting groups, which demonstrates the ability to
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NH2 O
y
O BnO
O
X
O
H2N
z NH2
HN O O
O
PBLG BLG NCA
Scheme 2. Synthesis of rod-coil block copolymers via ROP of benzyl glutamate NCA using a triamino poly(propylene oxide) (PPO) macroinitiator.[43]
OBn H2N O
N H
2
HN
(i) R-SH, hυ
R
(ii) TFA/HBr
R
PBLG
PLGA
O O
O
R’ BLG NCA O
H
R’
Si
H R
R’ Si O R’ Si O
O
O R’ Si O O Si R’ O O Si Si O
H
17
Octadecane (OD)
Si O
Cholesterol
R’
R’
Propylisobutyl POSS
3
Fig. 2. Synthesis of A2B-type star-like polymers consisting of octadecane, cholesterol, or POSS groups coupled to an alkyne terminated PBLG via thiol-alkyne chemistry, followed by deprotection to afford their PLGA derivatives.[46]
R R
BnO
Azido-alkyne copper click chemistry
HN O O
R Si O R Si O
O
O R Si O O Si R O O Si Si O R R
O H2N
O
Si
O Si O
Propargyl-PBLG
BLG NCA R
N3 O Si N3 O
Si
Scheme 3. Synthesis of 8-armed star polymer via azido-alkyne copper click chemistry between alkyl-terminated PBLG and an azido functionalized POSS derivative.[47]
efficiently produce bilayer assemblies with tailored hydrophobic core properties. These tailored properties could offer the ability to study membrane transport in various chemical/ physical environments as well as creating drug delivery vehicles with various release profiles.[46]
The grafting-to approach has also been utilised to prepare stars with POSS derivatives as the core.[47] Using click chemistry, alkyne terminated PBLG was coupled with an azido functionalized POSS derivative to afford 8-armed stars (Scheme 3). Wide-angle X-ray diffraction, 13C NMR spectroscopy, and
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(a) BnO
O
HN O O
Time of reaction 24 h 48 h 72 h 100 h 100 h
(b)
H 2N 4-Vinylbenzylamine
O
DVB
N H
FRP or RAFT
PBLG-styrene
BLG NCA Core cross-linked star polymer
12
16
20
24
Elution time [min]
Fig. 3. (a) Synthesis of CCS polymers using a combination of free radical polymerization (FRP) or RAFT between divinyl benzene (DVB) cross-linker and a styrenic terminated PBLG macromonomer. (b) Evolution of GPC RI chromatograms (–) during synthesis of CCS polymer via FRP and light scattering chromatogram (–) of final polymer.[48] (Reproduced with permission from Wiley.)
O
HN O O O Amino acid NCA
O
O
R1 TMSHN HMDS
NH
H N
O TMS
R1
O
S S
O HN
O (i) Cys NCA (CL)
O
(ii) Core functionalization ≡ (pyrene, propargyl, propyl amine)
R1 CBzNH(CH2)4 (Lys NCA) BnOOC(CH2)2 (Glu NCA)
O
n
MI
(iii) HBr/TFA
Scheme 4. Synthesis of amino acid-based CCS polymer via a one-pot, arm-first approach using protected lysine or glutamate NCA derivatives and hexamethyldisilazane (HMDS) as initiator.[49]
FT-IR analysis of the star revealed that the PBLG anchored onto the POSS core favoured a-helical conformation even at low DPs ($14), whereas the free PBLG normally adopts b-sheet configuration at this DP. It was hypothesised that the incorporation of the POSS moiety at the PBLG chain end leads to intramolecular hydrogen bonding between the POSS and PBLG units, which enhanced conformational stabilisation and constrained them in the a-helical secondary structure. Peptide-Based Star Polymers via the Arm-First Approach The synthesis of core cross-linked star polymers via the arm-first approach was investigated by Audouin et al.[48] using divinyl benzene as the cross-linker and a styrenic terminated PBLG macromonomer, prepared via ROP of benzyl glutamate NCA with an amino styrene initiator (Fig. 3a). Both RAFT polymerisation and conventional free-radical polymerisation (FRP) were employed to prepare stars with varying molecular weights, polydispersities, and yields (Fig. 3b). For FRP the star yield was found to vary between 43 and 73% depending on the conditions employed, whereas for RAFT polymerisation the yields were significantly lower and in some cases resulted in gelation, which was attributed to the lower extent of termination events for the controlled polymerisation technique. Although RAFT is used here, the cross-linking is not confined to the chain ends of the PBLG macromonomers. Removal of the benzyl protecting groups afforded water soluble PLGA CCS polymers that displayed pH responsive behaviour. Peptide-based CCS polymers composed entirely of amino acid building blocks were first developed by our group, and prepared via the arm-first approach in a one-pot strategy (Scheme 4). First, an amine initiator was added to a NCA monomer to generate a MI using metal free catalysis, that is then coupled together by the subsequent addition of a di-NCA
cross-linker to afford the desired star. The use of amino acids as both the monomer and cross-linker is considered to be advantageous in comparison to other synthetic hybrid materials as they are biocompatible and biodegradable by nature. These star polymers were composed of poly(L-lysine) (PLL) arms radiating from a poly(L-cystine) (PLC) core and could be core-functionalized via reaction with primary amines bearing different functional groups (e.g., pyrene, alkyne), ultimately yielding water soluble, biocompatible, and biodegradable star polymers with a hierarchy of functionalities spanning from the core, along the arms, to the periphery (Scheme 4).[49] The coreisolated moieties are accessible for further reaction as demonstrated by the click reaction of the alkyne core-functionalized stars with an azido pyrene derivative. Furthermore, the stars were capable of sequestering hydrophobic drugs, such as the anti-cancer drug pirarubicin, through physical interactions (e.g., p–p stacking) with the pyrene moieties isolated within the core.[49] As a result of the centrally located disulfide bond in the core building block, L-cystine, the stars can also be cleaved by reducing agents such as dithiothreitol, which mimics the action of naturally occurring reducing agents (e.g., glutathione). Since the arms of these stars are prepared via the ROP of NCA derivatives with functionalised amine initiators it is possible to prepare stars with functional peripheral groups that originate from the initiators. Thus, CCS polymers with PLL arms and PLC cores and peripheral allyl functionalities could be synthesised by simply using an allylamine initiator to prepare the linear MI (Fig. 4a).[50] The peripheral allyl groups allowed further functionalisation of the CCS polymers with thiol terminated poly(ethylene glycol) (PEG) via thiol-ene click chemistry. In addition, the other PEG terminus could be conjugated with folic acid to prepare stars with folic acid targeting moieties suitable for targeting cancer cells. In vitro studies with breast cancer cells revealed that the stars were non-toxic and that the
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O
(a) O
CbzHN 4
NHTMS
HN
O O O Lys NCA
H N
N n H CbzHN 4 O
PZLL
O NH
OTMS O
S
O
S
HN (i) O Cys NCA (CL) O (ii) Core functionalization ≡ (pyrene amine)
(iii) PEG-SH and Folic acid-PEG-SH (30%)
Thiol-ene click chemistry (iv) HBr/TFA
(b)
(c)
Fig. 4. (a) Synthesis of amino acid-based CCS polymer via a one-pot, arm-first approach using an allylamine initiator, which allows for further PEGylation via thiol-ene click chemistry. Confocal microscopy images of breast cancer cells incubated with (b) folic acid conjugated CCS polymers and (c) PEGylated CCS polymers without conjugated folic acid.[50] (Reproduced with permission from the ACS.)
(a)
(b) NH
O
S
O
S
MeO-PEG1900-NH2
HN Cys NCA
O O
O O
lll NH2
O BnO
HN BLG NCA
(c) 100 Cumulative release [%]
O
O
CCS polymer
Pure PBS PBS 10 mM GSH
80
60
40
20
0
0
O
20 40 60 80 100 120 140 160 180 200
Time [h]
Fig. 5. (a) Synthesis of CCS polymers (or nanogels) via ROP of cystine and benzyl glutamate NCA derivatives using MeOPEG1900-NH2 as a macroinitiator in a one-pot system. (b) TEM image of CCS polymer (scale bar is 280 nm). (c) Drug (indometacin) release profile of the CCS polymer in PBS and reducing media (0.01 mM glutathione).[52] (Reproduced with permission from Wiley.)
conjugated folic acid promotes higher accumulation of the CCS polymers within cancer cells (Fig. 4b) as compared with PEGylated CCS polymers without folic acid conjugated (Fig. 4c).[50] CCS polymers with PBLG arms and PLC cores have also been prepared by the same approach (Scheme 4) and subsequently arm-functionalised through reaction with hydrazine, which readily displaces the benzyl protecting groups to afford pendant hydrazide groups.[51] Such groups are particularly useful for attaching molecules via acid-labile hydrazone linkers. In addition, variation of the star-formation reaction parameters allowed the stars molecular weights, average number of arms, and core sizes to be tailored, providing access to a library of stars with selective loading capacities. Xing et al. synthesised CCS polymers using MeOPEG1900NH2 as a macroinitiator for ROP of equimolar amounts of cystine and benzyl glutamate NCA derivatives (Fig. 5a).[52] The resulting CCS polymers (or nanogels) were found to have 9700 PEG arms, with a molecular weight of ,4.2 107 Da (Fig. 5b). In vitro cytotoxicity studies of the nanogels incubated at various concentrations with HeLa cells for 72 h revealed a low cytotoxic response, which indicated their biocompatibility. The nanogels were subsequently used to encapsulate the hydrophobic drug indometacin within the large core via hydrophobic
interactions. The drug loading content and the drug loading efficiency were determined to be 20% and 40%, respectively. The release of the drugs was triggered by cleavage of the disulfide bonds within the core by glutathione and it was found that 100% of the encapsulated drugs were released after 200 h (Fig. 5c). Conclusion and Future Outlook There is significant potential for the development of hybrid and peptide-based star polymers as potential advanced materials in the nanomedical field, which importantly can be prepared via metal free catalysis. The incorporation of peptides into star polymers provides unique opportunities to augment their properties, increasing their applicability to new and exciting avenues of research. Thus far, the breadth of the study in this field has mainly focussed on preparing compositionally varied star polymers and studying their peptide directed self-assembly under a variety of conditions. It is only recently that peptidebased stars have been investigated as polymer therapeutics, and early results suggest that they are well tolerated by cells and possess good biocompatibility. The preferential accumulation within cancerous cells of peptide-based stars functionalised with targeting moieties also provides an indication of their possible
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application to drug delivery. However, given the limited number of studies conducted thus far it is unlikely that the true potential of hybrid stars and peptide-based polymers has been realised. Ultimately, in vivo studies need to be performed to further confirm their biocompatibility and to ensure that they do not cause undesired cell signalling or immune responses and/or genetic mutations, which may trigger gene-related diseases. Many of the naturally occurring amino acids, as well as physiologically benign non-natural amino acids, have yet to be explored as building blocks to make peptide-based architectures; application of these will undoubtedly expand the potential functionalities of the star polymers, which in turn creates a versatile platform with broad applicability, rather than a targeted program. Therefore, it is evident that peptide-star polymers have a bright future beyond nanomedicine, with advances anticipated throughout the fields of tissue engineering, biocoatings, bioimaging, and self-directing templating systems. References [1] A. Blencowe, J. F. Tan, T. K. Goh, G. G. Qiao, Polymer 2009, 50, 5. doi:10.1016/J.POLYMER.2008.09.049 [2] J. T. Wiltshire, G. G. Qiao, Aust. J. Chem. 2007, 60, 699. doi:10.1071/ CH07128 [3] A. K. Ho, P. A. Gurr, M. F. Mills, G. G. Qiao, Polymer 2005, 46, 6727. doi:10.1016/J.POLYMER.2005.06.049 [4] T. K. Goh, K. D. Coventry, A. Blencowe, G. G. Qiao, Polymer 2008, 49, 5095. doi:10.1016/J.POLYMER.2008.09.030 [5] C. Kojima, K. Kono, K. Maruyama, T. Takagishi, Bioconjug. Chem. 2000, 11, 910. doi:10.1021/BC0000583 [6] A. Blencowe, T. K. Goh, S. P. Best, G. G. Qiao, Polymer 2008, 49, 825. doi:10.1016/J.POLYMER.2008.01.001 [7] M. Spiniello, A. Blencowe, G. G. Qiao, J. Polym. Sci. Pol. Chem. 2008, 46, 2422. doi:10.1002/POLA.22576 [8] C. T. Adkins, E. Harth, Macromolecules 2008, 41, 3472. doi:10.1021/ MA800216V [9] H. Gao, K. Matyjaszewski, Macromolecules 2007, 40, 399. doi:10.1021/MA062640D [10] B. Helms, S. J. Guillaudeu, Y. Xie, M. McMurdo, C. J. Hawker, J. M. J. Fre´chet, Angew. Chem. Int. Ed. 2005, 44, 6384. doi:10.1002/ANIE. 200502095 [11] L. A. Connal, P. A. Gurr, G. G. Qiao, D. H. Solomon, J. Mater. Chem. 2005, 15, 1286. [12] L. A. Connal, R. Vestberg, P. A. Gurr, C. J. Hawker, G. G. Qiao, Langmuir 2008, 24, 556. doi:10.1021/LA702495P [13] L. A. Connal, Aust. J. Chem. 2007, 60, 794. doi:10.1071/CH07137 [14] L. A. Connal, G. G. Qiao, Adv. Mater. 2006, 18, 3024. doi:10.1002/ ADMA.200600982 [15] L. A. Connal, G. G. Qiao, Soft Matter 2007, 3, 837. doi:10.1039/ B700597K [16] T. Terashima, M. Kamigaito, K.-Y. Baek, T. Ando, M. Sawamoto, J. Am. Chem. Soc. 2003, 125, 5288. doi:10.1021/JA034973L [17] S. Seidlits, N. A. Peppas, Star Polymers and Dendrimers in Nanotechnology and Drug Delivery, in Nanotechnology in Therapeutics: Current Technology and Applications 2007, pp. 317–348 (Eds N. A. Peppas, J. Z. Hilt, J. B. Thomas) (Horizon Press: Norfolk, UK). [18] R. Duncan, Nat. Rev. Drug Discov. 2003, 2, 347. doi:10.1038/ NRD1088 [19] M. Liu, K. Kono, J. M. J. Fre´chet, J. Control. Release 2000, 65, 121. doi:10.1016/S0168-3659(99)00245-X [20] C. Kojima, K. Kono, K. Maruyama, T. Takagishi, Bioconjug. Chem. 2000, 11, 910. doi:10.1021/BC0000583 [21] H. Sun, F. Meng, A. A. Dias, M. Hendriks, J. Feijen, Z. Zhong, Biomacromolecules 2011, 12, 1937. doi:10.1021/BM200043U [22] C. L. van Eyk, C. J. McLeod, L. V. O’Keefe, R. I. Richards, Hum. Mol. Genet. 2012, 21, 536. doi:10.1093/HMG/DDR487
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