Controlled Syntheses of Functional Polypeptides - ACS Symposium

Chapter 8

Controlled Syntheses of Functional Polypeptides

Downloaded by UNIV OF FLORIDA on October 26, 2017 | http://pubs.acs.org Publication Date (Web): October 25, 2017 | doi: 10.1021/bk-2017-1252.ch008

Zhongyu Jiang, Jinjin Chen, Jianxun Ding,* Xiuli Zhuang, and Xuesi Chen Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, People’s Republic of China *E-mail: [email protected]

Polypeptides are one of the most versatile biocompatible and biodegradable synthetic polymers. Nowadays, the functional polypeptides prepared by the ring-opening polymerization (ROP) of α-amino acid N-carboxyanhydrides (NCAs) have attracted increased attention, especially in the biomedical fields. In this chapter, the recent advances in the functional modifications of polypeptides were summarizes, and an overview on the various methods for the controlled syntheses of functional polypeptides was presented.

Introduction The synthetic polypeptides are fascinating materials with unique properties, including controllable molecular weight and polydispersity, biocompatibility, biodegradability, regular secondary structures (e.g., α-helix and β-sheet), and so on (1–4). As a result, polypeptides are one of the most potential synthetic polymers for biomedical applications (1, 5, 6), such as biomineralization (e.g., organic–inorganic composite materials for tissue engineering) and biotechnologies (e.g., drug and gene delivery and tissue engineering) (5, 7, 8). Since the first synthesis of the amino acid N-carboxyanhydride (AA NCA) monomers by Leuchs in 1906 (9), the interest in well-defined polypeptides synthesized by the ring-opening polymerizations (ROPs) of AA NCA monomers has increased significantly. However, due to the insolubility or pH-dependent solubility, and lack of tunable properties or functional groups, the further applications of some kinds of polypeptides are untapped (5, 10). In the past few decades, a series of functional © 2017 American Chemical Society Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


polypeptides were synthesized to overcome the above disadvantages and expand the application fields (4, 11, 12). For example, the introduction of PEG segment can improve the water solubility of polypeptides (13). The syntheses of functional polypeptides initiated by different macromolecules can form many kinds of functional polypeptides, which have many different three-dimensional (3D) topological structures, such as di and triblock, multi-armed, Y-sharped, core-shell star-shaped, and dendritic ones (14–19). The introduces of stimuli-responsive linkages can change the polypeptides to a “smart” polymer that can be used for intelligent drug delivery, gene transfection, and tissue engineering (20). The additions of functional segments to the side groups of polypeptides by ester exchange, condensation, “click” or aminolysis reactions, et al., endow polypeptides with hydrophilicity, responsiveness, and bioactivities (21–26). Benefiting from the above advantages, the functional polypeptides have been extensively applied in the biomedical fields and present excellent prospects (1–4). This chapter described the preparations of functional polypeptides from the following three aspects: (1) polymerizations initiated by functional macromolecules; (2) (co)polymerizations of functional monomers; (3) postpolymerization modifications. Moreover, the potential applications of these functional polypeptides in biomedical engineering were also introduced.

Initiations of AA Monomers with Functional Macroinitiators Various macromolecules with one or more amino groups have been used to initiate the ROP of AA NCA, which can synthesize different copolymers with polypeptides as segments (1). Firstly, as shown in Figure 1, the linear, Y-shaped, and even multi-armed polypeptides can be obtained through changing structures of the macroinitiators. Secondly, some different properties, such as amphiphilicity, stimuli-responsiveness, and thermosensitivity can be introduced to various polypeptides by adjusting the compositions of macroinitiators. The mostly used macroinitiators, such as amino-contained poly(ethylene glycol) (PEG), poly(ε-caprolactone) (PCL), and polyethylenimine (PEI), have been shown in Table 1. The amino-terminated methoxy poly(ethylene glycol) (mPEG) is widely used as a linear macroinitiator to synthesize functional polypeptides due to its hydrophily and biocompatibility. In Chen’s group, a biocompatible reduction-responsive block copolymers based on disulfide-linked mPEG and poly(N(ε)-benzyloxycarbonyl-L-lysine) (PZLL) were synthesized for antitumor drug delivery. The polymers formed into micelles in phosphate-buffered saline (PBS) at pH 7.4 by the direct dissolution and dialysis methods. The disulfide bonds can be reductively degraded in the presence of glutathione (GSH), so the micelles were proved to be reduction-responsive (18, 27, 28). The linear macroinitiators with two or multiple amino groups as initiation sites are also used to prepare functional polymers. For example, Lin et al. synthesized a positively charged thermo-sensitive hydrogel prepared from poloxamer–poly(L-alanine-co-L-lysine) (29). The polymer was synthesized by the ROP of L-alanine N-carboxyanhydride (LA NCA) and N(ε)-benzyloxycarbonyl-L-lysine N-carboxyanhydride (ZLL 150 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


NCA) sequentially through the two amino-terminated poloxamer, and it was a potential in situ injectable depot for drugs and/or growth factors. Compared with directly using the macroinitiators, the functional polymers can also be achieved by the combination of two step polymerization. For example, Lecommandoux and coworkers reported an approach to synthesize poly(trimethylene carbonate)-block-poly(γ-benzyl-L-glutamate) (PTMC-b-PBGA) and poly(ε-caprolactone)-block-poly(γ-benzyl-L-glutamate) (PCL-b-PBGA) via the sequential ROP of TMC or CL, and γ-benzyl-L-glutamate N-carboxyanhydride (BLG NCA) by an hydroxyl group- and protected amino group-contained initiator (30). The amino-terminal PTMC (PTMC-NH2) was synthesized through the ROP of TMC in tetrahydrofuran (THF) using 3-(t-Boc-amino)-1-propanol as an initiator and diethyl zinc as a catalyst, while the amino-terminal PCL (PCL-NH2) was synthesized in toluene. And then, the t-Boc group was removed by trifluoroacetic acid (TFA) using dichloromethane (CH2Cl2) as a solution. Finally, the PTMC-b-PBLG and PCL-b-PBLG diblock copolymers were synthesized by the ROP of BLG NCA and further deprotection to obtain well-defined linear degradable PTMC-b-PLG and PCL-b-PLG diblock copolymers. Jsco Jacobs et al. demonstrated the versatile synthesis of a novel polymer combining reversible addition-fragmentation chain transfer (RAFT) and NCA polymerization (11). Due to the incompatibility of amino groups used as the initiation sites and chain transfer agents (CTAs) for RAFT polymerization, a protected amine functionality was used to incorporate in the CTA for chain extension. As shown in Figure 2, they firstly prepared poly(n-butyl acrylate) (PBA), polystyrene (PS), and poly(N-isopropyl acrylamide) (PNIPAM) via RAFT polymerization, and then the phthalimide was removing by using nearly 30 molar equivalents of hydrazine for several hours. Finally, the three copolymers were successfully synthesized by the ROP of ZLL NCA. The key to successful approach was the end-group engineering strategy that can prevent the presence of amino and CTA groups, simultaneously. The combination of the two polymerizations could be used in synthesizing a wide range of polymers. The nonlinear macromolecules with one or several amino groups are also employed to initiate the ROP of AA NCA to derive star polypeptides. Jing and coworkers synthesized a novel Y-shaped poly(L-lactide)2−poly(γbenzyl-L-glutamate) (PLLA2−PBLG) copolymer by the ROP of BLG NCA with the amino-bearing polymer PLLA2-NH2 as a macroinitiator (17). The atom transfer radical polymerization (ATRP) reaction was used to synthesize alkynyl-poly(2-aminoethyl methacrylate) as a macroinitiator in Chen’s group (31). And then, the ROP of BLG NCA was used to synthesize alkynyl-PAMA-g-PLGA. The obtained copolymers could self-assemble into micelles or vesicles in PBS at pH 7.4, and doxorubicin (DOX), a model antitumor drug, was loaded into the nanoparticles. Adjusting the composition of comb copolymer and the pH of release medium could alter the release behaviors. Therefore, the pH-responsive copolymers were promising materials for cancer diagnosis and therapy. A lot of studies have paid attention to the inorganic nanoparticles based on the grafting of organic polymers onto the surface of the inorganic materials. As a typical instance, the hydroxyapatite (HAP, Ca10(PO4)6(OH)2) is widely used in the biomedical field due to its good biocompatibility (32). Shan and coworkers 151 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


let the HAP surface be modified by the addition of β-alanine, and then the novel inorganic−organic nanocomposite was successfully synthesized by the ROP of BLG NCA (33). Similarly, the silica nanoparticles can also be used to create a inorganic−organic hybrid materials (34).

Figure 1. Schematic illustration of topological structures of macroinitiators.

Figure 2. Synthesis of block copolymer combining RAFT and NCA polymerization (11). (Reproduced with permission from reference (11). Copyright 2013 John Wiley & Sons.)

Polymerizations or Copolymerizations of Functional Monomers Apart from the functionalization of macroinitiators, the functional polypeptides can also be synthesized through the ROP of functional NCA. As shown in Table 2, various AA NCA monomers have been designed and synthesized. The properties of synthetic polypeptides are markedly affected by the functional monomers, such as solubility, charge density, polarity, and stimuli-responsibility. The approach of “functionalization first and polymerization later” can ensure the completion of functionalizations of the side groups and broad their utility. 152 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Table 1. Chemical structures of macroinitiators for polypeptide syntheses.

Continued on next page.

153 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Table 1. (Continued). Chemical structures of macroinitiators for polypeptide syntheses.



Table 2. Chemical structures of functional AA monomers




Table 2. (Continued). Chemical structures of functional AA monomers




Table 2. (Continued). Chemical structures of functional AA monomers

The functional components used to modify the R groups of amino acids usually endow the final polymers with biomedical properties. As a typical example, Wu, Li, and coworkers synthesized the OEGi-functionalized PLGs (i = 1, 2, and 3) to improve hydrophilicity by using the ROP of modified LG NCAs with a narrow PDI (49–52). As shown in Figure 3, the thermo-responsive oligo(ethylene glycol)-functionalized poly(L-cysteine) was synthesized in Li’s group (53). The thiol−ene Michael addition was used between L-cysteine and monomethoxy oligo(ethylene glycol)-functionalized methacrylates or acrylates to synthesize a series of novel functional amino acids. They used triphosgene to convert the OEGylated cysteine derivatives into NCA monomers in THF. Subsequent ROP of the NCA could give a series of polypeptides. These polypeptides could display different secondary structures and solubility in water due to their different lengths of OEG side chains.



Figure 3. Synthetic routes toward poly-EGxMA-C (1c−4c) and poly-EGxA-C (5c−8c) homopolypeptides (53). (Adapted with permission from reference (53). Copyright 2013 American Chemical Society)

The stimuli-responsive groups can also be introduced to the polypeptides to construct some intelligent materials. The reduction-responsive methoxy poly(ethylene glycol)−poly(L-cystine-co-L-phenylalanine) (PEG−P(LC-co-LP)) nanogel with controllable performances was synthesized as a macroinitiator for targeting intracellular drug delivery in vivo (54). First of all, the L-cystine NCA was synthesized from (Z-Cys-OH)2 after the addition of thionyl chloride. And then, the copolymerization of Trt-His NCA and L-Cys NCA by using mPEG-NH2 as a macroinitiator lasted for 8 days. Finally, the received polymers were suspended in CH2Cl2, and the product could be collected after 1 h by adding TFA to remove the protect group. DOX was used as a model antitumor drug, and the drug would quickly release because of the high concentration of intracellular glutathione (~10.0 mM) (55). In Chen’s group, the pH-responsive poly(L-glutamic acid-co-L-Lysine) (P(LG-co-LL)) copolymers were synthesized (56). The carboxyl and amino groups presented on P(LG-co-LL) could be protonated or deprotonated to become charged, so that the pH of the solution and LG/LL ratio can affect the surface charges of P(LG-co-LL) aggregates. These indicated that the nanoparticles could be used for drug delivery. Furthermore, the reduction-responsive, or pH and reduction dual-responsive polypeptide nanogels could also be successfully synthesized in Chen’s group through the ROP of LC NCA and LP NCA, BLG NCA or ZLL NCA, and subsequent removing the protecting groups separately (18, 28, 57). Compared with directly using functional group to modify amino acid, the method that endows amino acid with reactive functional groups is more flexible. In particular, the “click chemistry” reaction is an efficient and convenient way to synthesize series of functional AA monomers. These clickable groups include vinyl, alkynyl, and azido groups could be easily decorated to the polypeptides for further modification. In particular, Xu et al. used a methacryloyl-substituted L-lysine N-carboxyanhydride (LysMA NCA) to prepared a series of methacryloly-functionalized polypeptides and copolypeptides through the ROP of the monomers (58). As shown in Figure 4, the click chemistry, including alkyne−azide reaction and thiol−ene reaction, was used for 158 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


post-polymerization functionalization of the polypeptides. This study presented a strategy for development of various functional polymers.

Figure 4. Synthesis of PLysMA-b-PPLG and sequential modification of PLysMA-b-PPLG through an orthogonal reaction (58). (Reproduced with permission from reference (58). Copyright 2015 Royal Society of Chemistry.)

Postpolymerization Modifications of Polypeptides As aforementioned, the method of modifying amino acids directly with a functional group is a common technique for preparing the functional polymers. Due to the highly reactive amino and carboxyl groups of amino acids, the side reactions may occur in the process of modifying the R groups. The undesired reaction leads to the formation of by-products, so that the yield of main product is reduced and difficult to be purified. Compared with the direct ROP of functional monomers, the post-modification of the polypeptides is a more convenient and efficient way to obtain the functionalized polypeptides. As shown in Table 3, the side groups (carboxyl, amino, and thiol groups) of the polypeptides can be modified by the functional molecules through the ester exchange reaction, condensation reaction, aminolysis reaction, and so on. 159 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Table 3. Chemical structures of polypeptides before and after postpolymerization modifications.




Table 3. (Continued). Chemical structures of polypeptides before and after postpolymerization modifications.









Ester exchange reaction with functional alcohols, such as allyl alcohol, propargyl alcohol, 2-chloroethanol, 3-chloropropan-1-ol, 2-azidoethanol, 3-azidopropan-1-ol, and even OEG has been widely used as a convenient approach to synthesize functional polypeptides (21, 94). Huang and coworkers synthesized the functional PBLGs by the ester exchange reactions between PBLG and functional alcohols in 1,2-dichloroethane by using p-toluenesulfonic acid (p-TSA) as a catalyst (Figure 5A) (21). As shown in Figure 5B, they successfully synthesized a series of functional PBLGs including partially alkylated PBLG (PBALG), propargylated PBLG (PBPLG), chlorinated PBLG (PBCLG), and azidized PBLG (PBN3LG). The functional groups on the copolymers were still active and could be further modified. The functional PBLGs could also form microspheres, which showed the potential application as the microcarriers. Condensation reaction, a common approach, in which two molecules combine to form a larger molecule and a small molecule (generally referred to as water molecule), was used to synthesize functional polypeptides. For instance, Lv et al. reported the synthesis of an amphiphilic methoxy poly(ethylene glycol)-block-poly(L-glutamic acid)-block-poly(L-lysine) triblock copolymer decorated with deoxycholate (mPEG-b-PLG-b-PLL/DOCA) (95). The triblock copolymer was used for the co-delivery of two antitumor drugs, DOX and paclitaxel (PTX). The different domains of copolymer performed different functions: PEG provided prolonged circulation, hydrophilic PLG was used to load DOX through electrostatic interaction, and PLL was modified by the hydrophobic deoxycholate as a reservoir for the lipophilic PTX. Li et al. synthesized a pH-sensitive drug delivery vector for co-delivery of antitumor siRNA and drugs (96). N,N-Diisopropylamino ethylamine (DIP) was modified by the condensation reaction between PLAsp and DIP, and DIP exhibited the proton-buffering properties in the pH range of 5.5 and 7.4, which was used to control the release of drugs. Kiick et al. synthesized a series of galactose-functionalized glycopolypeptides with various weight-average molecular weight (Mw) using the condensation reaction between PLG and N-(ε-aminocaproyl)-β-D-galactosylamine (97). 163 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 5. (A) Syntheses of functional PBLGs through ester exchange reaction, and (B) alkynal−azido and thiol−ene “click chemistry” reactions of functional PBLGs (21). (Reproduced with permission from reference (21). Copyright 2009 Elsevier.) Some functional amines can be used to modify the side groups by the aminolysis reaction. The functional amines including ethylenediamine (EDA), diethylenetriamine (DET), triethylenetetramine (TET), tetraethylenepentamine (TEP), dipropylene triamine (DPT), 1,5-diaminopentane (AP), 4-(3-aminopropyl)morpholine (MP), etc. (24, 98–101). For instance, series of functional PBLAs were prepared through the ROP by Kataoka and coworkers, and the diaminopentane was added to modify the side chain by the aminolysis reaction.

Conclusion In this chapter, the syntheses of functional polypeptides have been reviewed. There are three main approaches that are exploited to functionalize polypeptides: (1) initiating the AA NCAs with functional macromolecules; (2) (co)polymerizing 164 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

monomers with functional groups; (3) modifying the side groups of synthesized polypeptides. Despite various kinds of functional polypeptides have been successfully synthesized to meet the requirements of different applications, the polypeptides are still in their infancy compared with the natural proteins. The functional polypeptides are still not yet reached their full potential. Therefore, the researchers still need continue to explore the novel and innovative works.


Acknowledgments The authors gratefully acknowledge the financial support provided by the National Natural Science Foundation of China (Grant Nos. 51673190, 51303174, 51673187, and 51473165).

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

He, C. L.; Zhuang, X. L.; Tang, Z. H.; Tian, H. Y.; Chen, X. S. Adv. Healthcare Mater. 2012, 1, 48–78. Huang, J.; Heise, A. Chem. Soc. Rev. 2013, 42, 7373–7390. Deng, C.; Wu, J.; Cheng, R.; Meng, F.; Klok, H. A.; Zhong, Z. Prog. Polym. Sci. 2014, 39, 330–364. Lu, H.; Wang, J.; Song, Z.; Yin, L.; Zhang, Y.; Tang, H.; Tu, C.; Lin, Y.; Cheng, J. Chem. Commun. 2014, 50, 139–155. Ding, J.; Xiao, C.; Tang, Z.; Zhuang, X.; Chen, X. Macromol. Biosci. 2011, 11, 192–198. Tian, H.; Tang, Z.; Zhuang, X.; Chen, X.; Jing, X. Prog. Polym. Sci. 2012, 37, 237–280. Deming, T. J. Prog. Polym. Sci. 2007, 32, 858–875. Xu, X. H.; Li, Y. K.; Jian, Y. T.; Wang, G.; He, B.; Gu, Z. W. Acta Polym. Sin. 2012, 10, 1128–1135. Leuchs, H. Ber. Deut. Chem. Ges. 1906, 39, 857–861. Yu, M.; Nowak, A. P.; Deming, T. J.; Pochan, D. J. J. Am. Chem. Soc. 1999, 121, 12210–12211. Jacobs, J.; Gathergood, N.; Heise, A. Macromol. Rapid Commun. 2013, 34, 1325–1329. Zhou, J.; Chen, P.; Deng, C.; Meng, F.; Cheng, R.; Zhong, Z. Macromolecules 2013, 46, 6723–6730. Kwon, G.; Naito, M.; Yokoyama, M.; Okano, T.; Sakurai, Y.; Kataoka, K. Langmuir 1993, 9, 945–949. Ding, J.; Zhuang, X.; Xiao, C.; Cheng, Y.; Zhao, L.; He, C.; Tang, Z.; Chen, X. J. Mater. Chem. 2011, 21, 11383–11391. Tian, H.; Chen, X.; Lin, H.; Deng, C.; Zhang, P.; Wei, Y.; Jing, X. Chem., Eur. J. 2006, 12, 4305–4312. Tian, H.; Deng, C.; Lin, H.; Sun, J.; Deng, M.; Chen, X.; Jing, X. Biomaterials 2005, 26, 4209–4217. Sun, J.; Chen, X.; Guo, J.; Shi, Q.; Xie, Z.; Jing, X. Polymer 2009, 50, 455–461. 165 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


18. Ding, J.; Shi, F.; Xiao, C.; Lin, L.; Chen, L.; He, C.; Zhuang, X.; Chen, X. Polym. Chem. 2011, 2, 2857–2864. 19. Harada, A.; Nakanishi, K.; Ichimura, S.; Kojima, C.; Kono, K. J. Polym. Sci., Part A: Polym. Chem. 2009, 47, 1217–1223. 20. Kwon, G.; Suwa, S.; Yokoyama, M.; Okano, T.; Sakurai, Y.; Kataoka, K. J. Controlled Release 1994, 29, 17–23. 21. Guo, J.; Huang, Y.; Jing, X.; Chen, X. Polymer 2009, 50, 2847–2855. 22. Li, C. Adv. Drug Delivery Rev. 2002, 54, 695–713. 23. Engler, A. C.; Lee, H. i.; Hammond, P. T. Angew. Chem., Int. Ed. 2009, 48, 9334–9338. 24. Oana, H.; Kishimura, A.; Yonehara, K.; Yamasaki, Y.; Washizu, M.; Kataoka, K. Angew. Chem., Int. Ed. 2009, 48, 4613–4616. 25. Lee, S. J.; Min, K. H.; Lee, H. J.; Koo, A. N.; Rim, H. P.; Jeon, B. J.; Jeong, S. Y.; Heo, J. S.; Lee, S. C. Biomacromolecules 2011, 12, 1224–1233. 26. Zhao, X.; Poon, Z.; Engler, A. C.; Bonner, D. K.; Hammond, P. T. Biomacromolecules 2012, 13, 1315–1322. 27. Ding, J.; Chen, J.; Li, D.; Xiao, C.; Zhang, J.; He, C.; Zhuang, X.; Chen, X. J. Mater. Chem. B 2013, 1, 69–81. 28. Shi, F.; Ding, J.; Xiao, C.; Zhuang, X.; He, C.; Chen, L.; Chen, X. J. Mater. Chem. 2012, 22, 14168–14179. 29. Lin, J. Y.; Lai, P. L.; Lin, Y. K.; Peng, S.; Lee, L. Y.; Chen, C. N.; Chu, I. M. Polym. Chem. 2016, 7, 2976–2985. 30. Le Hellaye, M.; Fortin, N.; Guilloteau, J.; Soum, A.; Lecommandoux, S.; Guillaume, S. M. Biomacromolecules 2008, 9, 1924–1933. 31. Ding, J.; He, C.; Xiao, C.; Chen, J.; Zhuang, X.; Chen, X. Macromol. Res. 2012, 20, 292–301. 32. Wei, J.; Liu, A.; Chen, L.; Zhang, P.; Chen, X.; Jing, X.. Macromol. Biosci. 2009, 9, 631–638. 33. Shan, Y.; Qin, Y.; Chuan, Y.; Li, H.; Yuan, M. Molecules 2013, 18, 13979–13991. 34. Borase, T.; Iacono, M.; Ali, S. I.; Thornton, P. D.; Heise, A. Polym. Chem. 2012, 3, 1267–1275. 35. Harada, A.; Cammas, S.; Kataoka, K. Macromolecules 1996, 29, 6183–6188. 36. Schappacher, M.; Soum, A.; Guillaume, S. M. Biomacromolecules 2006, 7, 1373–1379. 37. Rong, G.; Deng, M.; Deng, C.; Tang, Z.; Piao, L.; Chen, X.; Jing, X. Biomacromolecules 2003, 4, 1800–1804. 38. Cho, C. S.; Cheon, J. B.; Jeong, Y. I.; Kim, I. S.; Kim, S. H.; Akaike, T. Macromol. Rapid Commun. 1997, 18, 361–369. 39. Deng, C.; Rong, G.; Tian, H.; Tang, Z.; Chen, X.; Jing, X. Polymer 2005, 46, 653–659. 40. Thambi, T.; Deepagan, V.; Yoo, C. K.; Park, J. H. Polymer 2011, 52, 4753–4759. 41. Floudas, G.; Papadopoulos, P.; Klok, H. A.; Vandermeulen, G.; RodriguezHernandez, J. Macromolecules 2003, 36, 3673–3683. 42. Cui, H.; Zhuang, X.; He, C.; Wei, Y.; Chen, X. Acta Biomater. 2015, 11, 183–190. 166 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


43. Ding, J.; Li, C.; Zhang, Y.; Xu, W.; Wang, J.; Chen, X. Acta Biomater. 2015, 11, 346–355. 44. He, X.; Fan, J.; Zhang, F.; Li, R.; Pollack, K. A.; Raymond, J. E.; Zou, J.; Wooley, K. L. J. Mater. Chem. B 2014, 2, 8123–8130. 45. Fu, X.; Shen, Y.; Ma, Y.; Fu, W.; Li, Z. Sci. China, Chem. 2015, 58, 1005–1012. 46. Chiang, P. R.; Lin, T. Y.; Tsai, H. C.; Chen, H. L.; Liu, S. Y.; Chen, F. R.; Hwang, Y. S.; Chu, I. M. Langmuir 2013, 29, 15981–15991. 47. Zhai, S.; Song, X.; Feng, C.; Jiang, X.; Li, Y.; Lu, G.; Huang, X. Polym. Chem. 2013, 4, 4134–4144. 48. Tian, H.; Xiong, W.; Wei, J.; Wang, Y.; Chen, X.; Jing, X.; Zhu, Q. Biomaterials 2007, 28, 2899–2907. 49. Xu, X.; Wu, G.; Zhang, J.; Wang, Y.; Fan, Y.; Ma, J. Acta Chim. Sin. 2008, 66, 1102–1106. 50. Chen, C.; Wang, Z.; Li, Z. Biomacromolecules 2011, 12, 2859–2863. 51. Zhang, S.; Li, Z. J. Polym. Sci., Part B: Polym. Phys. 2013, 51, 546–555. 52. Zhang, S.; Chen, C.; Li, Z. Chinese J. Polym. Sci. 2013, 31, 201–210. 53. Fu, X.; Shen, Y.; Fu, W.; Li, Z. Macromolecules 2013, 46, 3753–3760. 54. Liu, X.; Wang, J.; Xu, W.; Ding, J.; Shi, B.; Huang, K.; Zhuang, X.; Chen, X. Int. J. Nanomed. 2015, 10, 6587–6602. 55. Jing, T.; Fu, L.; Liu, L.; Yan, L. Polym. Chem. 2016, 7, 951–957. 56. Huang, Y.; Tang, Z.; Zhang, X.; Yu, H.; Sun, H.; Pang, X.; Chen, X. Biomacromolecules 2013, 14, 2023–2032. 57. Ding, J.; Shi, F.; Li, D.; Chen, L.; Zhuang, X.; Chen, X. Biomater. Sci. 2013, 1, 633–646. 58. Xu, Q.; He, C.; Xiao, C.; Yu, S.; Chen, X. Polym. Chem. 2015, 6, 1758–1767. 59. Yu, L.; Fu, W.; Li, Z. Soft Matter 2015, 11, 545–550. 60. Tang, H.; Zhang, D. Polym. Chem. 2011, 2, 1542–1551. 61. Poché, D. S.; Thibodeaux, S. J.; Rucker, V. C.; Warner, I. M.; Daly, W. H. Macromolecules 1997, 30, 8081–8084. 62. Zhang, Y.; Lu, H.; Lin, Y.; Cheng, J. Macromolecules 2011, 44, 6641–6644. 63. Lu, H.; Bai, Y.; Wang, J.; Gabrielson, N. P.; Wang, F.; Lin, Y.; Cheng, J. Macromolecules 2011, 44, 6237–6240. 64. Lu, H.; Wang, J.; Bai, Y.; Lang, J. W.; Liu, S.; Lin, Y.; Cheng, J. Nat. Commun. 2011, 2, 206. 65. Xiao, C.; Zhao, C.; He, P.; Tang, Z.; Chen, X.; Jing, X. Macromol. Rapid Commun. 2010, 31, 991–997. 66. Engler, A. C.; Shukla, A.; Puranam, S.; Buss, H. G.; Jreige, N.; Hammond, P. T. Biomacromolecules 2011, 12, 1666–1674. 67. Quadir, M. A.; Martin, M.; Hammond, P. T. Chem. Mater. 2013, 26, 461–476. 68. Ding, J.; Xiao, C.; Zhao, L.; Cheng, Y.; Ma, L.; Tang, Z.; Zhuang, X.; Chen, X. J. Polym. Sci., Part A: Polym. Chem. 2011, 49, 2665–2676. 69. Tang, H.; Li, Y.; Lahasky, S. H.; Sheiko, S. S.; Zhang, D. Macromolecules 2011, 44, 1491–1499. 70. Tang, H.; Zhang, D. Biomacromolecules 2010, 11, 1585–1592. 167 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


71. Yan, L.; Yang, L.; He, H.; Hu, X.; Xie, Z.; Huang, Y.; Jing, X. Polym. Chem. 2012, 3, 1300–1307. 72. Kadoma, Y.; Ueno, A.; Takeda, K.; Uno, K.; Iwakura, Y. J. Polym. Sci.: Polym. Lett. Ed. 1974, 12, 715–718. 73. Kadoma, Y.; Ueno, A.; Takeda, K.; Uno, K.; Iwakura, Y. J. Polym. Sci.: Polym. Chem. Ed. 1975, 13, 1545–1553. 74. Wang, J.; Gibson, M. I.; Barbey, R.; Xiao, S. J.; Klok, H. A. Macromol. Rapid Commun. 2009, 30, 845–850. 75. Kramer, J. R.; Deming, T. J. J. Am. Chem. Soc. 2010, 132, 15068–15071. 76. Pati, D.; Shaikh, A. Y.; Hotha, S.; Gupta, S. S. Polym. Chem. 2011, 2, 805–811. 77. Liu, Y.; Chen, P.; Li, Z. Macromol. Rapid Commun. 2012, 33, 287–295. 78. Hernández, J. R.; Klok, H. A. J. Polym. Sci., Part A: Polym. Chem. 2003, 41, 1167–1187. 79. Hwang, J.; Deming, T. J. Biomacromolecules 2001, 2, 17–21. 80. Aoi, K.; Tsutsumiuchi, K.; Okada, M. Macromolecules 1994, 27, 875–877. 81. Aoi, K.; Tsutsumiuchi, K.; Yamamoto, A.; Okada, M. Tetrahedron 1997, 53, 15415–15427. 82. Aoi, K.; Tsutsumiuchi, K.; Yamamoto, A.; Okada, M. Macromol. Rapid Commun. 1998, 19, 5–9. 83. Gibson, M. I.; Hunt, G. J.; Cameron, N. R. Org. Biomol. Chem. 2007, 5, 2756–2757. 84. Ohkawa, K.; Saitoh, A.; Yamamoto, H. Macromol. Rapid Commun. 1999, 20, 619–621. 85. Huang, K.; Shi, B.; Xu, W.; Ding, J.; Yang, Y.; Liu, H.; Zhuang, X.; Chen, X. Acta Biomater. 2015, 27, 179–193. 86. He, L.; Li, D.; Wang, Z.; Xu, W.; Wang, J.; Guo, H.; Wang, C.; Ding, J. Polymers 2016, 8, 36. 87. Hayashi, S.; Ohkawa, K.; Yamamoto, H. Macromol. Biosci. 2006, 6, 228–240. 88. Sun, J.; Schlaad, H. Macromolecules 2010, 43, 4445–4448. 89. Huang, J.; Habraken, G.; Audouin, F.; Heise, A. Macromolecules 2010, 43, 6050–6057. 90. Yu, M.; Deming, T. J. Macromolecules 1998, 31, 4739–4745. 91. Masuhara, H.; Tanaka, J. A.; Mataga, N.; Sisido, M.; Egusa, S.; Imanishi, Y. J. Phys. Chem. 1986, 90, 2791–2796. 92. Yasui, S.; Keiderling, T.; Sisido, M. Macromolecules 1987, 20, 2403–2406. 93. Bilalis, P.; Varlas, S.; Kiafa, A.; Velentzas, A.; Stravopodis, D.; Iatrou, H. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 1278–1288. 94. Tang, D.; Lin, J.; Lin, S.; Zhang, S.; Chen, T.; Tian, X. Macromol. Rapid Commun. 2004, 25, 1241–1246. 95. Lv, S.; Tang, Z.; Li, M.; Lin, J.; Song, W.; Liu, H.; Huang, Y.; Zhang, Y.; Chen, X. Biomaterials 2014, 35, 6118–6129. 96. Li, Z.; Li, J.; Huang, J.; Zhang, J.; Cheng, D.; Shuai, X. Macromol. Biosci. 2015, 15, 1497–1506. 97. Polizzotti, B. D.; Maheshwari, R.; Vinkenborg, J.; Kiick, K. L. Macromolecules 2007, 40, 7103–7110. 168 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


98. Fukushima, S.; Miyata, K.; Nishiyama, N.; Kanayama, N.; Yamasaki, Y.; Kataoka, K. J. Am. Chem. Soc. 2005, 127, 2810–2811. 99. Uchida, H.; Miyata, K.; Oba, M.; Ishii, T.; Suma, T.; Itaka, K.; Nishiyama, N.; Kataoka, K. J. Am. Chem. Soc. 2011, 133, 15524–15532. 100. Miyata, K.; Oba, M.; Nakanishi, M.; Fukushima, S.; Yamasaki, Y.; Koyama, H.; Nishiyama, N.; Kataoka, K. J. Am. Chem. Soc. 2008, 130, 16287–16294. 101. Takae, S.; Miyata, K.; Oba, M.; Ishii, T.; Nishiyama, N.; Itaka, K.; Yamasaki, Y.; Koyama, H.; Kataoka, K. J. Am. Chem. Soc. 2008, 130, 6001–6009. 102. Zhao, C.; He, P.; Xiao, C.; Gao, X.; Zhuang, X.; Chen, X. J. Appl. Polym. Sci. 2012, 123, 2923–2932. 103. Bai, Y.; Zhang, Z.; Zhang, A.; Chen, L.; He, C.; Zhuang, X.; Chen, X. Carbohydr. Polym. 2012, 89, 1207–1214. 104. Zhao, C.; He, P.; Xiao, C.; Gao, X.; Zhuang, X.; Chen, X. J. Colloid Interface Sci. 2011, 359, 436–442. 105. Cabral, H.; Nakanishi, M.; Kumagai, M.; Jang, W. D.; Nishiyama, N.; Kataoka, K. Pharmacol. Res. 2009, 26, 82–92. 106. Deng, C.; Tian, H.; Zhang, P.; Sun, J.; Chen, X.; Jing, X. Biomacromolecules 2006, 7, 590–596. 107. Li, C.; Ke, S.; Wu, Q. P.; Tansey, W.; Hunter, N.; Buchmiller, L. M.; Milas, L.; Charnsangavej, C.; Wallace, S. Clin. Cancer Res. 2000, 6, 2829–2834. 108. Svobodová, J.; Rypáček, F. Eur. Polym. J. 2012, 48, 183–190. 109. De Marre, A.; Soyez, H.; Schacht, E.; Pytela, J. Polymer 1994, 35, 2443–2446. 110. Yang, H. Y.; Jang, M.-S.; Gao, G. H.; Lee, J. H.; Lee, D. S. Polym. Chem. 2016, 7, 1813–1825. 111. Bae, Y.; Fukushima, S.; Harada, A.; Kataoka, K. Angew. Chem., Int. Ed. 2003, 115, 4788–4791. 112. Bae, Y.; Nishiyama, N.; Kataoka, K. Bioconjugate Chem. 2007, 18, 1131–1139. 113. Dong, W. F.; Kishimura, A.; Anraku, Y.; Chuanoi, S.; Kataoka, K. J. Am. Chem. Soc. 2009, 131, 3804–3805. 114. Lee, Y.; Fukushima, S.; Bae, Y.; Hiki, S.; Ishii, T.; Kataoka, K. J. Am. Chem. Soc. 2007, 129, 5362–5363. 115. Oba, M.; Aoyagi, K.; Miyata, K.; Matsumoto, Y.; Itaka, K.; Nishiyama, N.; Yamasaki, Y.; Koyama, H.; Kataoka, K. Mol. Pharm. 2008, 5, 1080–1092. 116. Wu, S.; Qi, R.; Kuang, H.; Wei, Y.; Jing, X.; Meng, F.; Huang, Y. ChemPlusChem 2013, 78, 175–184. 117. Yi, H.; Liu, P.; Sheng, N.; Gong, P.; Ma, Y.; Cai, L. Nanoscale 2016, 8, 5985–5995. 118. Zhang, Y. X.; Chen, Y. F.; Shen, X. Y.; Hu, J. J.; Jan, J. S. Polymer 2016, 86, 32–41. 119. Zhou, Z.; Shen, Y.; Tang, J.; Fan, M.; Van Kirk, E. A.; Murdoch, W. J.; Radosz, M. Adv. Funct. Mater. 2009, 19, 3580–3589. 169 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 1 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


120. Lu, K.; Cao, M.; Mao, W.; Sun, X.; Tang, J.; Shen, Y.; Sui, M. J. Mater. Chem. 2012, 22, 15804–15811. 121. Zhou, D.; Xiao, H.; Meng, F.; Li, X.; Li, Y.; Jing, X.; Huang, Y. Adv. Healthcare Mater. 2013, 2, 822–827. 122. Xu, N.; Du, F. S.; Li, Z. C. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 1889–1898. 123. Qi, R.; Wu, S.; Xiao, H.; Yan, L.; Li, W.; Hu, X.; Huang, Y.; Jing, X. J. Mater. Chem. 2012, 22, 18915–18922. 124. Cai, X.; Dong, C.; Dong, H.; Wang, G.; Pauletti, G. M.; Pan, X.; Wen, H.; Mehl, I.; Li, Y.; Shi, D. Biomacromolecules 2012, 13, 1024–1034. 125. Li, L. Y.; He, W. D.; Li, J.; Zhang, B. Y.; Pan, T. T.; Sun, X. L.; Ding, Z. L. Biomacromolecules 2010, 11, 1882–1890. 126. Suo, A.; Qian, J.; Zhang, Y.; Liu, R.; Xu, W.; Wang, H. Mater. Sci. Eng. C: Mater. Biol. Appl. 2016, 62, 564–573. 127. Habraken, G. J.; Koning, C. E.; Heuts, J. P.; Heise, A. Chem. Commun. 2009, 3612–3614.


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