Biodegradable synthetic polymers: Preparation, functionalization and biomedical application

Progress in Polymer Science 37 (2012) 237–280

Contents lists available at ScienceDirect

Progress in Polymer Science journal homepage: www.elsevier.com/locate/ppolysci

Biodegradable synthetic polymers: Preparation, functionalization and biomedical application Huayu Tian, Zhaohui Tang, Xiuli Zhuang, Xuesi Chen ∗ , Xiabin Jing Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China

a r t i c l e

i n f o

Article history: Received 8 November 2009 Received in revised form 14 May 2011 Accepted 30 June 2011 Available online 18 July 2011 Keywords: Biodegradable Synthetic polymers Functionalization Biomedical application

a b s t r a c t Biodegradable polymers have been widely used and have greatly promoted the development of biomedical fields because of their biocompatibility and biodegradability. The development of biotechnology and medical technology has set higher requirements for biomedical materials. Novel biodegradable polymers with specific properties are in great demand. Biodegradable polymers can be classified as natural or synthetic polymers according to the source. Synthetic biodegradable polymers have found more versatile and diverse biomedical applications owing to their tailorable designs or modifications. This review presents a comprehensive introduction to various types of synthetic biodegradable polymers with reactive groups and bioactive groups, and further describes their structure, preparation procedures and properties. The focus is on advances in the past decade in functionalization and responsive strategies of biodegradable polymers and their biomedical applications. The possible future developments of the materials are also discussed. © 2011 Elsevier Ltd. All rights reserved.

∗ Corresponding author. Tel.: +86 431 85262112; fax: +86 431 85262112. E-mail address: [email protected] (X. Chen). Abbreviations: ADR, adriamycin; AP, 1,5-diamino pentane; APEG-DOX, polyacetal-doxorubicin; Apt, aptamers; AS-PNIPAM, amino-semitelechelic PNIPAM; ASGPR, asialoglycoprotein receptor; ATQD, N-(4-aminophenyl)-N -(4 -(3-triethoxysilyl-propyl-ureido) phenyl-1,4-quinonenediimine); ATRP, atom-transfer radical polymerization; BAA-NCA, ␥-benzyl aspartic acid N-carboxy-anhydride; BMPCL, ␥-(2-bromo-2-methyl propionyl)-␧-caprolactone; BECP, biodegradable electrically conducting polymer; BLA-NCA, benzyl-l-aspartate N-carboxyanhydride; BLG-NCA, ␥-benzyl l-glutamate N-carboxyanhydride; BTMC, 5-benzyloxy-trimethylene carbonate; CaB, cathepsin B; CaD, cathepsin D; CMMPL, ␣-chloromethyl-␣-methyl-␤-propionolactone; CPP, cell penetrating peptide; c(RGDfK)-PEG-b-P(Lys-MP), c(RGDfK)-poly(ethylene glycol)-b-poly[␧-(3-mercaptopropino nyl)-lysine]; CT, computerized axial tomography; DES, drug-eluting stents; DGBE, diethylene glycol bis(3-amino propyl) ether; DMSO, dimethyl sulfoxide; DOTA, designed macrocyclic 1,4,7,10tetraazacyclododecane-N,N ,N ,N  -tetraacetic acid; DOX, doxorubicin; DPT, dipropylene triamine; DTPA-Gd, diethylenetriaminepentaacetic acid Gd; Dtxl, docetaxel; EGFR, endothelial growth factor receptor; EPR, enhanced permeability and retention; FOL, folic acid; gal-PEG-b-PBLG, galactose-conjugated poly(ethylene glycol)-co-poly(␥-benzyl l-glutamate) block copolymer; Gd, gadolinium; GSH, glutathione; HEMA, 2-Hydroxyethylmethacrylate; HEMI, N-hydroxylethylmaleimide; HO-R1-OH, di-hydroxyl compounds; ICG, indocyanine green; IgG, immunoglobulin G; l-DOPA, l-3,4-dihydroxyphenyl-lalanine; LCST, lower critical solution temperature; LP-NCA, l-phenylalanine NCA; M-PCL, maleimido-terminated PCL; M-PLLA, maleimido-terminated PLLA; MAL-PEG-PCL, maleimide-terminated poly(ethylene glycol)-poly(␧-caprolactone); MBC, 5-methyl-5-benzyloxycarbonyl-1,3-dioxan-2-one; MBPEC, mono-4-methoxybenzylidene-pentaerythritol carbonate; MMP-2, matrix metalloprotease-2; MMPs, matrix metalloproteinases; Mn-SPIO, manganese doped superparamagnetic iron oxide; MP, 4-(3-aminopropyl) morpholine; MP-g-OEI, multi-armed poly(l-glutamic acid)-graft-oligoethylenimine; mPEG, poly(ethylene glycol) methyl ether; MRI, magnetic resonance imaging; NCA, N-carboxy-anhydride; NGF, neurotrophic growth factors; NHS, N-hydroxysuccinimide; NIPAM, N-isopropylacrylamide; NIR, near-infrared; NIRF, near-infrared fluorescent; NSCLC, non-small cell lung cancer; P(GA-co-BLG), poly[(l-glutamic acid)-co-(␥-benzyl l-glutamate)]; PAGA, poly(␥-(4-aminobutyl)-l-glycolic acid); PArg, polyarginine; PBALG, partially allylated PBLG; PBCLG, partially chlorinated PBLG; PBLG, poly(␥-benzyl-l-glutamate); PBN3 LG, partially azidized PBLG; PBPLG, partially propargylated PBLG; Ppy, polypyrrole; PCL, poly(␧-caprolactone); PCL-b-PBLG, poly(␧-caprolactone)-b-poly(␥-benzyl l-glutamate); PDI, polydispersity index; PEI, polyethylenimine; PEG, polyethylene glycol; PEG-b-PEI, poly(ethylene glycol)-b-polyethyleneimine; PEG-b-P(Glu-DP), poly(ethylene glycol)-bpoly(glutamic acid); PEG-b-P(LA-co-MCC/dtxel), poly(ethylene glycol)-block-poly(l-lactide-co-2-methyl-2-carboxyl-propylene carbonate/docetaxel; PEG-b-PLA-b-PLG, poly(ethyl glycol)-b-polylactide-b-poly(l-glutamic acid); PEG-P(Asp-Hyd), poly(ethylene glycol)-b-poly(aspartate-hydra zone); PEGP(Asp-Hyd-ADR), poly(ethylene glycol)-b-poly(aspartate-hydrazone-adriamycin); PEG-PBLA, poly(ethylene glycol)-poly(␥-benzyl-l-aspartate); PEGnLSer, mono- and diethyleneglycol modified PLSer; PET, positron emission tomography; PGS, planar gamma scintigraphy; PHB, poly[(R)-3-hydroxybutyrate]; 0079-6700/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.progpolymsci.2011.06.004

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Contents 1. 2.

3.

4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biopolymers with reactive groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Aliphatic polyesters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Aliphatic polyesters with carboxyl groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Aliphatic polyesters with amino groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Aliphatic polyesters with chloride groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4. Aliphatic polyesters with keto or hydroxyl groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.5. Aliphatic polyesters with bromide groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.6. Aliphatic polyesters with C C groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.7. Aliphatic polyesters with reactive groups by copolymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Polycarbonate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Poly(amino acids) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Poly(acidic amino acids) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. Poly(basic amino acid) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.3. Poly(neutral amino acid) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Polyphosphoesters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biopolymers with responsive activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Stimuli-responsive biopolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Temperature responsive . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. pH-responsive biopolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. Photo responsive biopolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4. Redox responsive biopolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Electroactive biomaterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Specific bonding biopolymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Biopolymers for tracing and bioimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.1. Biopolymers for optical tracing and bioimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.2. Biopolymers for MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4.3. Other biopolymer-based tracing and bioimaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biomedical application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Medical devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.1. Drug-eluting stents (DES) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Orthopedic devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.3. Disposable medical devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.4. Other medical devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Tissue engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Drug delivery and control release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Gene delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.1. Poly(l-lysine)-based degradable polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.2. Poly(␤-amino ester)s-based degradable polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.3. Polyphosphoester-based degradable polymers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.4. Polyethylenimine modified with degradable polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.5. Degradable polymers in siRNA delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4.6. Other degradable polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Bioseparation and diagnostics applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

239 239 239 239 239 239 240 240 240 240 241 246 246 250 252 252 254 254 254 255 255 256 257 258 259 262 262 265 266 266 266 266 267 267 267 267 268 269 269 269 270 270 271 271 271 272 272 272

PHF-b-PEG, poly[(l-histidine)-co-(l-phenylalanine)]-block-poly(ethylene glycol); PLA, poly(lactic acid), polylactide; PLC-b-PLA, poly(l-cysteine)b-polylactide; PLCys, poly(l-cysteine); PLCys-b-PLLA, poly(l-cysteine)-b-poly(l-lactide); PLDOPA, poly(l-DOPA); PLDOPA-PLL, poly(l-DOPA)-copoly(l-lysine); PLGA, poly(lactide-co-glycolide); PLHis, poly(l-histidine); PLL, poly(l-lysine); PLL-b-PPA, poly(l-lysine)-block-poly(l-phenylalanine); PLL-co-PArg-b-PLLeu, poly(l-lysine)-co-polyarginine-b-poly(l-leucine); PLL-g-PCL, poly(l-lysine)-g-poly(␧-caprolactone); PLL-g-PEG, poly(l-lysine)-gpoly(ethylene glycol); PLL-g-PLLA, poly(l-lysine)-g-poly(l-lactide); PLLA, poly(l-lactide); PLSer, poly(l-serine); PMDETA, pentamethyldiethylene-triamine; PNIPAM, poly(N-isopropylacrylamide); PNIPAM-b-(HEMA-PCL), poly(N-isopropylacrylamide)-b-[2-hydroxyethyl methacrylate-poly(␧-caprolactone)]; PNIPAM-b-PGA, poly(N-isopropylacrylamide)-block-poly(glutamic acid); PNIPAM-b-P(GA-co-BLG), PNIPAM-b-poly[(l-glutamic acid)-co-(␥-benzyl-lglutamate)]; PPA, polyphosphoramidate; PPE, polyphosphoester; PPE-EA, poly(2-aminoethyl propylene phosphate); PPZ, polyphosphazene; PS 2, performance status; PSI, polysuccinimide; PTMC-b-PBLG, poly(trimethylene carbonate)-b-poly(␥-benzyl l-glutamate); p-TSA, p-toluenesulfonic acid; PZLL-PDGBE-PZLL, poly(␧-benzyloxycarbonyl l-lysine)-block-poly[diethylene glycol bis(3-amino propyl) ether]-block-poly(␧-benzyloxycarbonyl l-lysine); QDs, quantum dots; QD-strep, quantum dot-streptavidin; RGD, arginine-glycine-aspartic acid; ROP, ring-opening polymerization; SCL, shell crosslinked; siRNA, small interfering RNA; Sn(OTf)2 , trifluoromethane sulfonate; SPDP, N-succinimidyl 3-(2-pyridyldithio)-propionate; SPIO, superparamagnetic iron oxide; SPECT, single photon emission computed tomography; Sr-PO, amino isopropoxyl strontium; TMBPEC, 6-trimethoxybenzy-lidenepentaerythritol carbonate; TSP50, testis-specific protease 50; VEGF, vascular endothelial growth factor; Z2 Arg-NCA, di-N-benzyloxycarbonyl-l-arginine N-carboxyanhydride; ZLCys-NCA, ␤-benzyloxycarbonyl-l-cysteine N-carboxyanhydride1 .

H. Tian et al. / Progress in Polymer Science 37 (2012) 237–280

1. Introduction A biomaterial can be defined as a material intended to interface with biological systems to evaluate, treat, augment or replace any tissue, organ or function of the body [1]. Biomaterials play an important role in human health. Biopolymers are the main type of biomaterials. According to their degradation properties, biopolymers can be further classified into biodegradable and non-biodegradable biopolymers. Many implants, such as bone substitution materials, some bone fixing materials, and dental materials, should possess long term stable performance in the body. In recent years, developments in tissue engineering, regenerative medicine, gene therapy, and controlled drug delivery have promoted the need of new properties of biomaterials with biodegradability. Biologically derived and synthetic biodegradable biopolymers have attracted considerable attention [1]. Polysaccharides and protein are typical biologically derived biopolymers, while aliphatic polyesters and polyphosphoester (PPE) are typical synthetic biopolymers. Biopolymers with diverse specific properties are needed for in vivo applications because of the diversity and complexity of in vivo environments. Nowadays, synthetic biopolymers have become attractive alternatives for biomedical applications for the following reasons: (1) although most biologically derived biodegradable polymers possess good biocompatibility, some may trigger an immune response in the human body, possibly one that could be avoided by the use of an appropriate synthetic biopolymer; (2) chemical modifications to biologically derived biodegradable polymers are difficult; (3) chemical modifications likely cause the alteration of the bulk properties of biologically derived biodegradable polymers. A variety of properties can be obtained and further modifications are possible with properly designed synthetic biopolymers wihout altering the bulk properties. Specific properties are sometimes required for biomaterials. For example, tissue engineering scaffolds should have both good biocompatibility and cell adhesive properties, in addition to needed biodegradable properties. Drug delivery systems should be endowed with stimuli-responsive properties for intelligent-control release. Functionalization is inevitable to improve the properties of traditional synthetic biopolymers. There are two commonly used functionalization strategies: (1) functional groups are introduced to the monomers of polymers, sometimes in a protected form before polymerization, to be deprotected after polymerization; (2) functional groups are introduced to polymer chains by further chemical modification of the as-prepared polymers. This review is focused on recent progress of different strategies of functionalization of synthetic biodegradable polymers and the applications of these. 2. Biopolymers with reactive groups

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copolymers, have been widely investigated for biomedical application because of their biodegradability, bioresorbability, and biocompatibility. Aliphatic polyesters with reactive groups have attracted attention because of the demand of synthetic biopolymers with tunable properties, including features such as hydrophilicity, biodegradation rates, bioadhesion, drug/targeting moiety attachment, etc. [2]. In particular, polymeric biomaterials with properties that can be tailored by introducing functional groups, such as carboxyl, hydroxyl, amino, ketal, bromo, chloro, carbon–carbon double bonds or triple bonds, etc., are needed. Aliphatic polyesters with reactive groups can be prepared by the homopolymerization or copolymerization of cyclic monomers bearing protected functional groups (Fig. 1). Representative examples of the monomers and the polymers are shown in Table 1. 2.1.1. Aliphatic polyesters with carboxyl groups Aliphatic polyesters with pendant carboxyl groups can be prepared by the ring-opening polymerization (ROP) of cyclic esters bearing benzyl-protected carboxyl groups. Ouchi and Fujino prepared poly(␣-malic acid) as a carboxyl functional analogy of PLA by the ROP of malide dibenzyl ester followed by acid deprotection [3]. Kimura et al. first reported the synthesis of poly[(␣-malic acid)-alt(glycolic acid)], a glycolide-based poly(ester) with pendant carboxylic acid, by the ROP of 3(S)-[(benzyloxycarbonyl)methyl]-1,4-dioxane-2,5-dione followed by debenzylation. These aliphatic copolyesters are hydrolyzed more rapidly than PLA [4]. Weck and coworkers prepared sidechain-functionalized lactide analogues from commercially available amino acids. The resulting functionalized cyclic monomers can be homopolymerized and copolymerized with lactides and then quantitatively deprotected, forming functional PLA-based materials with amino, hydroxyl or carboxyl side chains [5]. Guerin et al. reported the synthesis and polymerization of benzyl malolactonate [14]. The benzyl protecting groups could be readily removed by catalytic hydrogenolysis to give poly(␤-malic acid). He et al. reported the synthesis of poly(l-lactide-co␤-malic acid) with a high molecular weight by the copolymerization of l-lactide and benzyl malolactonate [15]. PCLs with pendant carboxylic acid groups were prepared by Hedrick and coworkers via the ROP of benzyl ␥-(␧-caprolactone)carboxylate or tert-butyl-␥-(␧caprolactone)carboxylate followed by acid deprotection [6] (Fig. 2). 2.1.2. Aliphatic polyesters with amino groups Hedrick and coworkers synthesized amino-functionalized PCL by the ROP of 4-trifluoroacetyl7-oxo-1,4-oxazaperhydroepine followed by the deprotection with NaBH4 [6]. Fiétier et al. reported the preparation of an aliphatic polyester bearing lateral amino groups by the ROP of N-tritylated serine ␤-lactones [16].

2.1. Aliphatic polyesters Aliphatic polyesters, such as poly(lactic acid) (PLA), poly(glycolic acid), poly(␧-caprolactone) (PCL) and their

2.1.3. Aliphatic polyesters with chloride groups Liu and coworkers synthesized a chloro-substituted four-membered lactone, ␣-chloromethyl-␣-methyl-␤-

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Homopolymerization

O R

O

O R

O + O

(CH2)x

O R

O

n

Copolymerization

O

O R

O

m

(CH2)x O

O n

R: reactive groups, including protected carboxyl, amino, chloro, ketal, hydroxyl, bromo, carbon-carbon double bonds, etc Fig. 1. Preparation of aliphatic polyesters with reactive groups.

propionolactone (CMMPL). CMMPL was polymerized and copolymerized with various amounts of ␧-caprolactone. The pendant chloromethyl groups of the copolymers were converted into quaternary ammonium salts by the reaction with pyridine, which increased the hydrophilicity of the copolymer [7,17]. 2.1.4. Aliphatic polyesters with keto or hydroxyl groups Aliphatic polyesters bearing keto groups were synthesized by the ROP of 5-ethylene ketal ␧-caprolactone followed by deprotection [8,9,18,19]. The keto groups of the copolymers were efficiently reduced into hydroxyl groups by using NaBH4 in a mixture of CH2 Cl2 /EtOH at room temperature without any apparent chain degradation, resulting in aliphatic polyesters with pendant hydroxyl groups [9]. PCL containing pendant hydroxyl groups were prepared by the ROP of ␧-caprolactone monomer bearing triethylsilyloxy pendant groups that can be selectively deprotected into hydroxyl groups under mild conditions [20]. Hedrick and coworkers reported the synthesis and polymerization of ␥-benzyloxy-␧-caprolactone and ␥-2,2bis(phenyldioxymethyl)propionate-␧-caprolactone; the catalytic hydrogenolysis of the benzyl protection group of the products afforded PCL with pendant hydroxyl or bishydroxyl groups, respectively [6]. 2.1.5. Aliphatic polyesters with bromide groups Hedrick and coworkers reported the preparation of aliphatic polyesters with pendant bromide groups by the ROP of a bromo-substituted cyclic ester, ␥-(2-bromo-2methyl propionyl)-␧-caprolactone (BMPCL) containing a pendent-activated alkyl bromide functional group [10]. The pendent-activated alkyl bromide group could initiate controlled atom-transfer radical polymerization (ATRP) of methyl methacrylate; therefore, PCL-graft-poly(methyl methacrylate) copolymers were obtained in a simple one-

step approach by the concurrent polymerization of an ␧-caprolactone, BMPCL, and methyl methacrylate with an appropriate initiator for the ROP and a catalyst for the ATRP. 2.1.6. Aliphatic polyesters with C C groups Unsaturated aliphatic polyesters can be prepared by the ROP of cyclic esters bearing double bonds. Hedrick and coworkers reported the preparation of unsaturated aliphatic homopolyesters or random copolyesters bearing pendant double bonds by the ROP of 4-(acryloyloxy)-␧caprolactone, or 6-hydroxynon-8-enoic acid lactone with ␧-caprolactone and l-lactide [11,12]. Bizzarri and coworkers reported the preparation of aliphatic polyesters bearing double bonds by the ROP of four-membered lactones in the presence of a quaternary ammonium salt as the initiator [13,21]. Unsaturated aliphatic polyesters with inner double bonds were prepared by the ROP of unsaturated ␧-caprolactones with inner double bonds. Jérôme and coworkers prepared unsaturated aliphatic polyesters by the ROP of 6,7-dihydro-2(5H)-oxepinone and 6,7-dihydro2(3H)-oxepinone using aluminum isopropoxide as the initiator [22–24]. 2.1.7. Aliphatic polyesters with reactive groups by copolymerization The copolymerization of morpholine-2,5-dione derivatives with lactide or lactones is a convenient way to prepare aliphatic biopolymers bearing reactive groups. Feijen and coworkers demonstrated the ROP of either ␧-caprolactone or dl-lactide with morpholine-2,5-dione derivatives could protect functional substituents such as benzyl-protected carboxylic acid, benzyloxycarbonyl-protected amine and p-methoxy-protected thiol groups. Polyesteramides with pendant carboxylic acid groups, pendant amine groups, or pendant thiol groups were obtained after deprotection of the copolymers [25].

Fig. 2. Preparation of PCL with pendant carboxylic acid groups [6]. Copyright 2000, American Chemical Society. Reprinted with permission.

H. Tian et al. / Progress in Polymer Science 37 (2012) 237–280

2.2. Polycarbonate Aliphatic polyesters and copolyesters are among the most commonly used degradable materials for the preparation of clinical devices. In this field, aliphatic polycarbonates are good materials because they possess functionalizable side chains (OH, NH2 , COOH, etc.) that

241

can easily meet the need for functionalization of biomaterials. Moreover, aliphatic polycarbonates have good biocompatibility, low toxicity, and good biodegradability [26,27]. High molecular weight aliphatic polycarbonates can be prepared by the ROP of cyclic carbonates [28]. The most commonly used cyclic carbonates for ROP are the five- and six-membered cyclic monomers. Polymerization

Table 1 Aliphatic polyesters and functional cyclic monomers. Monomer

Polyester

Reference

[3]

[4]

[5]

[5]

[5]

[6]

[6]

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Table 1 (Continued) Monomer

Polyester

Reference

[6]

[6]

[6]

[7]

[8]

[9]

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243

Table 1 (Continued) Monomer

Polyester

Reference

[10]

[11]

[12]

[13]

of five-membered cyclic aliphatic carbonates can produce poly(ester-carbonate)s with a content of units lower than 50 mol% through a partial decarboxylation regardless of the initiator and reaction conditions [27]. In contrast to five-membered cyclic carbonates, six-membered cyclic carbonates are easily polymerized and copolymerized with various heterocyclic monomers to form polycarbonates without any decarboxylation under proper conditions. In the 1930s, cyclic carbonates, first reported by Carothers and coworker [29], were obtained by depolymerization of respective linear polycarbonates at a high temperature and in the presence of different catalysts. In recent years, researchers synthesized several functionalized cyclic carbonate monomers. For the first time, Bisht and coworker [30] designed and synthesized a novel carbonate monomer, 5-methyl-5-benzyloxycarbonyl-1,3dioxan-2-one (MBC); Zhuo and coworkers [31] prepared 5-methyl-5-methoxycarbonyl-1,3-dioxan-2-one and 5methyl-5-ethoxy carbonyl-1,3-dioxan-2-one in a similar way to that for MBC. Cyclic carbonates with pendant amino groups [32,33], double-bonds [28,34–36] and triple-bond [37] have seldom been reported. Lee et al. [38] first reported water soluble polycarbonate with pendant amino and carboxylic groups on the main-

chain carbon. Zhuo and coworkers [39] successfully prepared the poly(carbonate-ester)s with amido-amine pendent groups by the reaction of poly(MSTC-co-CL) with ethylenediamine. Jing and coworkers [37] synthesized 5methyl-5-propargyloxycarbonyl-1,3-dioxan-2-one. More cyclic carbonate monomers containing hydroxyl groups have been prepared. For example, Cross and coworkers [40] synthesized a six-membered cyclic carbonate monomer with ketal protected saccharide containing two hydroxyl groups. Zhuo and coworkers [41] first reported 5-benzyloxy-trimethylene carbonate (BTMC) that was synthesized from 2-benzyloxy-1,3-propanediol. Moreover, Cao and coworkers [42] prepared 5-ethyl-5benzyloxymethyl trimethylene carbonate in a similar way to that for BTMC. A great variety of functional cyclic carbonate monomers have been successfully used for homopolymerization and copolymerization with various heterocyclic monomers through ROP. Bisht and coworker [30] first synthesized the MBC’s homopolymer by lipase-catalyzed ROP, of which the protecting benzyl groups were removed by catalytic hydrogenation to give polycarbonate containing pendant carboxylic groups. Jing and coworkers [43] prepared block copolymer PCL-b-PMBC of ␧-caprolactone and MBC by the ROP of the ␧-CL and MBC monomers with amino

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Table 2 Polymers and functional cyclic carbonate monomers. Monomer

Polymer

Referen-ce

O O

O O

R1

R2

O

*

O

O R1

*

R2

n

R1 = CH3 ; R2 = COOCH2 Ph H2 C O

H2 C

[30,41]

O

[43] [36]

R1 = H; R2 = OCH2 CH CH2 H2 C

H2 C

[28] [31] [31]

R1 = CH3 ; R2 = COOCH3 R1 = CH3 ; R2 = COOCH2 CH3

O O

O

O

*

O

O

R1

O

R2

O n R1

or

R2

O *

*

O

O

O

m

R1

O

R2

n

R1 = CH3 ; R2 = CH2 OOCCH CHPh R1 = CH3 ; R2 = COOCH2 CH = CH2 R1 = CH3 ; R2 = COOCH2 C CH R1 = H; R2 = NHCOOCH2 Ph H2 C

[44] [35] [35] [33]

H2 C

[34]

H2 C

O

H2 C

O

Ph [45]

Q Q

Q

Q ,

RGI

T3

Q

T4

Q n T3

or

T4

Q RGI

,

Q m Q

R1 = CH3 ; R2 = COOCH2 Ph

Q

Q

Q T3

T4

Q n

[46]

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245

Table 2 (Continued) Monomer

Polymer

Referen-ce

O

H2C

Ph O

H2C

[47] [48]

R1 = CH3 ; R2 = COOCH2 CH CH2 O O

O

O R1

R2

PEG

O

H n

O R1

R2

R1 = CH3 ; R2 = CO2 CH2 Ph-o-NO2 R1 = CH3 ; R2 = CO2 CH2 Ph O

O

[49] [50]

O

O C

O

O

O

COOCH2Ph

HO

C

H

CO2H

N H

O

[38]

n

O O

O

O O

O O

*

O

O

m O

O

n* O

[51]

O

O O

O

O

O

O *

OH OH

O O

O

O

O O

isopropoxyl strontium (Sr-PO) as an initiator. Zhuo and coworkers [44] prepared poly[(5-benzyloxy-trimethylene carbonate)-co-(5,5-dimethyl-trimethylene carbonate)] by using immobilized porcine pancreas lipase on silica particles with different sizes to catalyze ROP. Representative examples of the monomers and the polymers are shown in Table 2 [30,43,45–53,33–36,28,31,38,40]. Free functional pendant groups on poly(estercarbonate)s are expected to facilitate further modifications such as attaching drug molecules and short peptides onto the functional groups of the polymers.

O

O O

O

O

*

O

[39]

n

Grinstaff and coworker [54] attached a nonsteroidal anti-inflammatory drug, 4-isobutylmethylphenylacetic acid, to the copolymer by esterification of free hydroxyl groups of 4-isobutylmethylphenylacetic acid. Jing and coworkers successfully attached antitumor drugs paclitaxel [55] and docetaxel (Dtxl) [56], biotin [57] and oligopeptide Gly-Arg-Gly-Asp-Ser-Tyr (RGD) [33] to the pendants on the backbone of the copolymers. The results indicate further possible application of poly(ester-carbonate)s in specific drug delivery and tissue engineering.

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Fig. 3. Synthesis of functional PBLGs through the ester exchange reaction (A) the click reaction, and the thiol-ene reaction of functional PBLGs (B) [60]. Copyright 2009, Elsevier Ltd. Reprinted with permission.

2.3. Poly(amino acids) Poly(amino acids) are an important kind of biocompatible and biodegradable synthetic polymers and have been studied for biomedical application in many fields [58]. However, their application is limited because of their insolubility or pH-dependent solubility and lack of functional groups [59]. This section summarizes recent developments in the functional modifications of poly(amino acids) focusing on the preparation of materials with potential applications in medicine. Representative examples of the poly(amino acids) before and after functionalization are shown in Table 3. 2.3.1. Poly(acidic amino acids) 2.3.1.1. Poly(l-glutamic acid). Poly(l-glutamic acid) (PLG) is composed of naturally occurring l-glutamic acid residues linked together through amide bonds with active carboxyl groups on the side. Methods can be used in functionalizing PLG include: (1) polymerizing or copolymerizing monomers with functional groups, (2) modifying the monomer with functional molecules, (3) functional modification of the side groups, such as condensation, aminolysis and ester exchange, and (4) introduction of a second component to achieve a block, branch, hyper-branched or dendron-like architecture. Functionalizing poly(␥-benzyl-l-glutamate) (PBLG) through ester exchange with functional alcohols such as 2-chloroethanol, 2-azidoethanol and poly(ethylene glycol) methyl ether (mPEG) is a convenient method to obtain polymers that have controlled amounts of functional groups on the side chains without protection and de-protection processes. Huang and coworkers used the

ROP of N-carboxy-anhydride (NCA) and ester exchange to prepare functional PBLG with functional alcohols [60]. PBLG was synthesized in anhydrous chloroform by the ROP of ␥-benzyl l-glutamate N-carboxy-anhydride (BLG-NCA) at room temperature using n-hexylamine as an initiator [73]. Functional PBLGs were then synthesized by the ester exchange reactions between PBLG and functional alcohols in 1,2-dichloroethane using p-toluenesulfonic acid (p-TSA) as a catalyst [60]. Four kinds of functional PBLGs including partially chlorinated PBLG (PBCLG), partially azidized PBLG (PBN3 LG), partially allylated PBLG (PBALG) and partially propargylated PBLG (PBPLG) were synthesized. The activity of the functional groups on PBLG was examined through click chemistry between PBN3 LG or PBPLG and propargyl mPEG2000 or 2-azidoethanol, or the thiol-ene reaction between PBALG and thioglycol yielding PBPN3 LG, PBN3 LG-g-mPEG and PBALG-s-OH, respectively (Fig. 3). In a similar manner, Lin and coworkers synthesized the graft copolymer, PBLG-g-mPEG, through the ROP and the ester change reaction [74]. Condensation reactions are a common method to functionalize PLG and its copolymers. Jing and coworkers reported the synthesis of RGD-grafted triblock copolymer poly(ethyl glycol)-b-polylactide-b-poly(l-glutamic acid)/RGD (PEG-b-PLA-b-PLG/RGD) by the combination of a condensation reaction and ROP. The PEG-PLA-NH2 macroinitiator was prepared by the ROP of l-lactide in the presence of methoxy-poly(ethylene glycol) (Mn = 750) with stannous octanoate as the catalyst followed by the replacement of the hydroxy end group by an amino group via a two-step reaction [75]. The resulting PEG-PLA-NH2 was used as a macroinitiator for the living polymerization of ␥-benzyl-l-glutamate to eventually obtain

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247

Table 3 Poly(amino acids) before and after functionalization. Monomer or Poly(amino acid) before functionalization

O

H N

Poly(amino acid) after functionalization

Method for functionalization

Reference

Ester Exchange

[58]

Condensation Reaction

[59]

n O

H N

O

n

O R

O O R1 Cl

Cl

N3 N3

R=H

R1 = RGD

HO OH HO

H HO H

H

H N

OH H

[60]

NH O

SH

HN

[61]

O O O

O

N H

O

O

O

Ring Opening Polymerization

O O O

O

N H

O

O

O

O

O

O

H N

O

n O

O R O

H N

R1

n

[62]

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Table 3 (Continued) Monomer or Poly(amino acid) before functionalization

Poly(amino acid) after functionalization

O O

OH

Method for functionalization

Reference

Condensation Reaction

[63,64]

Aminolysis Reaction

[65]

NH N OH OH

R=H

O

O

OH

O

O OH

NH2

H N

HN

NH2 NH2

O

[66]

N

HN O

H N

NH2

n O

R

[67]

H N

n

NH

NH R1

O R=H

SH

Condensation Reaction

[68]

Michael Addition

[69]

Ring Opening Polymerization

[70]

O O

n

O O O

H N

n

O

H N

O R

n

n

O R1

O O O

N H

O

O O

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Table 3 (Continued) Monomer or Poly(amino acid) before functionalization

Poly(amino acid) after functionalization

Method for functionalization

Reference

O O O

N H

O

O

O

O

a well-defined polymer-polypeptide triblock copolymer (Mw/Mn < 1.2). PEG-b-PLA-b-PLG was obtained by removing the protective benzyl groups in PEG-b-PLA-b-PBLG through catalytic hydrogenation; RGD was grafted onto PEG-b-PLA-b-PLG by first activating the side chain carboxyl groups of PEG-b-PLA-b-PLG with N-hydroxysuccinimide (NHS) and then coupling them with RGD [61,76]. Kiick and coworkers synthesized a family of galactosefunctionalized PLA-based glycopolymers of various molecular weights using a condensation reaction between PLG and N-(␧-aminocaproyl)-␤-d-galactosylamine [62]. Similarly, Kataoka and coworkers synthesized thiolated poly(ethylene glycol)-b-poly(glutamic acid) (PEG-b-P(GluDP)) via ROP and a condensation reaction subsequently [63]. Polymerizing or copolymerizing monomers with functional groups is widely used in the preparation of polymers with well controlled molecular weight and architecture. Wu and coworkers used the ROP of NCA to synthesize mono- and diethyleneglycol functionalized PLGs directly [64]. EGn-l-glutamates were first prepared through the reaction of l-glutamic acid and monoethylene glycol monomethyl ether or di(ethylene glycol) monomethyl ether; then the reaction of EGn-l-glutamates with triphosgene yielded EGn-l-glutamate-NCAs. The formation of NCA allowed facile polymerization into high molecular weight polymers with a narrow polydispersity index (PDI) via ROP. PLG may be functionalized by the incorporation of components into the system to form copolymers with different architectures, such as block, graft, dendron-like and so on. Chen and coworkers synthesized a series of poly(N-isopropylacrylamide) (PNIPAM) and poly[(lglutamic acid)-co-(␥-benzyl l-glutamate)] (P(GA-co-BLG)) diblock copolymers using radical polymerization and ROP [77]. PNIPAM is a widely used polymer, with temperature sensitivity exhibiting a reversible coil-to-globule transition at about 32 ◦ C (the lower critical solution temperature, LCST). It is soluble in water below the LCST. However, when the temperature increases above the LCST, the polymer becomes insoluble and precipitates from its aqueous solution. Amino-semitelechelic PNIPAM (AS-PNIPAM) was synthesized by monomer telomerization of N-isopropylacrylamide (NIPAM) with AIBN as the initiator and AET·HCl as the chain transfer reagent. Temperature sensitive PNIPAM-b-PBLG diblock copolymers were prepared by the ROP of BLG-NCA using AS-PNIPAM as the macroinitiator. PNIPAM-b-poly[(l-glutamic acid)-co(␥-benzyl-l-glutamate)] (PNIPAM-b-P(GA-co-BLG)) were synthesized through partial debenzylation of PNIPAMb-PBLG using HBr/CH3 COOH. An alternative synthetic approach was investigated by synthesizing graft copolymers instead of block copolymers, using the same materials

O

as those used in the preparation of the PLG-g-PNIPAM graft copolymer [78]. Block copolymers prepared with biocompatible and biodegradable components are targets for applications in the medical field. Guillaume and coworkers reported an approach to synthesize poly(trimethylene carbonate)-bpoly(␥-benzyl l-glutamate) (PTMC-b-PBLG) and poly(␧caprolactone)-b-poly(␥-benzyl l-glutamate) (PCL-b-PBLG) via the ROP of TMC or CL and BLG-NCA [79]. A PTMCNH2 or a PCL-NH2 macroinitiator was synthesized by ROP in THF for TMC or in toluene for CL using diethyl zinc as the catalyst and t-Boc-NH(CH2 )3 OH as the initiator followed by removing t-Boc groups with trifluoroacetic acid at 0 ◦ C for 45 min upon stirring. The well-defined PTMC-b-PBLG and PCL-b-PBLG diblock copolymers were obtained using PTMC-NH2 or PCL-NH2 as a macroinitiator via ROP. A Dextran-b-PBLG block copolymer was synthesized via ROP and click chemistry in Schatz’s group [80]. First, the reducing end of dextran (Mn = 6600 g mol−1 , PDI = 1.35) was modified with an alkyne group by reductive amination with propargylamine in acetate buffer (pH 5.0) in the presence of sodium cyanoborohydride, which reduced double bonds in Schiff bases selectively; secondly, PBLG that was end-functionalized with an azide group and had a degree of polymerization (DP) of 59 was obtained through the ROP of BLG-NCA with 1-azido-3aminopropane as the initiator; thirdly, the final dextron Dextran-b-PBLG block copolymer was obtained via coupling of dextran and PBLG blocks in dimethyl sulfoxide (DMSO) at room temperature using a copper(I) catalyst (CuBr) and ligand pentamethyldiethylene-triamine (PMDETA). An extension in this chemistry was proposed by Jing and coworkers, reporting a well-defined Y-shaped copolymer (poly(l-lactide))2 -b-PBLG (PLLA-PBLG) via the consecutive ROP of l-lactide and living NCA polymerization [81]. Multi-armed PBLGs were prepared via the ROP of BLGNCA by Chen and coworkers [82,83]. The macroinitiator poly(ethylene glycol)-b-Polyethyleneimine (PEG-b-PEI) diblock copolymer was prepared via a two-step reaction: (1) mPEG was allowed to react with HMDI in large excess to obtain PEG-NCO; (2) PEG-NCO in CHCl3 was dropwise added into a CHCl3 solution of hyper branched PEI. Then multi-armed PBLGs were synthesized via ROP with PEG-b-PEI diblock copolymer or PEI as the macroinitiator by dissolving the mixture in dried chloroform and stirring for 72 h at room temperature. Dong and coworkers synthesized dendron-like PBLG/linear poly(ethylene oxide) block copolymers with both asymmetrical and symmetrical topologies (i.e., ABn type Dm-PBLG-b-PEG and BnABn type Dm-PBLG-b-PEG-b-Dm-PBLG; n = 2m , m = 0, 1, 2, and 3; Dm is the propargyl focal point of poly(amido

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Fig. 4. Synthesis of dendron-like PBLG/linear poly(ethylene oxide) block copolymers with both asymmetrical and symmetrical topologies via the combination of ROP and click chemistry [84]. Copyright 2009, American Chemical Society. Reprinted with permission.

amine) type dendrons having 2m terminal primary amine groups) via the combination of ROP and click chemistry [84]. Two synthesis methods, “arm-first” and “core-first” approaches, were used to prepare Dm-PBLG-b-PEG and Dm-PBLG-b-PEG-b-Dm-PBLG. In the “arm-first” approach, the propargyl modified dendrons Dm with 2m terminal primary amine groups were synthesized and then used as an initiator in the ROP of BLG-NCA, followed by coupling of the product with azide-terminated PEG (i.e., mPEG-N3 or N3 -PEG-N3 ) through click chemistry to produce the dendron-like/linear PBLG-b-PEG hybrid copolymers. In the “core-first” strategy, the dendrons Dm were click conjugated with azide-terminated PEG to generate primary amine-terminated PEG-dendrons (i.e., PEG-Dm), which were then used to initiate BLG-NCA to produce the targeted hybrid copolymers, with both asymmetrical and symmetrical topologies (Fig. 4). 2.3.1.2. Poly(aspartic acid). Poly(aspartic acid) can be synthesized from aspartic acid by the ROP of ␥-benzyl aspartic acid N-carboxy-anhydride (BAA-NCA) followed by removal of the protective benzyl groups. The two main approaches to modify poly(aspartic acid) are: (1) functional modification of the side groups, such as condensation and aminolysis, and (2) introduction of a second component to achieve different architectures. Condensation is a simple and common method to modify poly(aspartic acid) and its copolymers. Kataoka and coworkers reported the synthesis of glycol)-b-poly(aspartate-hydrazonepoly(ethylene adriamycin) (PEG-P(Asp-Hyd-ADR)) using poly(ethylene glycol)-poly(␤-benzyl-l-aspartate) (PEG-PBLA) as a template [65,66]. PEG-b-PBLA was synthesized via the ROP of benzyl-l-aspartate N-carboxyanhydride (BLA-NCA) with mPEG-NH2 as the macroinitiator. Hydrazide groups were attached to the end of the aspartate side carboxyl groups of the block copolymer through an acid anhydride reaction after removing the benzyl groups of PEG-b-PBLA. ADR

was then conjugated to the polymer backbone through an acid-labile hydrazone bond between C13 of ADR and the hydrazide groups of the PEG-b-P(LA-Hyd) block copolymer (Fig. 5). Aminolysis is extensively used in functionalizing PBAA with functional amines, such as dipropylene triamine (DPT), 1,5-diamino pentane (AP), 4-(3-aminopropyl) morpholine (MP), etc.; it is a convenient and simple method to obtain polymers with a controlled fraction of functional groups. PEG-b-poly-(3-[(3-aminopropyl)amino] propyl aspartamide) was prepared through ROP and an aminolysis reaction by Kataoka and coworkers. PEG-b-PBLA was synthesized by ROP and PEG-b-DPT was obtained by a side-chain aminolysis reaction of PEG-b-PBLA. In a similar way, poly([5-aminopentyl]-␣,␤-aspartamide) and PEG-bpoly[(3-morpholinopropyl) aspartamide]-b-poly-l-lysine were synthesized by the same research group via the ROP of BLA-NCA and an aminolysis reaction using AP and MP, respectively [67–69]. 2.3.2. Poly(basic amino acid) 2.3.2.1. Polylysine. Poly(l-lysine) (PLL) with reactive amido groups on the side chain can be prepared through the ROP of ␧-carbobenzoxy-l-lysine N-carboxyanhydride (ZLL-NCA) and deprotection. PLL is a polyelectrolyte (polycation) which displays pH-dependent solubility, limited circulation lifetime due to aggregation with oppositely charged biopolymers, and high toxicity [59,85]. Similar to those for PLG and poly(aspartic acid), several approaches are effective in functionalizing PLL: (1) functional modification of the side groups, such as condensation, Michael addition and so on, and (2) introduction of a second component to achieve block, branch, dendron-like architectures, etc. A condensation reaction is a simple and convenient way to functionalize poly(l-lysine) directly. Cyclic RGD functional block copolymer c(RGDfK)-poly(ethylene glycol)-b-poly[␧-(3-mercaptopropionyl)-lysine]

H. Tian et al. / Progress in Polymer Science 37 (2012) 237–280

251

Fig. 5. Synthesis of PEG–p(Asp–Hyd–ADR) block copolymers. The Schiff base formed between the C13 ketone of ADR and the hydrazide groups of the PEG–p(Asp–Hyd) block polymer is most effectively cleavable under acidic conditions at about pH 5.0, which corresponds to the pH value of lysosome in cells. Boc = tert-butoxycarbonyl, TFA = trifluoroacetic acid [65]. Copyright 2003, Wiley-VCH Verlag GmbH & Co. KGaA. Reprinted with permission.

(c(RGDfK)-PEG-b-P(Lys-MP)) was prepared by ROP and a condensation reaction in Kataoka’s group [70]. Acetal-PEG-b-PLys was synthesized through the ROP of ZLL-NCA with acetal-PEG-NH2 as the macroinitiator and deprotection; subsequent reaction with N-succinimidyl 3-(2-pyridyldithio)-propionate (SPDP) yielded acetal-poly(ethylene glycol)-b-poly[␧-3-(2pyridyldithio)propionyl lysine] (acetal-PEG-P(Lys-PDP)). c(RGDfK)-PEG-P(Lys-MP) was achieved through terminal group modification and cleavage of the disulfide bonds of PDP with dithiothreitol. Michael addition is an effective and fascinating method to modify PLL with active amino groups. Li and coworkers synthesize poly(l-lysine)-g-poly(␧-caprolactone) (PLLg-PCL) and poly(l-lysine)-g-poly(l-lactide) (PLL-g-PLLA) graft copolymers via the ROP of l-Lys-NCA, CL, LLA and Michael addition [71]. PLL was synthesized by the ROP of ZLL-NCA with n-butylamine as the initiator and was kept at 40 ◦ C for 72 h, followed by deprotection with HBr/HOAc. Maleimido-terminated PLLA (M-PLLA) and maleimidoterminated PCL (M-PCL) were synthesized by the ROP of LLA and CL monomer with N-hydroxylethylmaleimide (HEMI) as the initiator and Tin (II) trifluoromethane sulfonate (Sn(OTf)2 ) as the catalyst. The graft copolymers PLL-g-PCL and PLL-g-PLLA were synthesized via the Michael addition of M-PLLA and M-PCL with amino groups on the side chains of PLL. Chen’s group investigated an synthetic approach in which BLG-NCA was replaced by ZLL-NCA; after the removal of the benzyl protecting group to prepare a series of PNIPAM-b-PLL diblock copolymers using radical polymerization and ROP as described in the above paragraph for PLG [86]. Jing and coworkers prepared a series of poly(␧-benzyloxycarbonyl l-lysine)-blockpoly[diethylene glycol bis(3-amino propyl) ether]-blockpoly(␧-benzyloxycarbonyl l-lysine) (PZLL-PDGBE-PZLL) via the ROP of ZLL-NCA with diethylene glycol bis(3-

amino propyl) ether (DGBE) as the initiator [87]. In the same group, Jing and coworkers synthesized poly(llysine)-block-poly(l-phenylalanine) (PLL-b-PLPA) diblock copolypeptides via the ROP of NCA [88]. The PZLL-bPLPAs were synthesized in two steps: (1) synthesizing of PZLL by the ROP of ZLL-NCA in DMF with proportional n-hexylamine as the initiator, and (2) synthesizing of PZLLb-PPA through the ROP of l-phenylalanine NCA (LP-NCA) in DMF in the presence of PZLL-NH2 as the macroinitiator. Harada et al. prepared a PLL-b-PAMAM dendron copolymer through ROP and the Michael addition [89]. The block copolymer was synthesized in two steps: (1) a PAMAM dendron with generation 3.5 was synthesized via four Michael additions with methyl acrylate and three amidations with ethylenediamine using tert-butyl N(2-aminoethyl)-carbamate, of which one primary amino group was protected by t-Boc groups, as the starting reagent followed by deprotection of t-Boc with trifluoroacetic; (2) a PLL-b-PAMAM dendron copolymer was prepared by the ROP of ZLL-NCA with a PAMAM dendron as the macroinitiator; subsequently the benzyloxycarbonyl group was removed by HBr and the methyl ester at the periphery was converted to carboxylate groups. Rendle and coworkers used a condensation reaction and the ROP of ZLL-NCA to synthesize mannose-capped lysinebased dendrimers [90]. Six generations of lysine-based dendrimers, G0 to G5, containing two to sixty-four ‘valence’ amines, respectively, protected by t-Boc, were synthesized by a condensation reaction with benzhydrylamine as the core. The final mannose-capped lysine-based dendrimers were obtained through a condensation reaction between deprotected dendrimers and mannosyl derivatives. 2.3.2.2. Polyarginine (PArg). PArg is composed of arginine residues with guanidino groups which can help cell uptake of nanoparticles. The functionalization of PArg with the ROP of NCA is difficult. In a report by

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Deming’s group [91] the block copolymer poly(l-lysine)co-polyarginine-b-poly(l-leucine) (PLL-co-PArg-b-PLLeu) was synthesized via the ROP of NCA in three step preparation: (1) di-N-benzyloxycarbonyl-l-arginine Ncarboxyanhydride (Z2 Arg-NCA) was synthesized through the reaction between tri-N-benzyloxycarbonyl-l-arginine and ␣,␣ -dichloromethylmethyl ether in dry methylene chloride, with a similar preparation for ZLL-NCA; poly(di-N-benzyloxycarbonyl-l-arginine-random(2) N-benzyloxy-carbonyl-l-lysine)-b-Poly(l-leucine), PZLL-co-PZ2 Arg-b-PLLeu, was synthesized by the ROP of ZLL-NCA and Z2 Arg-NCA with Co(PMeB3 B)B4 as the catalyst, followed by addition of BLG-NCA in the dry box; (3) PLL-co-PArg-b-PLLeu was obtaind after deprotection with HBr. 2.3.2.3. Poly l-histidine. The electron lone pair on the unsaturated nitrogen of the imidazole ring endows poly(l-histidine) (PLHis) with an amphoteric nature. Protonation–deprotonation on the side chain can facilitate synthesize of LHis-NCA by a ROP, but the method is difficult and has limited application. Bae and coworkers prepared PLHis and block copolymers with PEG, PLLA-b-PEG. PLHis was synthesized by the ROP of protected l-Histidine NCA (i.e., Nim -DNP-l-histidine NCA) (NDLhis-NCA); the coupling of PLHis with PEG yielded PLHis-b-PEG block copolymer after deprotection [92,93]. The block copolymer was prepared in three steps as follows: (1) NDLhis-NCA was obtained by a reaction between Nim -DNP-l-histidine and thionyl chloride in THF at room temperature; (2) PLHis was synthesized by the ROP of NDLhis-NCA with hexylamine or isopropylamine as the initiator, followed by polymerization at room temperature for 72 h, with evolution of carbon dioxide; (3) PLHis-bPEG was prepared via a coupling reaction with NHS and EDC under deprotection of 2-mercaptoethanol., A triblock copolymer PLLA-b-PEG-b-PLHis was prepared by a similar method with the ROP of NDLhis-NCA, via coupling and deprotecting reactions [94]. In the same group, poly(l-histidine-co-phenylalanine)b-poly(ethylene glycol) (i.e., PLHis-co-PPhe-b-PEG) was prepared by the ROP of NDLhis-NCA and Phe-NCA, via a condensation reaction and deprotection as described above [95,96]. 2.3.3. Poly(neutral amino acid) In the neutral amino acid family, there exist amino acids with active groups, such as l-serine with a hydroxy group, l-3,4-dihydroxyphenyl-l-alanine (l-DOPA) with a dihydroxybenzyl group, and l-cysteine with a mercapto group. Deming’s group prepared functionalized poly(lserine) (PLSer), poly(l-cysteine) (PLCys) and poly(l-DOPA) (PLDOPA) through the ROP of modified monomers in combination with other components [72]. Monoand diethyleneglycol modified PLSer (PEGnLSer) polymers were synthesized by the ROP of functionalized LSer-NCA directly in three steps: (1) EGn-l-Serines were obtained by coupling N␣ -tertbutyloxy-carbonyll-serine and 1-bromo-2-(2-methoxyethoxy) ethane or 2-bromoethyl methyl ether with sodium hydride fol-

O P

O

R1

O

n

R2 Fig. 6. General structure of PPE.

lowed by deprotection with HCl; (2) EGn-l-Serine-NCAs were prepared with the reaction between EGn-l-Serines and 1,1-diclorodimethylether; (3) PEGnLSers were prepared by the ROP of EGn-l-Serine-NCAs directly and the degree of polymerization of the polymer was controlled with a narrow PDI. In a similar way, well-controlled diethyleneglycol-modified poly(l-cysteine) was prepared by using (2-(2-methoxyethoxy)ethyl)chloroformate instead of 1-bromo-2-(2-methoxyethoxy) ethane. A series of water soluble poly(l-DOPA)-co-poly(llysine) (PLDOPA-PLL) copolymers were prepared by the ROP of ␣-amino acid NCA monomers [97]. PLDOPA-co-PLL copolymers were synthesized via the ROP of N␧carbobenzyloxy-l-lysine NCA and O,O -dicarbobenzyloxyl-DOPA NCA with sodium tert-butoxide as the initiator followed by the removal of carbobenzyloxy groups with HBr in acetic acid at room temperature. In addition, synthesis of copolymers including PLCys and other components is an efficient approach to modify PLCys. Jing and coworkers synthesized poly(l-cysteine)b-poly(l-lactide) (PLCys-b-PLLA) diblock copolymer by the ROP of NCA [98]. PLCys-b-PLLA was prepared in two steps: (1) PLLA-NH2 was obtained through the ROP of l-lactide with stannous octoate as the catalyst and NH2 -protected aminoethanol as the initiator followed by deprotection; (2) the finial copolymer PLCys-b-PLLA was prepared by the ROP of ␤-benzyloxycarbonyl-l-cysteine N-carboxyanhydride (ZLCys-NCA) with PLLA-NH2 as a macroinitiator and then removal of the t-Boc group. 2.4. Polyphosphoesters PPEs with repeating phosphoester units in the backbone (Fig. 6) are attractive biocompatibile and biodegradable biomaterials because of their structural similarity to the naturally occurring nucleic acid and easy functionality as compared to conventional polyesters [99]. The synthesis of PPE as the analogue of nucleic and teichoic acid was pioneered by Penczek and coworkers at the end of 1970s [100,101]. Since then, a number of synthesis methodologies and mechanisms have been extensively investigated, including ROP, polyaddition, polycondensation, polytransesterification and enzymecatalyzed polymerization [102–108]. PPEs with different properties, such as stimuli-responsiveness, photo-crosslinkability, and reactiveness, can be easily achieved by varying the R1 or R2 group (Fig. 6). In the 1990s, Zhuo’s group and Leong’s group further developed the synthesis strategies of functional PPEs for various biomedical applications such as tissue engineering scaffolds and drug/gene delivery vehicles [109,110]. Several functional groups such

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A TE l 4, C C (H) NH R' 2

O P

O

R1

H

O

n

Cl 2,

O

Deprotection

P

O

(H)N

NH

H2N

NH

H2N

P

O

R1

R2OH, TEA

O

H N

NH

MEA

N+

N

BA

NH

DMEA

N

N

H2N

NH2

SP

R2O:

H2N EA

Deprotection

n

P

O

O

R2

R1

O

NH

TMEA

NH

DEEA

n

PA

N

O

n

O

EA

NH

H2N

O

R'2

Cl H2N

R1

O CH Cl

3

R2'N(H):

253

DEA O

H2N

3

HA

H2N

NH2

N H

O

N DPA

O

HO

NH2

EH

MEA

Fig. 7. Postpolymerization modification of polyphosphite.

as hydroxyl, amino and unsaturated bonds were introduced as the R1 or R2 group for PPEs. Recently, controlled ROP initiated by stannous octoate or aluminum isopropoxide was employed by Wang and colleagues to synthesize PPEs with well-defined architectures and versatile functionalities [111–113]. These living polymerization methods may facilitate the synthesis of PPEs with tunable properties for biomedical applications [114]. PPEs with R1 functionalities were first prepared by Penczek and coworkers as teichoic acids mimics [100,101]. Interactions between bio-related polymers and cations were studied, important for the use of these polymers for active transportation of cations (Mg2+ , Ca2+ ) through biomembranes and mimicks of the biomineralization processes [115]. Polycondensation of di-hydroxyl compounds (HO-R1-OH) with ethyl dichlorophosphate is an effective route to the R1 functional PPEs. Low-molecular-weight PLAs can serve as HO-R1-OH compounds to prepare PPEs with a wide range of physical properties based on the variation of phosphoester mass fraction. Wen at al. [116] synthesized a novel HO-R1-OH compound to prepare a PPE carrying a positive charge in its backbone, and a lipophilic cholesterol structure in a side chain. The biodegradable polymer obtained self-assembled into micelles in aqueous buffer, and could efficiently condense and deliver plasmid DNA into different cell lines. An unsaturated HO-R1-OH compound was also synthesized and used to prepare PPEs. The unsaturated groups in the polymer backbone allowed thermally-induced free radical cross-linking between polymer chains to form a biodegradable gel in situ, which may be promising as an injectable tissue engineering scaffolds [117]. Different from the tetravalency of carbon atoms in polyesters, the pentavalency of phosphorous atoms makes

PPEs more favorable for side chain (R2) functionalization. Two general methods, postpolymerization modification and polymerization of functionalized monomers, have been widely used in the preparation of PPEs with side chain (R2) functionalities. In the case of postpolymerization modification, poly(Hphosphate), also called polyphosphite, are usually synthesized as precursor polymers. Several methods reported to prepare side chain functionalized polymers are shown in Fig. 7. A direct approach to convert the P–H bond to the P–N bond resulting in polyphosphoramidates (PPAs) with diverse amino groups (R2 in Fig. 7) in the polymer pendants was achieved through the Atherton-Todd reaction in the presence of CCl4 as an oxidant. All of the

O

P

O

O

OR:

Cl

O

+ HO R

TEA

O

P

O O

1

O 2

O

O

5 O

OR O

O 3 O

O

4

H N

O

6

O O

O

O

OH

O 7

O

8

Fig. 8. Cyclic phosphoester monomers.

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synthesized PPAs are biodegradable cationic polymers and have been extensively studied as the non-viral gene carriers [118–120]. Functional PPEs with P–O connected side chains also could be obtained using polyphosphite as the starting material. A chlorination process was adopted to convert the P–H bond into the P–Cl bond followed by a reaction with hydroxyl-compounds to generate PPEs with functional side chains (Fig. 7, R2). This method was First reported by Wang et al. to synthesize poly(2-aminoethyl propylene phosphate) (PPE-EA) with a biodegradable phosphoester backbone and a ␤-aminoethoxy side chain that was shown to be an effective, nontoxic and biodegradable gene carrier [121]. Subsequently, PPEs with HA and MEA were synthesized to study the effect of side chain structures on the gene transfer efficiency [122]. Using the same method, Huang et al. also prepared a biodegradable PPE with hydroxyl pendant groups as a nonionic noncondensing agent to enhance gene expressing in muscles [123]. More recently, Koseva et al. [124] reported a new method to prepare functional PPEs with reactive 1,3-dioxolan-2one pendants through homolytic addition of P–H groups to the C C double bond of 4-ethenyl-1,3-dioxolan-2-one. The ring-opening aminolysis of the cyclic carbonate in the side chains led to the ability of the polymers to conjugate with peptides/proteins or drug molecules conveniently, rendering new functional PPEs as candidates for drug delivery application. ROP of cyclic phosphoester monomers provides another strategy to prepare side chain-functionalized PPEs. Recent efforts on the controlled ROP of cyclic phosphoester monomers have developed synthetic PPEs with various architectures and defined compositions [125–129]. Functionalized PPEs can be achieved by the ROP of functionalized monomers. A monomer bearing vinyl group (monomer 5, Fig. 8) was employed in the synthesis of vinyl group-functional PPEs that were used to prepare hydrogels with different physical properties through crosslinking of the vinyl group in the pendants [130,131]. Unlike monomers with a vinyl group, monomers with amino and hydroxyl groups need to be protected (monomer 6 and 7, Fig. 8) for them to be compatible with the polymerization conditions. For example, an amphiphilic triblock copolymer PEG-b-PCL-b-PPEEA was synthesized by sequential polymerization of ␧-caprolactone and monomer 6, followed by deprotection to release amino groups. An amphiphilic and cationic block copolymer self-assembled into micelles as a promising delivery vehicle for small interfering RNA (siRNA) [132]. Similarly, Song et al. reported a series of diblock PPEs bearing reactive hydroxyl groups that could self-assemble into either micelles or vesicles in aqueous solution [133]. A novel unprotected hydroxyl functionalized cyclic monomer 8 in Fig. 8) was recently designed and synthesized by Liu et al. [134], and a hyperbranched PPE was successfully synthesized by selfcondensing ROP of this monomer in the absence of a catalyst. 2.5. Others Polyanhydrides [135] and polyurethane [136] have been utilized for a variety of biomedical applications because

Fig. 9. Functional end group-bearing PNIPAMs synthesized by chain transfer radical polymerization.

of their biocompatibility and degradability. The functionalization of these biopolymers can further improve their properties, such as biological activity, hydrophilicity, cytocompatibility, etc. Uhrich and coworkers reported the chemical incorporation of mono-functional antiseptics based upon phenols into polyanhydrides via pendant ester linkages. Because a wide range of bioactive materials may be used to form pendant ester linkages, this method can be potentially expanded for the incorporation of many other bioactive materials, including mono-functional therapeutic agents into a polymer. These materials may be useful in antiseptic coatings for surfaces such as tables, floors, and medical instruments in healthcare settings or applied to prevent and control infection [137]. Gao and coworkers reported the modification of polyurethane by grafting polymerization of methacrylic acid, acrylamide, hydroxyethyl methacrylate, or N,Ndimethylaminoethyl methacrylate. In vitro human endothelial cell cultures of the modified polyurethane scaffolds showed improved hydrophilicity and endothelial cell adhesion in comparison with the unmodified control matrix [138,139].

3. Biopolymers with responsive activities 3.1. Stimuli-responsive biopolymers Due to the ability to mimick the basic response process of living systems, stimuli-responsive polymers have attracted increased attention. These polymers can respond to small changes in environmental stimuli with distinct transitions in physical-chemical properties, including conformation, polarity, phase structure and chemical composition [140]. According to the stimulus differences, stimuli-responsive polymers may be classified as temperature-, pH-, photo-, electro- and multi-responsive polymers. Nowadays various materials based on these “intelligent polymers” have been designed and applied in biomedical fields including drug delivery, tissue engineering, bioseparation and biosensor designing [141]. Among them, synthetic biodegradable polymer based materials attracted attention due to their promising in vivo applications. Therefore, designing convenient and effective synthetic strategies to modify biopolymers to provide intelligent functions is important for further progress of biomedical materials.

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3.1.1. Temperature responsive Temperature is the most commonly studied among various environmental stimuli because of its physiological significance. Most temperature-responsive polymers contain both hydrophilic and hydrophobic moieties. When the temperature changes to an appropriate range, the balance between these moieties is broken and reversible phase separation or precipitation can occur. PNIPAM is one of the most popular thermosensitive polymers, undergoing a rapid coil-to-globule (hydration-to-dehydration) transition in an aqueous solution at its LCST of 31–32 ◦ C [142]. The LCST can be appropriately elevated or reduced by copolymerizing NIPAM with more hydrophilic monomer or more hydrophobic monomers, respectively. Although there are many other temperature-responsive polymers synthesized by the radical polymerization, PNIPAM is discussed here as a typical example. There are mainly two strategies to conjugate PNIPAM with synthetic biopolymers. One is to prepare end-functionalized PNIPAM first for use as an initiator for the ROP of cyclic monomers or for coupling with a synthetic biopolymers. Another pathway is to synthesize functionalized biopolymer macroinitiators first for use in the polymerization of NIPAM. The end functionalization of PNIPAM is conveniently achieved through the chain transfer radical polymerization of NIPAM (structures are shown in Fig. 9). Amine-terminated PNIPAM can also be obtained by RAFT polymerization using an amine-bearing initiator [143]. It is well known that most biodegradable synthetic polymers are prepared by the polymerization of cyclic monomers initiated by hydroxyl or amine groups. Therefore, various temperature-sensitive block copolymers have been obtained by this strategy. PNIPAM-b-PLA was prepared through the ROP of lactide initiated by PNIPAMOH; PNIPAM-b-PLA self-assembled into micelles with temperature-sensitive shells [144]. A similar approach was used in our group to prepare temperature- and pH-responsive polypeptide-based block polymers such as poly(N-isopropylacrylamide)-block-poly(glutamic acid) (PNIPAM-b-PGA) and PNIPAM-b-PLL [77,86]. As demonstrated in the preceding paragraphs, many functional groups can be incorporated into synthetic biopolymers. Conjugation is a popular method to introduce functional end group-bearing PNIPAM to synthetic biopolymers. For example, PGA-g-PNIPAM and PLL-g-PNIPAM were synthesized through the condensation of amine and carboxyl groups in the presence of carbodiimide [78,145]. However, a limitation of the conjugation reaction is that the purification of the final product is complicated by unwanted polymers. Recent progress in controlled living radical polymerization provided more alternative routes to synthesis of PNIPAM-based biodegradable polymers. These techniques made it possible to prepare well-defined and controlled molecular weight polymers not easily obtained by traditional radical polymerization. PLA-b-PNIPAAM-b-PLA was synthesized by the ROP of lactide initiated from two hydroxyl groups of a RAFT agent and then used as an initiator for the RAFT polymerization of NIPAM [146]. Amphiphilic triblock copolymers with two hydrophilic PNIPAM blocks flanking a central hydrophobic poly[(R)-

255

3-hydroxybutyrate] (PHB) were prepared, in which the PNIPAM was initiated by the PHB macroinitiator through ATRP [147]. Polypeptide copolymers containing PNIPAM were also synthesized using similar approaches. For example, PNIPAM-b-PGA was synthesized by a combination of the ROP of BLG-NCA and the RAFT polymerization of NIPAM [143]. It should be pointed out that the order of ROP and RAFT polymerization in this system could be interchanged, with a narrower PDI when PNIPAM is used as the initiator. 2-Hydroxyethylmethacrylate (HEMA) is a commonly used monomer to promote favorable biocompatibility of its polymers. Because of the pendent hydroxyl group, HEMA is also used as an initiator for the preparation of polyesters bearing double bonds at the end. The resulting macromonomer can be copolymerized with NIPAM or initiated by the PNIPAM macroinitiator. For example, poly(N-isopropylacrylamide)-b-[2-hydroxyethyl methacrylate-poly(␧-caprolactone)] (PNIPAM-b-(HEMAPCL)) was synthesized by combining a macromonomer method with RAFT polymerization [148]. The molecular weights of the macromonomers were generally low, which favors further polymerization. Copolymers of polyester and PEG exhibiting reversible sol–gel phase-transition in response to temperature have also attracted considerable interest [149]. Their molecular architectures can be designed as ABA, BAB, AB and (AB)n types, and they are also expanded into other structures, such a star-shape polymers [150]. Its thermo-responsive properties mainly depend on molecular parameters such as the copolymer composition, hydrophilic/hydrophobic block length and molecular weight. Recently, Lee and coworkers prepared a series of this kind of in situ gelling copolymers with pH sensitive segments. The gelling of these materials could be tuned by the combination of pH and temperature stimuli, which could expand the application of this kind of materials [149]. 3.1.2. pH-responsive biopolymers pH is a well-studied stimulus because of pH variation within the body. For example, the pH in the stomach is acidic while in the intestine is more basic (pH 5–8). Generally, the pH in normal tissue and blood is about 7.4, but in some tumors the pH is 0.5–1.0 lower than the normal. When the polymers are taken up by cells there is also pH variation at different states. For example, in endosomes the pH is about 5.0–6.5, whereas lysosomes have an even lower pH (4.5–5.0) [151]. Thus, synthetic biodegradable polymers responsive to pH have promising application in drug delivery. A number of polypeptides bearing pendant ionizable groups exhibit pH-responsive properties, such as poly(glutamic acid), poly(aspartic acid), poly(histidine), poly(lysine) and poly(arginine). Among these, poly(glutamic acid) and poly(aspartic acid) are acidic polypeptides while the others are basic., Poly(glutamic acid) and poly(histidine) are the most practical pH-responsive polypeptides for in vivo application because their appropriate pH sensitivity ranges and the physiological pH ranges overlap each other [58]. Moreover, poly(glutamic acid) undergoes a sharp helixto-coil conformational induced by pH changes, which can mimic the naturally occurring peptides to some extent.

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Fig. 10. Structure of amino-pendent polyacetals.

Poly(histidine) contains imidazole groups that can be easily protonated at pH 6.5–5.0 to give a positively charged polyion, so this material can be used as a carrier for genetic materials. The pKa of polypeptides can be tuned by introducing hydrophobic groups to expand their application. For example, Kim et al. synthesized poly[(l-histidine)-co-(lphenylalanine)]-block-poly(ethylene glycol) (PHF-b-PEG) diblock copolymers to prepare pH-sensitive polymeric micelles [152]. It was found that the pKa value of the copolymer can be controlled by adjusting the ratio of histidine to phenylalanine in the copolypeptide and by adjusting its molecular weight. In our previous work, the influence of hydrophobic benzyl groups on the phase transition of PNIPAM-b-P(GA-co-BLG) copolymers was studied. The diblock copolymer responded sharply to a narrow pH change in the region of pH 7.4–5.5 when the BLG content in the P(GA-co-BLG) block was more than 30 mol% [77]. The introduction of pH-responsive properties can also be achieved by the conjugation of ionizable groups with the polymer chain. For example, citraconic anhydride reacted with an amine modified PEG-b-PAsp was negatively charged owing to the carboxylate groups. The citraconic amide is stable at both neutral and basic pH, but it becomes unstable at acidic pH and promptly degrades back to the cationic primary amine [153]. This approach can be used to prepare a charge-conversion polymer in response to endosomal pH for gene delivery. However, the disadvantage of biodegradable polyions is that the excess charges can induce undesired interactions with serum proteins leading to rapid elimination of the polyions before reaching specific sites. One strategy to overcome this difficulty is to develop polymers bearing acid-labile groups, including mainly acetal/ketal and hydrazide. These groups are uncharged and cleavable in acidic media. Bae et al. designed acid-sensitive amphiphilic block copolymers in which ADR was conjugated to the polymer backbone through an acid-labile hydrazone bond between C13 of ADR and the hydrazide groups of the poly(ethylene glycol)-b-poly(aspartate-hydra zone) (PEG-P(Asp-Hyd)) block [65]. Tomlinson et al. [154] prepared water soluble and hydrolytically labile polyacetals, bearing pendant amine groups suitable for drug conjugation (Fig. 10). Then doxorubicin was conjugated to polyacetal to get a polyacetal-doxorubicin (APEG-DOX). This polyacetals-drug conjugate displayed pH-dependent polymer main-chain degradation. In mild degradation conditions, this conjugate can generate serinol-succDOX, which displayed antitumor activity in vitro. In vivo biodistribution studies in B16F10 tumor beared animals showed that APEG-DOX had prolonged plasma circulation. Moreover, administration of APEG-DOX conjugates led to significantly less deposition of DOX in liver and the spleen. Polycarbonate and PEG diblock copolymers

comprising acid-labile groups were prepared by the ROP of mono-2,4,6-trimethoxybenzylidene-pentaerythritol carbonate (TMBPEC) and mono-4-methoxybenzylidenepentaerythritol carbonate (MBPEC). The resultant micelles showed a high drug loading capacity and a significantly faster drug release rate at endosomal pH values than that at the physiological pH [155]. However, a limitation of these micelles is that they are not stable at physiological pH level for a long time.

3.1.3. Photo responsive biopolymers Light is indispensable in human lives and also is a useful stimulus for clinical operation. Therefore, synthesis of photosensitive polymers has attracted great interest in recent years. The most studied photo-chromic groups are azide groups, cinnamoyl groups, spiropyran, coumarin and 2nitrobenzyl groups (Fig. 11) [156–158]. Photosensitive properties can be applied as a trigger of conformational change of polypeptides. For example, the conformation of PLL modified with azobenzene was investigated in connection with their photochromic behavior caused by the trans  cis photoisomerization of the azo groups present in the side chains. These photosensitive polypeptides exhibited photoinduced ˇ  helix changes, explained on the basis of the differences in geometry and hydrophobic character of the trans and the cis azobenzene units [159]. Fissi et al. prepared spiropyran modified high molecular weight poly(glutamic acid). It was demonstrated that the photoisomerization of the photochromic side chains is able to trigger the coil/␣-helix transition of the macromolecular main chains only in a narrow “window” of solvent composition [160]. Besides polypeptides, aliphatic polyesters with chromophoric units have also been extensively investigated. For example, photocross-linkable polycarbonate was prepared by the ROP of a functionalized cyclic carbonate monomer containing a cinnamate moiety [46]. Li and coworkers reported a well-defined photosensitive polymer, with chromophores connected by pH-labile cyclic acetal linkages [161]. It was demonstrated that the stability of pH-labile cyclic acetal linkages could be tuned by the photoisomerization of cinnamyl chromophores, which makes these polycarbonates interesting in potential applications for photosensor development and light-triggered drug delivery. Coumarin has widespread occurrence in plants and is used in biology, medicine, cosmetic and polymer science [162]. It is used as a photoinduced cross linker in biomedical applications. Yamamoto et al. prepared copoly(l-lysine) containing ε-7-coumaryloxyacetyl-l-lysine residues. When irradiated by light, the photo-cross-linking reaction proceeded slowly between coumarin moieties in the side chains to give a cis head-to-head cyclo coumarin

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N (A)

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Fig. 11. Chemical structures and photo-induced transitions of chromophores. (A) Reversible trans (left) and cis (right) geometric isomers of azobenzene. (B) Reversible photodimerization of cinnamoyl groups. (C) Reversible photoisomerization of spirobenzopyran derivatives [156]. Copyright 2009, Royal Society of Chemistry. Reprinted with permission. (D) Photo-cross-linking of the coumarin-modified polymers [157]. Copyright 2001, Wiley-VCH Verlag GmbH & Co. KGaA. Reprinted with permission. (E) Dissociation of 2-nitrobenzyl derivatives [158]. Copyright 2007, Wiley-VCH Verlag GmbH & Co. KGaA. Reprinted with permission.

[163]. Matsuda and coworker prepared a series of liquid polymers of coumarin-endcapped poly(ε-caprolactone-cotrimethylene carbonate) with different arms. These liquid photocurable precursors were used to obtain desired geometries of cross-linked biodegradable materials for the microfabrication of medical devices and drug encapsulation [164]. 3.1.4. Redox responsive biopolymers The distinct redox potential difference between the intracellular space (reducing) and the extracellular space (oxidizing) provides an opportunity for promising delivery of drug based on disulfide-containing polymers [165]. Disulfide bonds are widespread covalent bonds in natural peptides and proteins and play an important role in the folding and stability of proteins. They are readily

cleaved in reducing conditions and reoxidized in oxidizing conditions. Due to these unique properties some micelles sensitive to redox were prepared. In our previous work, poly(l-cysteine)-b-polylactide (PLC-b-PLA) was prepared. Because of the ease of disulfide exchange with thiols, the obtained micelles are reversible shell crosslinked (SCL) micelles [98]. Lu et al. designed macrocyclic 1,4,7,10-tetraazacyclododecane-N,N ,N ,N -tetraacetic acid (DOTA) Gd(III) chelate and PGA conjugate containing a degradable disulfide spacer as a magnetic resonance imaging (MRI) contrast agent. The degradable disulfide spacer between Gd(III)-DOTA and PGA is crucial for the release and excretion of Gd(III) chelates, which shows great promise to solve the safety problems suffered by macromolecular Gd(III) complexes [166]. The cleavage of disulfide bonds can also be designed as a trigger for drug

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delivery. Tang et al. prepared a disulfide-linked biodegradable diblock copolymer of PCL and poly(ethyl ethylene phosphate) to develop a micellar nanoparticle system for intracellular drug release triggered by glutathione (GSH) in tumor cells. As expected the intracellular DOX release was accelerated at a higher GSH concentration, which led to more significant growth inhibition to A549 cells [167]. Kataoka and coworkers prepared PEG-SS-P[Asp(DET) containing biocleavable disulfide linkage between PEG and polycation segments to trigger PEG detachment. They explained that the detachment of PEG at the cell surface can increase the cellular uptake of the micelles. On the other hand, the detachment of PEG inside endosomes would cause the interaction between the exposed cation segments and the endosomal membrane and/or would increase endosomal pressure, enabling effective endosomal escape [168]. Many other stimuli-responsive polymers are used in the biomedical fields including polymers that are responsive to glucose, electric or magnetic fields, ionic strength responsive polymers. However, little work has been done to incorporate these stimuli-responsive polymers into synthetic biodegradable polymers. Therefore, they not included here. 3.2. Electroactive biomaterials After the discovery that electrical signals can regulate cell attachment, proliferation and differentiation [169], many researchers sought to incorporate conducting polymers into biomaterials to take advantage of electrical stimuli. In conducting polymers, polypyrrole (Ppy) has been widely studied in biomedical applications. Schmidt and coworkers made significant contributions to the application of PPy in the biomedical field [170,171]. They first employed PPy for tissue engineering purposes, demonstrating that an electrical stimulus in neurotrophic growth factors (NGF) induced PC-12 cells cultured on PPy significantly enhanced PC-12 neurite outgrowth and spreading. Moreover, they further studied the cause of this enhancement and concluded that the electrical stimulation increased the adsorption of serum proteins, which helped improve the growth and proliferation of cells. Subsequently, Lakard et al. [172], George et al. [173] and several other groups investigated cell adhesion and proliferation by culturing different cell lines on PPy [174–176]. Another conducting polymer, PANi, was studied by Mattioli-Belmonte et al., demonstrating that PANi was biocompatible in vitro and in long-term animal studies in vivo [177]. Wei and coworkers [178] reported that PANi films functionalized with the bioactive laminin-derived adhesion peptide YIGSR (Tyr-Ile-Gly Ser-Arg) exhibited significant enhanced PC-12 cell attachment and differentiation. Despite the advantage of these conducting polymers, some issues related to their application still exist: poor solubility in most common solvents, poor polymer-cell interaction and the lack of biodegradability. Therefore, it is a very important and challenging task to overcome these limitations if conductive polymers are to be applied as tissue engineering scaffolds.

As models of conducting polymers, oligomers showed many advantages over polymers, such as good solubility and easier synthesis. Because of the same redox behavior, oligomers were used instead of conductive polymers to obtain electroactive biomaterials. In 2002, Rivers et al. first incorporated pyrrole and thiophene oligomers with aliphatic chains using degradable ester linkages to fabricate a biodegradable electrically conducting polymer (BECP). The polymer showed good biocompatibility in vitro and in vivo as shown in Fig. 12 [169]. Guo et al. [179] demonstrated that the electroactive silsesquioxane precursor, N-(4-aminophenyl)-N -(4 -(3-triethoxysilylpropyl-ureido) phenyl-1,4-quinonenediimine) (ATQD), containing aniline trimer covalently modified by oligopeptide could be a kind of promising biomaterial for tissue engineering. Bioactive material ATQD-RGD could support PC-12 cell adhesion and proliferation and could stimulate spontaneous neuritogenesis in PC-12 cells in the absence of NGF as shown in Fig. 13. Based on the above work, Chen and coworkers., chose aniline oligomers (especially aniline pentamer with dicarboxyl end groups) as an electroactivity resource, which was incorporated with degradable polymers such as PLA, PCL and natural biopolymer chitosan, to prepare new biodegradable electroactive biomaterials. First, triblock and multiblock copolymers of PLLA and aniline pentamer were prepared by a condensation polymerization reaction [180,181]. These copolymers possessed good electroactivity, solubility and biodegradability similar to pure PLA. In vitro cell evaluation showed that the electroactive copolymers were innocuous and could indeed promote the attachment and growth of rat C6 glioma cells. Moreover, in comparison experiments with and without applied electrical potentials, the doped electroactive copolymers improved the differentiation of PC-12 cells, as shown in Fig. 14. Most electroactive polymers containing oligomers cannot dissolve in water, hindering their application in vivo. A new kind of water-soluble electroactive polymer, aniline pentamer cross-linking chitosan, was prepared by Chen’s group [182,183]. This new polymer showed good electroactivity even in aqueous solution. The MTT assay, cell adhesion test, and degradation assessment in the presence of enzyme confirmed that these polymers had good biocompatibility and biodegradability. Electroactive polymers can improve the neuronal differentiation of PC-12 cells, even without the extra electrical stimulation, as shown in Fig. 15. For conducting polymers, high conductivity is considered to affect the growth and differentiation of cells; however, oligomers without high conductivity and polymers containing oligomers also showed improvement in cell differentiation even without extra electrical stimulation. In order to find the reason, aniline pentamer cross-linking chitosan with a low molecular weight was prepared [183]. Adding this electroactive polymer in culture medium can promote the differentiation and proliferation of the cells because the cells readily exhibited neural-like phenotype (Fig. 16(a and b)). While the cells showed only proliferation without electroactive polymer in culture medium (Fig. 16(c and d)). In the culture medium,

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Fig. 12. In 2002, Rivers et al. firstly incorporated pyrrole and thiophene oligomers with aliphatic chains using degradable ester linkages to fabricate a BECP. Biocompatibility assessment of BECP showed good biocompatibility in vitro and in vivo for this polymer. (A) Human neuroblastoma cells cultured in vitro on BECP films demonstrated attachment and neurite extension after 1 day(left) and significant proliferation after 8 days (right), indicating good cell compatibility. (B) BECP and FDA-approved poly(lactic-co-glycolic) (PLGA) (control) were implanted subcutaneously in rats to assess in vivo compatibility. Histological tissue sections (stained with hematoxylin and eosin) of implanted BECP (left) and PLGA (right) demonstrated comparably low inflammatory responses on the 29th day [169]. Copyright 2002, Wiley-VCH Verlag GmbH & Co. KGaA. Reprinted with permission.

the only difference due to the electroactive polymers may be the exchange of the ions between the medium and polymer, and between the polymer and cells, so that the electroactivity changed the ion exchange between the cells and the medium. Although conducting polymers have good biocompatibility and can stimulate cell differentiation under electrical stimulation, the non-degradability of the polymer and difficulty in processing have inhibited the medical applications. Polymers containing electroactive oligomers not only have good solubility and biocompatibility, but also can stimulate the differentiation of cells even without extra stimulation. If the mechanism between the electroactivity and cell differentiation could be elucidated, the electroactive biomaterials could have more applications in fields such as neuronal tissue engineering, cardiovascular tissue engineering, etc. 3.3. Specific bonding biopolymers Alternative biodegradable platforms have been described in studies of nanoconjugate drug delivery polymers such as poly(l-glutamic acid)s, PLHis, polysaccharides, and PLLA, PLGA [184–186]. As drug or DNA carriers, they can self-assemble into small sized (10–200 nm) particles when conjugate to hydrophilic, hydrophobic or pH and thermo sensitive polymers. This enhances the permeability and retention effect in tumor vasculature and makes them suitable for injection and enhances their deposition in tumors, a strategy called passive targeting [187]. Passive targeting can make nanoparticles approach tumor cells and deposit to a degree, but not interact with cancer cells directly. This results in decreased efficiency for tumor therapy.

Specific targeted delivery is an active targeting method directed to a particular function group-target conjugate to help overcome the deficiency in the passive targeting protocol. Targeted delivery can deposit anticancer drugs or DNA at desired sites, reducing systemic toxicity and enhancing therapeutic efficacy [188–190]. Active targeting is achieved by linking targeting ligands such as antibodies, peptides, nucleic acid aptamers (Apt), carbohydrates, and small molecules to the surface of long-circulating nanoparticles, to deliver the drug encapsulated nanoparticles to specially identified sites to minimize undesired effects [191]. Specific targeting can be induced by conjugation of targeting ligands to the shell of the micelles, which are prone to uptake into tumor cells. Recent studies showed that targeted nanoparticles have better antitumor activity compared with nontargeted nanoparticles [192–195]. Antibodies that retain the specificity for their targets are now more commonly used for active targeting therapeutics. Several antibodies have been used in clinic to target receptors expressed specifically on tumor cells. For example, Herceptin® is an antibody against Her-2 and Avastin® (bevacizumab) is a monoclonal antibody targeting the vascular endothelial growth factor (VEGF) [196]. McCarron et al. constructed nanoparticles comprising a layer of peripheral antibodies (Ab), directed towards the Fas receptor (CD95/Apo-1) covalently attached to PLGA nanoparticles loaded with camptothecin. Cytotoxicity studies of the camptothecin contained nanoparticles comprising a layer of peripheral antibodies on HCT116 cells showed that they were very effective, with almost 100% efficiency at 72 h [197]. Peptides with short sequences of 5–10 amine acids can be used in binding assays to target tumors. One example is a cRGD peptide with a sequence of cyclic (Arg-Gly-Asp-d-

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Fig. 13. Wei et al. demonstrated that the electroactive silsesquioxane precursor, ATQD, containing aniline trimer covalently modified by oligopeptide could be a kind of promising biomaterial for tissue engineering. Bioactive material ATQD-RGD could support PC-12 cell adhesion and proliferation and could stimulate spontaneous neuritogenesis in PC-12 cells in the absence of NGF as shown in this figure. (A) Phase contrast images of PC-12 cell morphology of (a) TCP, (b) TCP with NGF, (c) ATQD-RGD, and (d) ATQD-RGD with NGF on day 10; (B) Neurite length distribution chart for ATQD-RGD substrates with and without NGF [179]. Copyright 2007, American Chemical Society. Reprinted with permission.

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Fig. 14. Triblock and multiblock copolymers of PLA and aniline pentamer possessed good electroactivity, solubility and biodegradability similar to pure PLA. In vitro cell evaluation showed that the electroactive copolymers were innocuous and could indeed promote the attachment and growth of rat C6 glioma cells. Moreover, in the comparison experiments with and without applying electrical potentials, the doped electroactive copolymers had the ability of improving the differentiation of PC-12 cells. (A) Representative fluorescence micrographs of PC-12 cells for the substrates (a) TCPS (−) without electrical stimulation, (b) TCPS (+) exposed to electrical stimulation, (c) EM PLAAP (−) doped with CSA without electrical stimulation, (d) EM PLAAP (+) doped with CSA exposed to electrical stimulation on day 4; (B) the mean neurite length of PC-12 cells cultured on the substrates of EM PLAAP (−), TCPS (+), and EM PLAAP (+) on day 4 [181]. Copyright 2008, American Chemical Society. Reprinted with permission.

Phe-Lys), which targets the ␣v ␤3 integrin. Nasongkla et al. conjugated cRGD to maleimide-terminated poly(ethylene glycol)-PCL (MAL-PEG-PCL) copolymer with a fluorescent marker in the micelle core [198]. The result by flow cytometry showed that the percentage of cell uptake increased with increasing cRGD density on the micelle surface and there was a 30-fold increase with 76% cRGD attachment. Nucleic acid ligands such as Apt and spiegelmers are DNA or RNA oligonucleotides that represent novel classes of target agents. In vivo studies were carried out by Farokhzad and coworkers [194] by intratumoral injection of xenografted nude mice with LNCaP tumor cells using Dtxl-encapsulated nanoparticles of

poly(d,l-lactic-co-glycolic acid)-block-poly(ethylene glycol) copolymer with the A10 2 -fluoropyrimidine RNA Apt. The result showed that five of seven xenografted nude mice demonstrated complete tumor reduction with Dtxl-Nanoparticles-Apt bioconjugates injection while only two of seven xenografted nude mice demonstrated complete tumor reduction with Dtxl-Nanparticles injection. This result demonstrates the potential utility of nanoparticle-Apt bioconjugates for cancer therapy. Carbohydrates such as galactose and mannose are found to be specific ligands to the asialoglycoprotein receptor (ASGPR), which is overexpressed in hepatocellular carci-

Fig. 15. Aniline pentamer cross-linking chitosan can obviously improve the neuronal differentiation of PC-12 cells even without the extra electrical stimulation. The visualization of PC-12 neurite outgrowth by micrographs are given here for the substrates (A) without electroactivity (chitosan), and (B) with electroactivity (aniline pentamer cross-linking chitosan) on the fifth day [183]. Copyright 2008, American Chemical Society. Reprinted with permission.

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Fig. 16. After adding the aniline pentamer cross-linking chitosan polymer in the culture medium directly, the cells showed obvious differentiation with electroactivity, but the cells showed obvious proliferation without electroactivity. Here is the visualization of C-6 outgrowth by micrographs in the culture medium with electroactivity ((a) and (b)), and without electroactivity ((c) and (d)).

noma [199], making it a useful target for liver-specific chemotherapy. Cho and coworkers loaded paclitaxel inside the galactose-conjugated poly(ethylene glycol)-co-poly(␥benzyl l-glutamate) block copolymer (gal-PEG-b-PBLG) micelles [200]. A comparison study showed that the in vitro cytotoxicity of micelles loaded with galactose demonstrated a 30% increase compared to an analogous non-ASGPR expressing cell line SK-Hep01. As a form of vitamin B, folic acid (FOL) is a small organic molecule for cancer targeting. The expression of folate receptors is higher in many epithelial tumors than in normal tissue. It is over expressed in more than 90% of ovarian carcinoma. For example, the FOL receptor is overexpressed (100–300 times) in a variety of tumors [201]. Park and coworkers functionalized DOX-containing PEGPLGA micelles with FOL to show significantly increased uptake and cytotoxicity in KB cells [200]. 3.4. Biopolymers for tracing and bioimaging Bioimaging and tracing, such as optical imaging, MRI, nuclear imaging, and ultrasound have been important tools for disease diagnosis and treatment, and are used in clinical applications to provide predominantly either anatomical information or functional information at a macroscopic level [202]. However, current imaging probes are poor in

sensitivity and specificity, hampering their application. In recent years, biopolymer-based bioimaging probes have emerged from the combination of imaging components and biodegradable synthetic polymers such as block, graft, branched, multivalent copolymers and dendron-like polymers with enhanced stability, low toxicity, long half-life and improved target specificity [203]. This section reviews the current development in biopolymer-based imaging and tracing probes and their potentials in biomedical applications. 3.4.1. Biopolymers for optical tracing and bioimaging Optical tracing and bioimaging are among the most important technologies in the biomedical field and suit clinical application in that fluorescent probes have low toxicity, high sensitivity, and can recognize molecules, proteins, etc. Optical tracing and bioimaging include many different acquisition techniques using light with various wavelengths. Near-infrared fluorescent (NIRF) imaging probes are particularly useful because near-infrared (NIR) light can penetrate tissue due to relative weak absorption of NIR by the components in the surface tissue, such as hemoglobin, water and lipids. Ideal NIRF probes for optical imaging in vivo should have the characteristics of peak fluorescence in a range from 700 to 900 nm, high quantum yields, narrow excitation/emission spectra, functional

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groups for chemical conjugations, high chemical and photo stability, excellent biocompatibility, biodegradability, excretability, etc. [204]. Biopolymer based NIRF probes are more available in clinic because of their long half-life in vivo circulation, stability, low toxicity, high targeting ability and a low background signal. In this part, the development of biopolymer based NIRF probes is summarized. 3.4.1.1. Biopolymer-based organic probes. Most NIRF biopolymer-based organic probes are similar to indocyanine green (ICG) in structure. ICG is a tricarbocyanine dye, approved for clinical ophthalmic retinal angiography, cardiac function, and liver function testing by FDA. Many NIRF cyanine dyes have been synthesized, and several of them including Cy5.5 and Alexa 680 are commercially available [205]. The most widely-applied biopolymer-based organic probes, for which some barriers such as rapid clearance in vivo were avoided, were developed by Weissleder and colleagues. This group explored the use of biocompatible and optically quenched NIRF imaging probes with an enzymatically cleavable polymer backbone that can generate a strong NIRF signal after enzyme activation [206]. A graft copolymer consisting of PLL sterically grafted by multiple MPEG chains was used as a vehicle of quenched probes to tumors. Each PLL backbone includes an average of 92 MPEG molecules and 11 Cy5.5 molecules, yielding (Cy5.5)11 -PLL-g-MPEG92 . The graft copolymer contains 44 unmodified lysines on the backbone as sites for cleavage by enzymes, such as trypsin and cathepsines with lysinelysine specificity. In in vivo experiments, the NIRF probe carrier accumulated in solid tumors due to its long circulation time and the enhanced permeability and retention (EPR) effect. EPR effects exit in solid tumors. They have rich blood vessels which have irregular and imcomplete architectures. Large gaps exit between endothelial cells. At same time, impaired lymphatic clearance also exit in solid tumors. All these factors lead to high selective permeability and retention of macromolecules and lipids in solid tumors, which was defined as EPR effect [187]. In vivo imaging showed a 12-fold increase in NIRF signal after the copolymer was cleaved by lysosomal proteases in tumor cells, allowing the detection of tumors with submillimetersized diameters. The family of matrix metalloproteinases (MMPs) that is overexpressed in tumor comprising over 20 enzyme subtypes is an important target site for NIRF probes. Matrix metalloprotease-2 (MMP-2) (i.e., gelatinase) can cause the degradation of the extracellular matrix, and is involved in tumor infiltration and tumor-induced neovascularization. The MMP-2-activatable NIRF probes with the MMP-2 substrate peptide Gly-Pro-Leu-Gly-Val-Arg-Gly-Lys(FITC)Cys-NH2 can be used to distinguish an MMP-2-positive cell line, the human fibrosarcoma cell line (HT1080), from an MMP-2-negative cell line, the human breast cancer cell line (adenocarcinoma, BT20), and to determine the expression level of tumoral MMP-2 in vivo [207]. As MMPs, cathepsins including cathepsin D (CaD) and cathepsin B (CaB) are overexpressed in tumor and have potential use as tumor imaging targeting sites. A biopolymer PLL-g-MPEG based NIRF probe with CaD-

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specific peptide Gly-Pro-Ile-Cys(Et)-Phe-Phe-Arg-Leu-GlyLys(FITC)-Cys-NH2 was prepared by Weissleder and coworkers, and used to demonstrate for the first time that CaD enzyme has activity directly in vivo [208]. 3.4.1.2. Biopolymer-based inorganic probes. Compared with organic probes, inorganic probes such as quantum dots (QDs) and gold nanoparticles (AuNPs) have several advantages, including tunable excitation and emission wavelengths, high quantum yields, specific targeting ability, high quality photos and chemical stability [209]. Biopolymer conjugated inorganic probes have long circulation time, low immunogenicity, low toxicity and the ability to penetrate leaky endothelial barriers to overcome the limitation of nude inorganic probes [204]. QDs are among the most promising and fascinating fluorescent labels for biotracing and bioimaging. Wu and coworkers used amphiphilic PEG-b-PLL diblock copolymer coated QDs that could highly specifically link to immunoglobulin G (IgG) and streptavidin to label the breast cancer marker Her2 on the surface of fixed and live cancer cells. Compared with organic dyes such as Alexa 488, functional QDs are more specific, bright and photostable. This group simultaneously detected two cellular targets with one excitation wavelength through functional QDs with different emission spectra [210]. Chen and coworkers reported a biopolymer based probe labeled with arginine-glycine-aspartic acid (RGD) peptide using PEG as the linker (Fig. 17) [211]. The probe was demonstrated to target integrin ˛v ˇ3 overexpressed by the majority of tumor vasculature in vitro, ex vivo, and in living mice. After six hours of the injection of the QD705-PEGRGD probe, the maximum fluorescence signal intensity was shown in tumor tissue, with good contrast to nude QD705 and Cy5.5-RGD. Park and colleagues prepared polyethylene glycol (PEG) modified-12 nm quantum dot-streptavidin (QDstrep) nanoparticles with a biotin-cell penetrating peptide (CPP) bound to the surface via biotin-streptavidin interactions, which could be specifically dePEGylated in response to the presence of the matrix MMP-2 enzyme (Fig. 18) [212]. More than nine PEG chains per single QD were needed to effectively inhibit the cellular uptake of modified QD particles. The cellular uptake of modified QD was down to around 20% compared with that of a nude QD. After the cleavage of the MMP-2-specific substrate in the immobilized PEG chains, the cells took up the QDs by exposing cell-penetrating peptides to the cell membrane. AuNPs are also potential fluorescent agents for biotracing and imaging. Mason and coworkers prepared a biopolymer based fluorescent probe using 15 nm AuNPs stabilized by heterobifunctional PEG and covalently combined with F19 monoclonal antibodies [213]. Darkfield microscopy was used to image the tissue samples near the nanoparticle resonance scattering maximum (560 nm). Tumor tissue samples treated with gold nanoparticles with nonspecific control antibodies and healthy pancreatic tissue treated with mAb-F19-conjugated gold nanoparticles both exhibited correctly negative results and showed no tissue imaging. Similarly, gold nanoparticles and gold nanorods immobilized by a PLGA-g-MPEG graft copolymer

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Fig. 17. A biopolymer based probe was labeled with RGD peptide using PEG as the linker. PEG denotes poly(ethylene glycol) (Mw = 2000) [211]. Copyright 2006, American Chemical Society. Reprinted with permission.

Fig. 18. Schematic presentation of MMP-2-enzyme-specific dePEGylation and intracellular QD delivery [212]. Copyright 2009, American Chemical Society. Reprinted with permission.

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showed excellent stability in aqueous solution at different pH values and elevated temperatures as well as in serum. These characteristics make these very powerful materials for in vivo applications including drug delivery or imaging [214]. 3.4.2. Biopolymers for MRI MRI can provide superb anatomical information and produce high quality imaging in vivo with high spatial and temporal resolutions. Compared with other imaging modalities, MRI yields several advantages such as being non-invasive, non-ionizing radiation, excellent soft tissue contrast, high sensitivity to blood flow and discrimination in any imaging plane. Biopolymer-based MRI bioimaging probes have some advantages such as low toxicity, increasing contrast, long half-life of in vivo circulation and easy functionalization. They have promising potentials in biomedical applicaition [202,203]. Several paramagnetic (Gadolinium (Gd) based) and superparamagnetic (iron oxide) MRI probes are discussed in detail below. 3.4.2.1. Biopolymer-based paramagnetic probes. Paramagnetic or positive contrast MRI probes are metal ions with unpaired electrons, such as Gd3+ , Mn2+ , etc. Biopolymerbased paramagnetic MRI probes are available in clinics because of their advantages, such as low toxicity and stability. Gd is an excellent MRI probe because of its short T1 and ferromagnetic properties. Gd-chelate probes modified with biocompatible synthetic polymers such as polypeptides and PEG have unique pharmacological properties and can be used in vivo. Gupta et al. reported a biopolymerbased MRI probe that was Gd-labeled and functionalized with a PLL-g-MPEG-DTPA (diethylenetriaminepentaacetic acid) graft copolymer to modulate functional properties [215]. In their experiments, twelve rats were treated with 1.5-T MRI after intravenous injection of Gd labeled MPEGPLL-DTPA with a dose of 35 ␮mol kg−1 . The vasculatures of the infected and contralateral normal legs were depicted well immediately after intravenous injection of the probe. The biopolymer-based probe was accumulated at the site of infection 12 h after injection and was more pronounced at 24 h; the signal intensity at inflammation sites went down to the baseline after 72 h. Lu and colleagues synthesized biodegradable biopolymer-based Gd-DTPA l-cystine bisamide copolymers (GCAC) as safe and effective probes for MRI and evaluated their biodegradability and efficacy in MR blood pool imaging in an animal model [216]. The polymeric Gd(III) chelates readily degraded into smaller molecules in incubation with 15 mM cysteine via disulfide-thiol exchange reactions in vitro and in vivo and showed strong contrast enhancement in the blood pool, major organs and tissues of rats at a dose of 0.1 mmol Gd kg−1 . The GCAC MRI probe, which can degrade into low molecular weight Gd(III) chelates and can be rapidly cleared from the body, has potential for use in cardiovascular and tumor MRI. In a similar manner and by the same group, PLGA-cystamine-(Gd-DO3A) was synthesized in high yield with 55% Gd-DO3A conjugation efficiency and the contrast-enhanced MRI was investigated in mice

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bearing MDA-MB-231 breast carcinoma xenografts [217]. The PLGA-cystamine-(Gd-DO3A) MRI probe resulted in significant contrast enhancement in the blood pool, major organs and tumor tissue, but minimal long-term tissue retention. Biodegradable polysuccinimide (PSI) derivatives conjugated with diethylenetriaminepentaacetic acid Gd (DTPAGd) [PSI-g-mPEG-C16-(DTPA-Gd)] were synthesized as biopolymer-based MRI probes by Cho and colleagues [218]. In vitro MRI tests with a concentration of Gd below 9.4 × 10−4 M showed an image contrast better than that of Omniscan® , a commercial product; the signal intensity of PSI-mPEG-C16-(DTPA-Gd) at 1.2 × 10−4 M (Gd) was similar to the signal intensity of Omniscan at 4.7 × 10−4 M (Gd).

3.4.2.2. Biopolymer-based superparamagnetic probes. Superparamagnetic or negative contrast MRI probes based on iron oxides can provide higher contrast and good biocompatibility, and are easily produced. Biopolymer-based superparamagnetic MRI probes are fascinating for their stability, low toxicity and good contrast [219]. Riffle and coworkers immobilized 8.8 nm superparamagnetic iron oxide (SPIO) particles with hydrophilic triblock copolymers containing controlled concentrations of carboxylic acid groups in the central segments and poly(ethylene oxide) tails (PEO-b-COOH-b-PEO). This MRI probe was stable at the physiological pH (7.4) and lower pH values than 7.4, suggesting that it will be stable in blood. The saturation magnetization of this probe was approximately 65–70 emu g−1 , which was better than others [220]. Superparamagnetic polymeric micelles with SPIOs stabilized by amphiphilic MPEG-b-PCL were prepared by Gao and colleagues as a new MRI probe with high sensitivity [221]. The hydrophilic PEG corona made the MRI probes stable in aqueous solution with an ultrasensitive MRI detection limit of 5.2 ␮g mL−1 (5 nM). Similarly, an alternative synthetic approach was investigated with manganese doped superparamagnetic iron oxide (Mn-SPIO) nanoparticles in place of SPIO to form ultrasensitive MRI contrast agents for liver imaging by Ai’s group [222]. The MPEG-bPCL based MRI probes had a T2 relaxivity of 270 (Mn+Fe) mM−1 s−1 . With these probes, the liver contrast signal intensity changed 80% at 5 min after intravenous injection and the time window for enhanced-MRI could reach at least 36 h. Gao and coworkers prepared multifunctional polymeric micelles from cRGD-PEG-b-PLA, composed of DOX that can be released through a pH-dependent mechanism. In this process cRGD ligands first target ␣v ␤3 integrins on tumor endothelial cells. and subsequently induce receptor-mediated endocytosis for cell uptake, and then SPIO nanoparticles are loaded inside the hydrophobic core for MRI detection [223]. With the biopolymer-based mulitifunctional MRI probes, efficient ␣v ␤3 -mediated endocytosis led to a more significant darkening contrast of MRI from cRGD-encoded micelles compared with that without cRGD. Specifically, at a level of 6.25 Fe ␮g mL−1 , the MRI signal intensity decreased from 73.8 ± 7.0 for micelles without cRGD to 30.2 ± 3.5 for cRGD-encoded micelles.

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3.4.3. Other biopolymer-based tracing and bioimaging In addition to optical bioimaging and tracing, nuclear bioimaging including planar gamma scintigraphy (PGS), single photon emission computed tomography (SPECT), positron emission tomography (PET), ultrasound imaging, and X-ray computerized axial tomography (CT) are also important imaging technologies used in clinic. Nuclear imaging techniques have the advantages of excellent sensitivity, so that a minute quantity of tracer molecules is needed and rich biochemical information on pathological conditions. Therefore, these techniques are widely used in clinics. PGS can compress the complex anatomical structure of organs into a two dimensional representation, with quantification of tissue distribution as a percentage of the injected dose. Biopolymer-based PGS probes have been developed with high stability and specificity. To increase targeting, Torchilin prepared a polychelating agent-biotin conjugate through the interaction of biotin-maleimide with PLL modified with multiple residues of diethylenetriaminepentaacetic acid, which contained amino-terminal pyridylthio-propionate groups. It can be easily loaded with multiple metal atoms such, as 111 In, and can interact specifically with avidin (as agarose) [224]. 111 In-loaded DTPA-PLL-Biotin could be delivered to an avidin-containing matrix with almost 15 times more radioactivity than DTPA-biotin under the same conditions. Similarly, Li and colleagues prepared a PGS radiotracer 111 In-DTPA-PEG-C225 using PEG as a linker between the monoclonal antibody and metal chelator DTPA. The probes can be selectively localized to A431 tumor xenografts, in which the endothelial growth factor receptor (EGFR) is overexpressed 3-fold higher than in MDA-MB-468 xenografts. They probes also can reduce liver uptake level, resulting in improved visualization of EGFR-positive tumors [225,226]. Single photon emission computed tomography (SPECT) can be used to obtain three-dimensional information with the same probes as those for PGS, and PET, offering more accurate imaging data with the limitation of short half-life of PET probes. 99m Technetium-labeled DTPAPEG-folate targeting the lymphatic system of metastatic tumors was prepared and tested by Lu and coworkers [227]. The biopolymer based SPECT radionuclide entered KB cells through the folate receptor endocytosis pathway in vitro. DTPA-PEG-folate was in excess of 98% in radiolabeled yield while specific activity of 7.4 kBq (0.2 ␮Ci ␮g−1 ) was achieved. After subcutaneous injection, the probes exhibited an initial increase and subsequent decline of accumulation in popliteal nodes in normal Wistar rats. A fast accumulation and clearance was observed with a radioactivity amount of 5.91 ± 1.55% ID g−1 in the lymph nodes at 15 min post-injection; it increased to the maximum (13.43 ± 2.21% ID g−1 ) at 1 h and then decreased to 2.31 ± 0.28% ID g−1 at 4 h. Except for the kidney, uptake of [99m Tc]DTPA-PEG-folate by other tissues was rather little. The lymphatic vessels were readily visualized by SPECT with this probe in a normal rabbit imagine study. Ultrasound bioimaging has many advantages, such as versatility, being noninvasive, low risk and being costeffective, so it is widely used in clinics. The most used approach of ultrasound bioimaging is the intravenous

injection of microbubbles, based on the principle of using sound waves to detect a difference in density between the probe (microbubbles) and the surrounding medium (blood or soft tissue) at different time points during the examination. Many biocompatible, biodegradable and nontoxic polymers such as PLA, PCL, poly(d,l-lactic-co-glycolic acid) and even polypeptides can be used to encapsulate microbubbles used as ultrasound bioimaging probes [228,229]. Like MRI, CT has high spatial and temporal resolutions and can provide superb anatomical information. Therefore, it is one of the most useful diagnostic tools. Current contrast agents for CT are based on iodinated small molecules because of their high X-ray absorption coefficient, with the limitation of short imaging times. Biopolymer-based CT probes are more available in clinics for their long circulation time in plasma and good efficacy/safety profile in vivo. AuNPs coated with PEG imparted with antibiofouling properties were prepared as a CT probe by Jon and coworkers [230]. The X-ray absorption coefficient of this CT probe was 5.7 times higher than that of Ultravist® , a current iodine-based CT contrast probe. This new probe showed a much longer blood circulation time (>4 h) than Ultravist (<10 min) after intravenous injection, and accumulated in the organs containing phagocytic cells, such as the spleen and the liver. In addition, a high contrast (2-fold) between hepatoma and the normal liver tissue on CT imaging was achieved after intravenous injection of this new CT probe. 4. Biomedical application 4.1. Medical devices Synthetic biodegradable polymers have attracted considerable attention for applications in medical devices, and will play an important role in the design and function of medical devices. The general criteria of polymer materials used for medical devices include mechanical properties and adegradation time appropriate to the medical purpose. In addition, the materials should not evoke toxic or immune responses, and they should be metabolized in the body after fulfilling their tasks. According to these requirements, various synthesized biodegradable polymers have been designed and used. Some synthesized biodegradable polymers that have been used or show potential in selected fields are summarized below. 4.1.1. Drug-eluting stents (DES) DES have been widely used as a default treatment for patients with coronary artery disease. Biodegradable polymers are always used as a biodegradable and bioresorbable coatings on stents to control the release of drugs [231]. Studies of some stainless steel stents coated with sirolimus and PLA, such as Excel® (JW Medical System, China), Cura® (Orbus Neich, Fort Lauderdale, Florida) and Supralimus® (Sahajanand Medical Technologies, India), showed some interesting preliminary results [231,232]. In addition, stents coated with polyurethane as drug control layers were also reported [233]. Beside being used as biodegradable coatings, biodegradable polymers are also candidate materials for fully

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biodegradable stents [234] because of their suitable properties for controlled drug release and good mechanical performance to prevent stents from deforming or fracturing. PLLA was used to prepare a fully degradable stent [235] and an everolimus-PLLA stent (BVS® , Abbott Laboratories, IL, USA), which were under clinical evaluations [236]. 4.1.2. Orthopedic devices In the 1960s, poly(glycolide) was used to prepare completely biodegradable and bioresorbable sutures [237]. Since then, poly(glycolide), poly(lactide) and other materials such as poly(dioxanone), poly(trimethylene carbonate), PCL and poly [d,l-(lactide-co-glycolide)] have been widely used for medical devices [238]. Orthopedic devices made from biodegradable materials have advantages over metal or nondegradable materials. They can transfer stress over time to the damaged area as it heals, allowing of the tissues, and there is no need of a second surgery to remove the implanted devices. Many commercial orthopedic fixation devices such as pins and rods for bone fracture fixation, and screws and plates for maxillofacial repair are made of PLLA, poly(glycolide) and other biodegradable polymers [238,239]. As summarized in the review by Middleton and Tipton [238], many orthopedic fixation devices are commercially available. However, the research on devices for load-bearing bone repair and implantable medical devices still has a long way to go. 4.1.3. Disposable medical devices In the 21st century, environment factors concern all manufacturing industries. Many disposable medical devices, such as syringes, injection pipes, surgical gloves, pads, etc., are usually made of non-degradable plastics, resulting in serious environmental and economic issues. PLA, poly(glycolide), poly[d,l-(lactide-co-glycolide)] and PCL are all biodegradable. Therefore, they are promising materials for use in disposable medical devices meeting environmental friendly requirements. These biodegradable polymers have been used to prepare some disposable medical devices and will likely have a widening commercial application. 4.1.4. Other medical devices Biodegradable polymers have also been used to prepare anastomosis rings used for intestinal resection [240], drug delivery devices [241–243], in situ forming implants [244,245] and stents used in urology [246]. 4.2. Tissue engineering Tissue engineering is an interdisciplinary field that applies the principles of engineering and life sciences towards the development of biological substitutes used to restore, maintain or improve tissue functions [247,248]. The main purpose of tissue engineering is to overcome the lack of tissue donors and the immune repulsion between receptors and donors. In the process of tissue engineering, cells are cultured on a scaffold to form a natural tissue, and then the formed tissue is implanted in the defect part in the patients. In some cases, a scaffold or a scaffold with cells is implanted in vivo directly, and the host’s body works as

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Table 4 Some applications and potential applications of synthetic biopolymers. Polymer Polyanhydrides

Tissue engineering Bone tissue engineering [262]

Polyurethane

Vascular tissue engineering [263] Bone tissue engineering [264]

Polyelectroactive materials Polyphosphoester Poly(propylene fumarate) Polyesterurathane

Nerve tissue engineering [177] Bone tissue engineering [266] Bone tissue engineering [273] Genitourinary tissue engineering [272]

a bioreactor to construct new tissues (Fig. 19). A successful tissue engineering implant largely depends on the role played by three-dimensional porous scaffolds. The ideal scaffolds should be biodegradable and bioabsorbable to support the replacement of new tissues. In addition, the scaffolds must be biocompatible without inflammation or immune reactions and possess proper mechanical properties to support the growth of new tissues. Synthetic biopolymers such as PLLA, PCL, PGA, poly(glycolide) and poly[d,l-(lactide-co-glycolide)] have excellent biocompatibility and good mechanical properties and have been licensed by FDA for in vivo applications, so they have been the most widely used materials for tissue engineering scaffolds [249]. Considerable research has been carried out about PLLA, PCL, PGA, poly(glycolide) and poly[d,l-(lactide-co-glycolide)] used in bone tissue engineering [249–252], cartilage tissue engineering [253,254], cardiovascular tissue engineering [255], arterial replacement [256], heart valve tissue engineering [257], small intestine tissue engineering [258], nerve regeneration tissue engineering [259–261], engineering of dermal substitutes for skin regeneration [262], ligament replacement [263], genitourinary tissue engineering [264,265] and other fields. Other synthetic polymers such as polyanhydride [266], polyurethane [267,268], polyelectroactive materials [181], PPE [269,270] polycarbonate [33,56], poly(ester amide) [271], poly(amino acid) [272,273] biodegradable hydrogels [274,275] polyesterurathane [276], poly(propylene fumarate) [277] are also biodegradable and have shown many potential applications in tissue engineering. Table 4 lists the application or potential applications of these biodegradable polymers in tissue engineering. A limitation of these synthetic polymers is that the materials lack biological cues that can promote cell adhesion, proliferation and tissue recovery. In order to improve the bioproperties of synthesized polymers and to enhance their interactions with cells, composites of synthetic biodegradable polymers and natural polymers or natural polymer modified synthetic biodegradable polymers, and biodegradable polymers blends have been used to prepare tissue engineering scaffolds [278–282]. In addition, biopolymers with functional groups or synthesized polymers modified with different methods are showing many potential applications. For example, Deng et al. [76] prepared a new type of triblock copolymer poly(glutamic acid)-b-poly(l-lactide)-b-poly(glutamic acid), with PLLA chains as the hydrophobic part and poly(glutamic acid) as the hydrophilic part. RGD was connected to the polymer

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Fig. 19. In the process of tissue engineering, cells are cultured on a scaffold to form a natural tissue, and then the formed tissue is implanted in the defect part in the patients. In some cases, a scaffold or a scaffold with cells is implanted in vivo directly, and the host’s body works as a bioreactor to construct new tissues [248]. Copyright 2009, Royal Society of Chemistry. Reprinted with permission.

chains, to prepare a polymer with improved biocompatibility and enhancied cells adhesion and spreading, showing potential applications in tissue engineering. Huang et al. [180] prepared a kind of bioelectroactive triblock copolymer (PLLA-PA-PLLA) possessed good electroactivity and biodegradability, demonstrating potential applications as a scaffold in neuronal or cardiovascular tissue engineering. Wang et al. [283] reviewed various methods modifying bulk or surface properties of PLA for use as scaffolds in tissue engineering. Synthesized biodegradable polymers have been used to prepare nanocomposites in tissue engineering to combine advantages of different materials together. Polymer/bioceramic composites such as PLLA/hydroxyapatite and PLLA/bioactive glass nanocomposites have been widely studied in bone tissue engineering [284,285]. Other inorganic based biodegradable polymer composites such as carbon nano-tube based composites are also used in tissue engineering [286]. However, most of the present research concerning the above-discussed materials is still under development; practical applications remain for the future. 4.3. Drug delivery and control release Biodegradable polymers with reactive groups or responsive characteristics have been widely investigated for applications drug delivery and control release. Biodegradable polymers, such as poly(␣-malic acid), with reactive pendant carboxyl groups, can conjugate drugs (via ester or amide bonds) to form a biodegradable macromolecular prodrug to reduce the

side-effects of free drugs. Drugs can be released via the degradation of biodegradable polymers. Ohya et al. prepared poly(␣-malic acid)/DOX conjugates by attaching DOX to poly(␣-malic acid) via ester or amide bonds [287]. The poly(␣-malic acid)/amide/DOX conjugate showed much lower cytotoxic activity than free DOX and poly(␣-malic acid)/amide/DOX conjugate [287]. Jing and coworkers reported a poly(ethylene glycol)block-poly(l-lactide-co-2-methyl-2-carboxyl-propylene carbonate)/Dtxl (PEG-b-P(LA-co-MCC/Dtxl)) conjugate [56]. The poly(ethylene glycol)-block-poly(l-lactideco-2-methyl-2-carboxyl-propylene carbonate/docetaxel (PEG-b-P(LA-co-MCC)/Dtxl) conjugate showed high cytotoxic activity against HeLa cancer cells. Poly(amino acids) such as poly(glutamic acid) and poly(l-lysine) have a high density of side reactive groups (carboxyl or amine) for coupling reactions. Poly(glutamic acid)-paclitaxel conjugate (CT-2103® , Cell Therapeutics) has reached phase III clinical stage [288], showing promise for the treatment of patients with advanced non-small cell lung cancer (NSCLC) and impaired performance status (PS 2). Patients on CT-2103 required fewer red blood cell transfusions, a smaller dose of hematopoietic growth factors, less opioid analgesics, and fewer clinic visits than patients receiving gemcitabine or vinorelbine [288]. Yoo et al. reported a folate-targeted biodegradable polymeric micellar system with DOX [289]. FOL and DOX were separately conjugated to poly[d,l-(lactide-co-glycolide)]mPEG to form DOX-poly[d,l-(lactide-co-glycolide)]-mPEG and poly[d,l-(lactide-co-glycolide)]-PEG-FOL. The two di-block copolymers were mixed with free base DOX in an aqueous solution to form mixed micelles, entrapping

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DOX aggregates within the core while exposing FOL on the micellar surface. The folate-targeted micelles exhibited enhanced and more selective targeting ability than folate unconjugated micelles in vitro tests. The results of in vivo animal experiments with the folate-targeted micellar system also showed significant regression in tumor volume and an increased accumulation of DOX in the tumor tissue. These results indicate that cellular-specific drug delivery systems can be obtained by attaching specificsite-targeting groups to biodegradable polymers with active groups. Stimuli-responsive biodegradable polymers, have been widely explored as potential drug-delivery systems [290–293]. Kim and coworkers prepared a MPEG-PCL diblock copolymer aqueous solution that was a sol at room temperature, undergoing a sol-to-gel phase transition as the temperature was increased above room temperature [294]. A drug-loaded MPEG-PCL solution at room temperature immediately transformed into a gel on subcutaneously injection into rats. Sustained release of drug was observed over 30 days in the system. Huang and coworkers reported the application of pH-responsive micelles of poly(acrylic acid-b-dl-lactide) in drug delivery and controlled release [295]. The release of prednisone acetate from the polymeric micelles in vitro showed a “burst” release at pH 7.4, while only a small part of loaded drug was released at pH 1.4. This pH-responsive delivery system has potential application for gastrointestinal tract delivery systems, where the pH environment is strongly acidic in the stomach, but basic in the intestine. Wang et al. developed reactive micelles based on diblock copolymer of poly(ethyl ethylene phosphate) and PCL [127]. The micelles were surface-conjugated with galactosamine to target the ASGPR of HepG2 cells. Paclitaxel-loaded micelles bearing galactose ligands targeted HepG2 cells via ASGP-R mediation, which made the micelles with galactose ligands showing comparable activity to free paclitaxel for inhibiting proliferation of HepG2 cells. And population of HepG2 cells arrested in G2/M phase was in positive response to paclitaxel released from the paclitaxel-loaded galactosamine conjugated micelles. This result indicates that surface functionalized micelles have potential for us as drug delivery systems for enhanced chemotherapy. 4.4. Gene delivery Gene delivery has great potential for treating various human diseases [296]. Recently, nonviral vectors have been proposed as safer alternatives to viral vectors for gene delivery [297]. However, many carriers are non-degradable and the risk arises of accumulation in the body, especially after repeated administration. Furthermore, most of cationic polymers show high cytotoxicity because of adverse interactions between the cationic polymers and the membranes when the gene carriers cross certain barriers to enter the cells (Fig. 20) [298], causing loss of cytoplasmic proteins, permeabilization of cellular membranes and collapse of the membrane potential [299]. A good gene carrier should be able to deliver the target gene to specific cells with high efficacy; it should also be degradable and be excreted from the body after a given

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time period. Consequently, there is a need for biodegradable gene delivery polymers. Recently, some research has evaluated non-degradable polymers with biodegradable polycations via hydrolyzable linkers as gene carriers.

4.4.1. Poly(l-lysine)-based degradable polymers Poly(l-lysine) was initially used for DNA delivery [300,301]. However, the efficacy and utility of PLL is hampered by its low transfection efficiency and a rather high toxicity [85]. This problem is especially serious in high molecular weight PLL (Mw 25 kDa), while lower molecular weight PLL (Mw 3 kDa) can hardly form stable nanosized complexes with DNA [302]. To reduce the cytotoxicity of PLL, biodegradable and hydrophobic PLGA grafts were attached to the PLL backbone [303]. Furthermore, PLL was modified with PEG and other various targeting moieties to improve its transfection efficiency. Wolfert et al. [304] demonstrated that PEG-b-PLL exhibited higher transfection efficiency and lower cytotoxicity than PLL in human primary embryonic kidney cells. Park et al. also attached PEG to the termini of PLL grafts [305,306]. In order to provide endosomal escape properties, histidine groups were conjugated to lysine units, which resulted in 6-fold higher transfection activity than that of PLL without significant cytotoxicity. After tail vein injection, these polymer systems remained in the circulation for 3 days [307,308]. In recent years, PLL has been modified with many cell ligands such as sugar residues [309], antibodies [310,311], folate [312], cell adhesion peptides [313], and endogenous lipids [314].

4.4.2. Poly(ˇ-amino ester)s-based degradable polymers Poly(␤-amino ester)s can be synthesized by Michael addition of primary amines to diacrylate esters [315]. Poly(␤-amino ester)s are suitable for gene delivery because they contain degradable linkages. The ease in synthesis and lack of byproducts make them even more favorable candidates for the purpose discussed above [316,317]. Poly(4-hydroxy-l-proline ester) was the first biodegradable cationic polymer used as a gene carrier [318], to protect DNA from enzyme degradation. Poly(␥-(4aminobutyl)-l-glycolic acid) (PAGA) was synthesized by Kim and coworkers [319,320]. A complex of PAGA and DNA showed slower degradation than the polymer alone and a 3-fold higher transfection activity in vitro compared with PLL, without cytotoxicity [320]. In vivo animal studies with PAGA showed that serum IL-10 level peaked 5 days after tail vein injection and the detection window for serum IL-10 lased for more than 9 weeks [319]. Langer and coworkers synthesized thiol-reactive 2-(pyridyldithio)ethylamine (PDA) with poly(amino ester) [321]. When the polymers/DNA complexes were subjected intracellularly, the existence of GSH accelerated DNA separation from the complexes and its release into the cells. Especially when a thiolated ligand was attached to the polyplexes, the polymers showed nearly 20-fold higher transfection efficiency than PEI-25k in vitro [322]. Anderson et al. used poly(␤amino ester) for in vivo evaluation and nearly 4 times higher than PEI-25k and 26 times higher transfection than naked

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Fig. 20. Barriers to gene delivery. Design requirements for gene delivery systems include the ability to (I) package therapeutic genes, (II) gain entry into cells, (III) escape from the endo-lysosomal pathway, (IV) affect DNA/vector release, (V) travel through the cytoplasm and into the nucleus, and (VI) enable gene expression [298]. Copyright 2007, Elsevier Ltd. Reprinted with permission.

DNA was observed when poly(␤-amino ester) was intratumorally administrated [323].

4.4.3. Polyphosphoester-based degradable polymers PPE-based degradable polymers such as PPA, PPE and polyphosphazene (PPZ) are known to be biodegradable and biocompatible in gene delivery. The polymers can be obtained by the ROP and subsequent derivatization of 4-methyl-2-oxo-2-hydro-1,3,2,-dioxaphospholane with spermidine and aminohexyl or(methyl-)aminoethyl side chains [121,324]. PPE-EA consists of a phosphoester backbone and aminoethoxy side chains [30]. PPE-EA could condense plasmid DNA efficiently and provide pDNA resistance against attacks from nucleases. After 4–9 days, complete DNA was observed to be released from the AE-PPE polyplexes at a suitable polymer/DNA ratio. The transfection efficiencies of PPE-AE polyplexes were about two-fold higher than that of pLL-mediated transfection. PPE-EA based polyplexes also showed enhanced gene expression in vivo [31]. PPA consists of a phosphoester backbone and different pendant chains via phosphoramidate bonds, and its molecular weight is about 40–50 K [118]. PPZs were prepared with dimethylaminoethyl side chains connected to the backbones either by oxygen (DMAE-PPZ) or nitrogen (DMAEA-PPZ) [325]. DMAEAPPZ was carried out successfully in vivo and a high expression level of the reporter gene in tumor was observed, while very low levels were seen in organs [326].

4.4.4. Polyethylenimine modified with degradable polymers PEI has been used for gene delivery under both in vitro [327,328] and in vivo [329] conditions. However, many studies demonstrated that the cytotoxicity of PEI may be due to a large excess of free polymer complexation with pDNA [330,331] owing to a lack of biodegradability [332,333]. Therefore, it is important to modify PEI with degradable polymers that can retain the high transfection efficiency of PEI. Many studies have established that hydrophobic moieties affect transfection activity of cationic polymers [334,335]. Kwon and coworkers reported the synthesis of a peptide-based (–NHCHCO–) PEI-25k analogue with higher transfection efficiency and greater biocompatibility as compared with PEI-25k in vivo [336]. Tian et al. investigated the hydrophobic amino acid poly(␥-benzyl l-glutamate) segments at the hyperbranched chain ends. The polymer could effectively condense pDNA and improve transfection efficiency significantly relative to that for PEI-25k in HeLa cells [337]. Transferrin, an 80 kDa glycoprotein, is a suitable ligand for tumor targeting because its receptors are over-expressed in cancers. Thereby, transferrin-PEI was used as a gene carrier in vivo, resulting in 100–500 times higher luciferase reporter gene expression in tumors compared with that in other organs [338]. Chen et al. reported a series of multi-armed poly(l-glutamic acid)-graft-oligoethylenimine (MP-g-OEI) copolymers that possessed different charge densities. All the MP-g-OEI copolymers exhibited lower cytotoxicity and higher gene

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Fig. 21. TSP50 was immobilized onto biodegradable polymer fibers. Then TSP50-immobilized polymer fibers could selectively adsorb the anti-TSP 50 [363]. Copyright 2008, Elsevier Ltd. Reprinted with permission.

transfection efficiency than PEI-25k in the absence and presence of serum with different cell lines [339]. 4.4.5. Degradable polymers in siRNA delivery RNAi has been widely used to silence the expression of a specific target gene by a post-transcriptional silencing mechanism. For efficient siRNA delivery, siRNA should be stably and efficiently delivered into the target tissue and cells. In recent years, many cationic degradable polymers have been used as the delivery agents for RNAi [340,341]. PLL was early tested for siRNA delivery, and then polyplexes were investigated using glycosylated PLL [342] and PEG-PLL [343]. Recently, researchers proposed to obtain polymer micelles using PEG conjugated to siRNA instead of PEG-polycation complexes [344]. In this case, biodegradable linkages, such as disulfide linkages that can be degraded by GSH [345,346], ester linkages that can be cleaved by esterases [347], and amide linkages degraded by amidases [348], must be used between siRNA and polymers. Recently, Desigaux et al. demonstrated that lipidic aminoglycoside derivatives displayed a remarkably high efficiency for siRNA-based gene knockdown in GFPexpressing human lung cancer d2GFP cells and HEK293 cells [349]. 4.4.6. Other degradable polymers Biodegradable microparticle-based polymers such as poly[d,l-(lactide-co-glycolide)] are commonly used for gene delivery systems. Poly[d,l-(lactide-co-glycolide)] is able to interact with DNA to form DNA-coated particles, which protects DNA from nuclease attacks and promotese delivery into cells [350]. Poly[d,l-(lactideco-glycolide)]-pDNA microparticles provided high levels of sustained expression for 100 days [351]. In order to increase the transfection efficiency of encapsulated pDNA, poly(␤-amino ester)s were coformulated with poly[d,l-(lactide-co-glycolide)]-pDNA microparticles. Surprisingly, enhanced immunogenicity of the particles was shown in mice [352]. The triblock copolymer of poly(d,l-lactic-co-glycolic acid)-b-poly(ethylene glycol)b-poly(d,l-lactic-co-glycolic acid) also increased cellular

uptake and transfection efficiency about 10-fold in various cells [353]. So far, various biodegradable polymers have been proved to be efficient in gene delivery. Some examples of those biodegradable polymers are dendrimers modified with degradable polymers [354], poly(amido ethylenimine)s [322], poly(2-(dimethylamino)ethyl methacrylate) [355], and other synthetic biodegradable polycations [356]. 4.5. Bioseparation and diagnostics applications The development of biomedical polymers conjugated with peptide or protein domains has mostly focused on their use as bioactive materials in controlled drug delivery or tissue engineering. A new challenge arises in the development of materials for bioseparation and diagnostics applications. For these applications, materials that are biocompatible with reduced non-specific absorption and denaturation, that are able to amplify and transmit signals, and that are beneficial for high-throughput screening with enhanced sensitivity and reduced size are in great demand. To meet these demands, polymeric materials in various shapes, such as membranes, thin films, micro/nano-particles, hydrogels, and micro/nano-fibers have been widely investigated. Surface modification with polymers and polymer coated surfaces are useful for preparing biochips with wide variety applications in food industry, diagnostics, environmental monitoring, etc. The development of the oligonucleotide and protein microarrays is receiving intense interest due to their high-throughput analysis ability, which offers the potential for powerful tools in diagnostics, drug discovery, and genomic analysis. One of the two main tasks for this application is the fabrication of suitable substrates for protein or DNA immobilization. Thus, polymer surface modification or surfaces coated with functional polymers are needed for the purpose to improve biocompatibility and introduce functional groups for immobilization of the targeted analyte [357]. For example, Kuennemann and co-worker have examined a platform biosensor surface for immobilization of proteins with poly(l-lysine)-g-poly(ethylene glycol) (PLL-g-PEG)

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[358,359]. The PLL-g-PEG coated sensor surface showed very low non-specific absorption and its structure could be fine-tuned by varying the polymer compositions. As a result, the density of the proteins on the surface was almost quantitatively controlled, which is significant for improving sensitivity of the sensors. Moreover, the reversibility of the surface immobilization enables the regeneration of the biosensors. Therefore, such fine-tunable platforms are promising for use as biosensors. Bioresponsive hydrogels that change properties in response to selective biological recognition events have recently gained increasing interest for application in drug delivery, diagnostics, and tissue engineering [360]. For diagnostics applications, the biological events are represented by the macroscopic volume changes that generate signals for detection. For example, Miyata et al. have reported tumor marker (␣-fetoprotein, AFP) responsive gels fabricated by a biomolecular imprinting technology [361]. Lectin Con A and polyclonal anti-AFP antibodies were conjugated into the gels to introduce the recognition sites for specific biomarker binding. The shrinking behavior of the gels in response to AFP molecules enables the visible and accurate detection of biomarker molecules, indicating that the biomolecule imprinted gels have potential application in sensing application for diagnostics. Polymeric micro/nano-spheres and micro/nano-fibers have attracted increasing attention because they can be used as substrates to immobilize biomolecules for biomedical applications, such as controlled drug delivery, tissue engineering, diagnostics and bioseparation. Due to their large specific surface areas and relatively small size, these materials are suited to the immobilization of more compact biomolecules with a reduced device size, but enhanced sensitivity. Jiang and coworkers have reported that using electrospinning polymer nanofibrous membranes as the solid substrates for microfludic immunoassay can dramatically improve the sensitivity and signal-tonoise ratio as compared to the commercially available polymer membranes [362]. Jing and co-workers investigated the immobilization of testis-specific protease 50 (TSP50) on biodegradable polymer fibers [363]. The results showed that the TSP50-immobilized polymer fibers could selectively adsorb the anti-TSP 50 (Fig. 21), even in the presence of high concentration of BSA (104 times). The anti-TSP 50 can then be eluted simply by changing the pH, and the polymer fibers are reusable. 5. Conclusions Compared to biologically derived biodegradable polymers, synthetic biodegradable polymers do not have immunogenicity, but it is easier for them to be chemically modified and functionalized. Functionalization of synthetic biodegradable polymers has extended the application scope for these biomaterials and has greatly promoted the development in the biomedical field. The developing trends in the functionalization of synthetic biodegradable polymers can be predicted as followings: (1) Functionalization processes will become easier and highly efficient as functionalization processes with mild reaction conditions and without harmful effects on bulk properties

of polymers are pursued; (2) Functionalization will be increasingly related to biomimetics, such that synthetic biodegradable polymers will not simply combine different functions into one polymer, but instead, the different functions should have synergistic actions; (3) The application of synthetic biodegradable polymers will be further expanded, including promising potential for in vivo applications. Since development in synthetic biodegradable polymers are closely related to chemistry, materials science and biomedical science, any new technology in these fields will promote the development of synthetic biodegradable polymers. Synthetic biodegradable polymers have been very important and will make more contribution to the development of biomedical science in the future.

Acknowledgments The authors thank Jun Hu, Changwen Zhao, Junchao Wei, Chunsheng Xiao, Jianxun Ding, Yadong Liu, Jie Chen, Zhaopei Guo for their help in this review. The authors are thankful to the National Natural Science Foundation of China (20604028, 20774092, 50873102, 20974109, 21074129 and Key Program No: 50733003), and the National Natural Science Foundation of China-A3 Foresight Program (20921140264), the International Cooperation fund of Science and Technology (Key project 20071314) and Support Project (2007BAE42B02) from the Ministry of Science and Technology of China, the Knowledge Innovation Project of Chinese Academy of Sciences (KGCXYW-208) for financial support to this work.

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