聚碳酸酯综述

Progress in Polymer Science 37 (2012) 211– 236 Contents lists available at ScienceDirect Progress in Polymer Science j ourna l ho me pag e: ww w.elsev ier .com/ locate /ppolysc i Construction of functional aliphatic polycarbonates for biomedical applications Jun Feng, Ren-Xi Zhuo, Xian-Zheng Zhang ∗ Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan, 430072, China a r t i c l e i n f o Article history: Received 25 April 2011 Received in revised form 19 July 2011 Accepted 22 July 2011 Available online 2 August 2011 Keywords: Cyclic carbonate Functional aliphatic polycarbonate Ring-opening polymerization Biomedical application a b s t r a c t Aliphatic polycarbonates are one important kind of biodegradable polymers and have been commonly used as integral components of engineered tissues, medical devices and drug delivery systems. As far as the biomedical application is concerned, traditional aliphatic polycarbonates usually suffer from the strong hydrophobicity, deficient functionality, and insufficient compatibility with cell/organs. Consequently, the application is quite limited in scope. Due to the imparted appealing properties, aliphatic polycarbonates bearing specif- ically designed functional/reactive groups attract great interest from researchers in the recent years. The present review outlines the development up to date concerning the design and biomedical application of functional aliphatic polycarbonates, with an emphasis on their ring-opening (co)polymerization preparation. © 2011 Elsevier Ltd. All rights reserved. Abbreviations: (ADMC)2, 6,14-dimethyl-1,3,9,11-tetraoxa-6,14-diaza-cyclohexadecane-2,10-dione; AFM, atomic force microscope; APC, aliphatic polycarbonate yl)carbamic a 5-(2-oxo-1,3-d tion; Con A, c DHC, dihydro tering; DMAP trimethylene 5-ethoxycarbo receptors; FTI HETC, 2-(2-hy lene carbonat MAMC, 5-me dioxan-2-one; mono-4-meth dioxan-2-one; 5-methyl-5-(2 MTT, 3-(4,5-d ylidene)-1,3-d PBS, phosphat poly(ethylene carbonate); PT merization; S transmission e trimethoxyben X-ray photoel benzyl ester. ∗ Correspon E-mail add 0079-6700/$ – doi:10.1016/j. ; ATMC, 5-allyloxy-1,3-dioxan-2-one; BETC, 2-(2-benzyloxyethoxy)-trimethylene carbonate; Boc-T-CC, (4-methyl-2-oxo[1,3]dioxan-5- cid tertbutyl ester; BSA, bovine serum albumin; BTMC, 5-benzyloxyl 1,3-dioxan-2-one; t-BuOK, potassium tert-butoxide; 65CCP, ioxolan-4-yl)methyl-5-propyl-1,3-dioxan-2-one; CDI, 1,10-carbonyldiimidazole; CL, �-caprolactone; CMC, critical micelle concentra- oncanava-lin A; DBTC, 5,5-dibromomethyl-trimethylene carbonate; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DHA, dihydroxyacetone; xyacetone carbonate; DHPC, 5,5-bis(hydroxymethyl)-1,3-dioxan-2-one; DIC, N,N′-diisopropylcarbodiimide; DLS, dynamic light scat- , 4-dimethylamiopryidine; DON, 1,4-dioxan-2-one; DOX, doxorubicin; DSC, differential scanning calorimetry; DTC, dimethyl carbonate; EDC, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide; EHDO, 5-ethyl-5-hydroxymethyl-1, 3-dioxan-2-one; EMTC, 5-methyl- nyl-1,3-dioxan-2-one; FA, folic acid; EOPDC, 2, 2-ethylenedioxypropane-1,3-diol carbonate; FITC, fluorescein isothiocyanate; FR, folate R, fourier transform infrared spectroscopy; GFC, gel filtration chromatography; cHTC, 2,2-(2-pentene-1,5-diyl) trimethylene carbonate; droxyethoxy) trimethylene carbonate; HETTMC, 5-{3-[(2-hydroxyethyl)thio]propoxy}-1,3-dioxan-2-one; HTMC, 5-hydroxyl trimethy- e; IBAO, iso-butyl aluminoxane; ITC, (5S,6S)-dimethyl-5,6-isopropylidene-1,3-dioxepin-2-one; LA, lactide; MAO, methyl aluminoxane; thyl-5-acetylenecarbonyl-1,3-dioxane-2-one; MTMC, methacryloyl trimethylene carbonate; MATMC, 5-methyl-5-allyloxycarbonyl-1,3- MBC, 5-methyl-5-benzyloxycarbonyl-1,3-dioxan-2-one; MBCG, methyl 4,6-O-benzylidene-2,3-O-carbonyl-d-glucopyranoside; MBPEC, oxybenzylidene-pentaerythritol carbonate; MC, 5-methyl-5-cinnamoyloxymethyl-1,3-dioxan-2-one; MCC, 5-methyl-5-carboxyl-1,3- MDI, diphenylmethane diisocyanate; MMTC, 5-methyl-5-methoxycarbonyl-1,3-dioxan-2-one; Mn , number average molecular weight; MNC, -nitro-benzoxycarbonyl)-1,3-dioxan-2-one; MOPDC, 2,2-dimethoxypropane-1,3-diol carbonate; mPEG, methyoxyl-poly(ethylene glycerol); imethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; Mw, weight average molecular weight; NBC, 5,5-(bicyclo[2.2.1]hept-2-en-5,5- ioxan-2-one; N-CBz-Hpr, trans-4-hydroxy-N-benzyloxycarbonyl-l-proline; NHS, N-hydroxysuccinimide; NMR, nuclear magnetic resonance; e-buffered saline; PCD, poly(5-methyl-5-lauryloxycarbonyl-trimethylene carbonate); PDTC, poly(dimethyl trimethylene carbonate); PEG, glycol); PEI, polyethylenimine; PLA, poly(lactic acid); PLGA, poly(lactic-co-glycolic acid); PLLA, poly(l-lactic acid); PTMC, poly(trimethylene O, 9-phenyl-2,4,8,10-tetraoxaspiro[5,5]undecan-3-one; RCA, ricinus communis agglutinin; RGD, Arg-Gly-Asp; ROP, ring-opening poly- CROP, self-condensing ring-opening polymerization; SEC, size exclusion chromatography; Sn(Oct)2, stannous 2-ethylhexanoate; TEM, lectron microscope; Tg, glass transition temperatures; TGA, thermo gravimetric analysis; Tm, melting temperature; TMBPEC, mono-2,4,6- zylidene-pentaerythritol carbonate; TMC, trimethylene carbonate; UMTC, 5-methyl-5-phenylureidoethylcarboxyl-1,3-dioxane-2-oxo; XPS, ectron spectroscopy; Z-S-CC, (2-oxo[1,3]dioxan-5-yl) carbamic acid benzyl ester; Z-T-CC, (4-methyl-2-oxo[1,3]-dioxan-5-yl) carbamic acid ding author. Tel.: +86 27 6875 5993; fax: +86 27 6875 4509. ress: xz-zhang@whu.edu.cn (X.-Z. Zhang). see front matter © 2011 Elsevier Ltd. All rights reserved. progpolymsci.2011.07.008 212 J. Feng et al. / Progress in Polymer Science 37 (2012) 211– 236 Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 2. Glycerol-based cyclic carbonates and their (co)polymers . . . . . . . . . . . . . . . . . . . . . . 3. Pentaerythritol-derived cyclic carbonates and their (co)polymers . . . . . . . . . . . . . 4. l-Tart 5. Sugar 6. 2-(Dih 7. Dihyd 8. Amin 9. Other 10. Summ Ackno Refer 1. Introdu Compar important e ates (APCs) poor therm decade, how in pace wit field, owing ity and bio the so-calle instead an safety conc ple, biodeg implantatio [6]. Along ing their s physiologic implanted [7,8]. So far, al tus in the d used in the sciences [9– tion of prot acid) (PLGA loaded bio course of p mainly due associated accumulati aseptic infl the inheren able biocom embodied i in vivo deg rate of poly desirable fo durability i Currentl commonly investigate carbonate) bonate) (P application suffer from aric acid derived cyclic carbonates and their (co)polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221 derived cyclic carbonates and their (co)polymers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221 ydroxymethyl)-propanoic acid derived cyclic carbonates and their (co)polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 roxyacetone derived cyclic carbonates and their (co)polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 o acid derived cyclic carbonates and their (co)polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 functional cyclic carbonates and their (co)polycarbonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 ary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 wledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 ences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 ction ed with aromatic polycarbonates known as ngineering plastics [1,2], aliphatic polycarbon- have been less interesting because of their al stability and easy hydrolysis. Since the last ever, APCs have attracted increasing attention h their significant applications in the medical to their unique combination of biodegradabil- compatibility [3–5]. For medical applications, d instability or temporal stability of APCs is attractive advantage from the perspectives of erns and biofunction requirements. For exam- radable polymers do not require removal after n, thereby avoiding a second surgical treatment with the degradation of APCs after complet- pecifically intended function, the undesired al response, often associated with permanently synthetic materials, is substantially reduced iphatic polyesters appear to hold a leading sta- evelopment of synthetic degradable polymers vast field of biomedical and pharmaceutical 12]. However, previous work on the encapsula- eins or plasmid DNA into poly(lactic-co-glycolic ) microspheres led to the conclusion that those molecules might undergo inactivation in the olymer degradation [13–15]. This process is to the creation of the acidic microenvironment with the degraded polyester oligomers. The on of acid components would cause the local ammation as well [16]. In comparison, besides tly excellent mechanical properties and accept- patibility, the outstanding advantage of APCs is n the absence of acidic compounds during the radation [17–20]. In addition, the degradation carbonates is slower than polyesters, which is r the application in need of relatively long-term n the body [21,22]. y, ring-opening polymerization (ROP) is the used method to prepare APCs [23–26]. The most d APCs are represented by poly(trimethylene (PTMC) and poly(dimethyl trimethylene car- DTC) [23–25]. As far as the biomedical is concerned, those traditional APCs usually strong hydrophobicity, lack of functional- ity and insufficient compatibility with cell/organs. Those drawbacks would lead to in vivo foreign body reactions such as infections, inflammation, local tissue necrosis, and thrombosis [27]. The main resolution is directed at the design of specifically functionalized APCs via the controlled incorporation of functional/reactive groups into polymer chains. Functional groups, properly located on a poly- mer chain, may tailor the chemicophysical and biological properties of polymeric materials including hydrophilic- ity/hydrophobicity, membrane permeability, bioadhesive ability, biocompatibility and biodegradability. More inter- estingly, the presence of functional/reactive groups offers great opportunities to further post-modification including sequential binding of appropriate biochemical cues, which in turn allows for the specific interaction between materials and cells/organs for drug targeting and tissue engineering purposes based on a tailor-made biomaterial-tissue inter- face. At this point, the biofunction of such polymers would be potentially extended enormously, and the application fields appear to be greatly expanded. With this framework as the motivation, more and more efforts turn to seeking functionalized APCs for biomedical applications. One important strategy is based on the inno- vative design and ROP of carbonate monomers substituted by functional/reactive groups. Relative to condensation polymerization which necessitates efficient removal of the condensate to shift the reaction equilibrium to polymer- ization, the ROP method has no leaving compounds and proceeds under mild reaction conditions. Precise control over functional APCs is readily accomplished with respect to the number–average molecular weight Mn and poly- mer architecture by means of ROP with selected initiators and catalysts. In addition, the preparation of functional monomers facilitates the manufacture of a variety of new materials with well-defined arrangement of functional groups along the backbone, through copolymerization with other available monomers such as trimethylene carbon- ate (TMC), lactide (LA), �-caprolactone (�-CL) and so on [28–31]. Compared to the tedious procedures involved in the fabrication of functional lactones/lactides, functional cyclic carbonates are more easily prepared via typical cyclization reactions between dihydroxyl compounds and phosgene or its analogues [29,32–37]. Note that most reported func- tional cyclic carbonates are six- and seven-membered rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 J. Feng et al. / Progress in Polymer Science 37 (2012) 211– 236 213 ed cycli since the m larger-sized One attr bonates is t the ring str high Mn. Fu amine and s bonate mon preparation ceptible to the whole p functional g prior to pol polymeriza mer chains. the appropr tor determ practically the protect group and b A wide included in tion of funct according t catalyzed m polymeriza approach f prominent alytic effici [45–50]. In light o in use as bi developme functional p opening (co 2. Glycero (co)polyme As know biocompati able mater should main formance o quickly upo the biocom into accoun oduct o hum bolize bioma uman se the norma ith th rol-de carbon er ch benzyl red fr ry hyd catalyz s or 2-ben red w ter de even iocom well d vivo de ysis in n rate biopo nt ma utocat muc PTMC bsence TMC c e whil anged The d ve intr xyl g Fig. 1. Typical preparation of six- and seven-member ethod described tends to generate oligomers for carbonates (Fig. 1). active trait of six- and seven-membered car- heir highly polymerizable activity ascribed to ain, which favors the preparation of APCs with nctional groups including hydroxyl, carboxyl, ugar groups, etc., have been attached to the car- omers [29,38–44]. As can be anticipated, the of functional aliphatic polycarbonates is sus- the interference of the reactive groups across rocess. In order to prevent side reactions, the roups in the monomers are usually protected ymerization, and must be easily removed after tion, with no or very little alteration to the poly- Hence, the functionalization strategy including iate select of protecting groups is a crucial fac- ining whether the designed materials can be used in future. It should be pointing out that ing groups can sometimes assume a functional ring about new functions to the raw materials. variety of functional carbonate monomers Fig. 2, have been designed for the ROP prepara- ional APCs using various initiators and catalysts o cationic, anionic, coordination and enzyme- echanisms. Note that metal-free enzymatic tion has recently attracted interest as a new or the preparation of functional APCs due to advantages involving the nontoxicity, high cat- ency and tolerance against functional groups f the increasing significance of functional APCs omaterials, this paper summarizes up-to-date nts concerning the design and applications of olycarbonates, with an emphasis on their ring- )polymerization preparation. l-based cyclic carbonates and their by-pr ful t meta able the h becau their W glyce lene polym of 2- prepa onda ROP lipase poly( prepa Af could cell-b been to in catal datio most impla the a has a tuted the a polyH stanc unch tion. invol hydro rs n, the appropriate biodegradation rate and high bility are important requisites for biodegrad- ials used in vivo. In most cases, the materials tain their mechanical and physiochemical per- ver a specified period of time, but degrade n the completion of their function [6]. Thus, patibility issue should be systematically taken t including that of the polymer and its degraded chain [60]. Copolym used strateg rials. The co is generally integrate th discovery o HTMC sugg into polyca pathway to c carbonates [29,32–37]. s, which should be nontoxic and not harm- ans; preferably, the degraded products are d or quickly cleared from the body. The degrad- terials starting from natural metabolites in body ought to present a higher safety profile resultant metabolites would be eliminated via l metabolic pathways. at in mind, the Zhuo group reported a rived polycarbonate poly(2-hydroxyl trimethy- ate) (polyHTMC) bearing OH groups along the ain (Fig. 3) [41]. The six-membered monomer oxyl trimethylene carbonate (BTMC) was first om the glycerol derivative in which the sec- roxyl group was protected by benzyl. Via the ed by stannous 2-ethylhexanoate (Sn(Oct)2), organic catalysts, the corresponding polymer zyloxy trimethylene carbonate), polyBTMC, was ith the Mn of 1.0–5.0 × 105 g/mol [41,51–54]. protection with Pd/C, OH-enriched polyHTMC tually be obtained, which demonstrated high patibility through MTT assay [39,41]. It has ocumented that aliphatic polyester is subject gradation, which possibly relates to enzymatic the body [55–58]. In contrast, the degra- of APCs is considerably lower than that of lyesters, which restricts their use as short-term terials. Due to the enhanced hydrophilicity and alysis effect from –OH presence [59], polyHTMC h faster degradation rate than the unsubsti- analog, with a structure differing merely in of pendent hydroxyl groups [39]. Specifically, an thoroughly degrade into water-soluble sub- e the weight loss of insoluble PTMC remained during a one-month incubation in PBS solu- egradation mechanism is assumed to also a-molecular nucleophilic attack by the pendant roups on the carbonate linkages of the main erization has developed as one of the most ies to adjust the properties of polymeric mate- mbination of two polymers into a single entity advantageous because the copolymers may e merits of the original homopolymers. The f the highly improved biodegradability of poly- ests that the copolymerization of HTMC units rbonate/polyester chains could pave a new degradable polymers with desired degradation 214 J. Feng et al. / Progress in Polymer Science 37 (2012) 211– 236 Fig. 2. Various carbonate monomers used for ROP preparation of functional APCs. J. Feng et al. / Progress in Polymer Science 37 (2012) 211– 236 215 rates in re would ben other seque HTMC-cont prepared vi with other For mos coordinatio with cyclic ily accompl with the co incorporati chains resu ity compar improveme the copolym Fig. 3. Synthesis and ring-opening (co)polymerization of glycerol-derive sponse to practical demands. Additionally, it efit the covalent drug attachment, as well as ntial OH-based modifications. In this way, the aining random and block copolymers have been a the ring-opening copolymerization of BTMC monomers [24,30,31,54,61–65]. t of the screened cata