Synthesis And Properties Of Functional Aliphatic Polycarbonates

In the past decades, aliphatic polycarbonates have been widely investigated for use assurgical sutures, bone fixation materials, drug controlled release and more, because of theirgood biocompatibility, biodegradability, and mechanical properties. There are four approachesfor the syntheses of aliphatic polycarbonates: transesterification method, polycondensation ofdiols with phosgene, addition polymerization of carbon dioxide and epoxides, andring-opening polymerization (ROP) of cyclic carbonate monomers. Among them, ROP hasbecome the main method because of mild reaction conditions, low thermal effect, fastpolymerization rate, and high molecular weight. By changing the chemical structure of mainchain, polycarbonates can have a wide range of physical, chemical, and biological propertiesto meet different needs. Introduction of functional pendant groups, such as carboxyl, amino,and hydroxyl groups, can achieve further chemical modification of the materials.Researchers have synthesized a variety of polycarbonates from glycerol, trimethylolethane/trimethylolpropane, pentaerythritol,2,2-bis(hydroxymethyl)propionic acid, dihydroxyacetone,carbonhydrates, and so on. The polycarbonates can be further functionalized to gain enrichedphysical and chemical properties. In this dissertation, we have designed and prepared severalfunctional aliphatic polycarbonates.Chapter1presents a detailed review of recent progress in alphatic polycarbonates about theclassification, synthetic methods, functional modification, applications in the biomedical.In chapter2, well-defined amphiphilic block-graft copolymersPCL-b-[DTC-co-(MTC-mPEG)] with polyethylene glycol methyl ether pendant chains weredesigned and synthesized. First, monohydroxyl-terminated polycaprolactones PCL-OH wereprepared. Then, ROP of2,2-dimethyltrimethylene carbonate (DTC) and cycliccarbonate-terminated PEG (MTC-mPEG) macromonomer was carried out in the presence ofPCL-OH in bulk to give the target copolymers. The amphiphilic block-graft copolymersPCL-b-[DTC-co-(MTC-mPEG)] have a degradable hydrophobic backbone consisted ofpolycaprolactone and polycarbonate and biocompatible hydrophilic PEG pendant chains.MTC-mPEG was chosen as the macromonomer because its synthesis is easier compared toother lactone monomers with a pendant chain. The amphiphilic block-graft copolymersself-assemble in water forming stable micelle solutions with a narrow size distribution.In chapter3, azido polycarbonates were prepared by direct ROP of azido cyclic carbonatemonomer. They could be further functionalized with alkynes via click chemistry. First, a novelsix-membered cyclic carbonate monomer with azido groups, 2,2-bis(azidomethyl)trimethylene carbonate (ADTC), was synthesized by the cyclization of2,2-bis(azidomethyl)propane-1,3-diol with ethyl chloroformate using triethylamine as a base.Then, azido polycarbonates PADTC-co-PDTC were gained via ROP of ADTC and DTC.Finally, azido copolycarbonates PADTC-co-PDTC were let to react with various alkynes(Propargyl-PEG, propargyl alcohol, N,N’-dimethylpropargylamine, and propargylmethacrylate) via click chemistry catalyzed by CuBr-Et3N to afford the functionalizedpolymers. It provides a platform for the preparation of various functionalized carbonatepolymers. The PEG-grafted polycarbonate PDTC-g-PEG can form stable micelle solutions viaself-assembly by dialysis, which is hopeful to be used as drug delivery carriers.In chapter4, amphiphilic block-graft copolymers mPEG-b-P(DTC-ADTC-g-Pal) weresynthesized by ROP of DTC and ADTC with mPEG as an initiator, followed by the clickreaction of propargyl palmitate with the pendant azido groups on the polymer chains. Stablemicelle solutions of the amphiphilic block-graft copolymers could be prepared by addingwater to a THF solution of the polymer followed by removal of the organic solvent by dialysis.Dynamic light scattering (DLS) measurements showed that the micelles had a narrow sizedistribution. Transmission electron microscopy (TEM) images displayed that the micelleswere in regular spherical shape. The grafted structure could improve the drug loading capacity(DLC) and entrapment efficiency (EE). Further, the amphiphilic block-graft copolymersmPEG-b-P(DTC-ADTC-g-Pal) were low cytotoxic and had more sustained drug releasebehavior.In chapter5, a water-soluble polycarbonate with dimethylamino pendant groups,poly(2-dimethylaminotrimethylene carbonate)(PDMATC), was synthesized. First, a novelsix-membered cyclic carbonate monomer,2-dimethylaminotrimethylene carbonate (DMATC),was prepared via the cyclization of2-(dimethylamino)propane-1,3-diol with triphosgene inthe presence of triethylamine. ROP of DMATC was successfully carried out withNovozym-435as a catalyst to give a water-soluble aliphatic polycarbonate PDMATC withlow cytotoxicity and good degradability. The preparation process is very facile because it isnot necessary to protect-deprotect the functional pendant groups.In chapter6, cationic polycarbonates with pendant ethylenediamino groups or lowmolecular polyethyleneimine (PEI) side chains were designed and synthesized. First, a novelsix-membered cyclic carbonate monomer,2-(methacrylamido)trimethylene carbonate(MATC), was prepared from2-amino-1,3-prapanediol by two steps of reaction. ROP ofMATC using1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a catalyst affordedpoly(2-metacrylamidotrimethylene carbonate)(PMATC). Then, cationic polycarbonates PTMC-EDA and PTMC-PEI were prepared by Michael addition of ethylenediamine and600Da PEI, respectively, on the methacrylamido pedant groups. Cationic polycarbonates couldform stable complexes with plasmid DNA at low N/P ratios. The characteristics of thecationic polycarbonates of forming polyplexes with pDNA were very similar to that of25kDaPEI. Their cytotoxicity measured by MTT assay, however, was very low. The excellent abilityfor DNA complexation and low toxicity suggest that the cationic polycarbonates might have agood potential for use as gene vectors.In chapter7, phenylboronic acid-functionalized amphiphilic block copolymerPluronic-PMCC-BA was synthesized via ROP of2-methyl-2-benzyloxycarbonyl-1,3-dioxan-2-one (MBC) with fumaric acid as a catalystfollowed by the deprotection of carboxyl groups by catalyzed hydrogenation and thecondensation of3-aminophenylboronic acid with the copolymer pendant carboxyl groups.Pluronic-PMCC-BA can form stable micelle solutions by self-assembly in water. Thephenylboronic acid groups are on the shell detected by1H NMR. Because two-thirds of therepeating units in the polycarbonate chains have pendent carboxyl and the remained one-thirdare conjugated with the phenylboronic acid groups, the polycarbonate blocks have goodhydrophilicity. Phenylboronic acid groups on the surface of Pluronic-PMCC-BA micelles canrecognize HepG2cells and promote the uptake of drugs into cells as revealed by confocallaser scanning microscopy (CLSM).