有机非金属催化的生物降解聚合物合成
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摘要
本论文主要研究了有机非金属催化剂催化的生物降解聚合物合成。使用的有机非金属催化剂包括布朗斯特弱酸(水杨酸),路易斯强酸(三(五氟苯基)硼烷),路易斯强碱(膦腈碱)。我们利用这些有机非金属催化剂催化开环聚合,合成了基于己内酯、戊内酯、丙交酯和三亚甲基碳酸酯的可降解聚合物,并研究了反应动力学、聚合机理和聚合物的生物降解性能。主要成果如下:
     1)用腈碱(t-BuP4)杂化共聚合成了聚(己内酯-co-甲基丙烯酸叔丁酯)(CL-co-BMA)共聚物,三氟乙酸水解合成的共聚物得到(己内酯-co-甲基丙烯酸)(CL-co-MAA),即带羧基的生物降解高分子。核磁共振、红外、差示扫描量热法和热重分析实验结果证明合成的聚合物为无规共聚物。用石英微晶天平(QCM-D)考察了共聚物的降解行为,结果表明共聚物的降解速率比己内酯均聚物要快很多。
     2)用膦腈碱(t-BuP4)合成了聚(己内酯-co-叔丁基缩水甘油醚)(CL-co-BGE)无规共聚物,水解叔丁基得到带羟基的两亲性无规共聚物聚(己内酯-co-缩水甘油)(CL-co-GD)。石英微晶天平(QCM-D)研究了共聚物在PBS酶溶液中的降解行为。结果显示随着GD含量的上升共聚物降解速率明显加快。MTT细胞毒性实验证明CL-co-GD共聚物具有较低的细胞毒性。
     3)用膦腈碱(t-BuP4)催化的杂化共聚合成了聚(丙交酯-co-2-(2-甲氧基乙氧基)甲基丙烯酸乙酯)(LA-co-MEO2MA):一种具有抗蛋白性的可降解的共聚物。核磁共振和差示扫描量热实验结果证明合成的聚合物为无规共聚物。石英微晶天平(QCM-D)实验结果说明LA-co-MEO2MA无规共聚物的酶降解速率快于PLA均聚物,且该共聚物对人血纤维原蛋白、牛血清蛋白和溶酶菌具有抗吸附性。随着MEO2MA在共聚物中含量的增加抗蛋白效果增强。MTT细胞毒性实验说明无规共聚物具有较低的细胞毒性。
     4)用水杨酸(SAA)为催化剂苯甲醇(BnOH)为引发剂80°C本体条件下开环聚合己内酯(CL),得到分子量可控分布较窄的聚己内酯(PCL)。甲基丙烯酸羟乙酯(HEMA)、丙炔醇(PGA)、叠氮己醇(AHA)和甲氧基聚乙二醇(mPEG)作为官能化引发剂进行开环聚合反应。核磁共振、体积排除色谱和基质辅助激光解吸电离飞行时间质谱测试结果证明PCL含有官能化引发剂末端,说明SAA催化CL开环聚合是按活化单体机理进行的。动力学实验证明SAA催化CL开环聚合是活性/可控的。
     5)用三(五氟苯基)硼烷(B(C6F5)3)为路易斯酸催化剂苯甲醇(BnOH)为引发剂80°C本体条件下开环聚合己内酯(CL),得到分子量可控分布较窄的聚己内酯(PCL)。甲基丙烯酸羟乙酯(HEMA)、丙炔醇(PGA)、叠氮己醇(AHA)和甲氧基聚乙二醇(mPEG)作为官能化引发剂开环聚合CL。核磁共振、体积排除色谱和基质辅助激光解吸电离飞行时间质谱测试结果证明合成的PCL含有引发剂末端。动力学和扩链实验证明B(C6F5)3催化CL开环聚合是活性/可控的。我们还合成了聚己内酯-b-聚戊内酯(PCL-b-PVL)、聚己内酯-b-聚三亚甲基碳酸酯(PCL-b-TMC)嵌段共聚物和大环PCL。
We have systematically studied the synthesis of biodegradable polymers with metal-freeorganic catalysts, such as weak Br nsted acid (salicylic acid), strong Lewis acid(tris(pentafluorophenyl)borane) and super base(1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)phophoranylidenamino]-2Λ5,4Λ5-catenadi(phosphazene)) in this PhD thesis. Biodegradable polymers based onε-caprolactone, δ-valerolactone, l-lactide and trimethylene carbonate cyclic monomers havebeen prepared with those organic metal-free catalysts proceeding ring-opening polymerization.The polymerization kinetic, mechanism and the biodegradability have also been studied. Theresults are as follows:
     1) We have synthesized poly(ε-caprolactone-co-tert-butyl methacrylate)(CL-co-BMA)random copolymer via hybrid copolymerization with1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)phophoranylidenamino]-2Λ5,4Λ5-catenadi(phosphazene)(t-BuP4) as the catalyst. The copolymer has been hydrolyzedinto poly(ε-caprolactone-co-methacrylic acid)(CL-co-MAA), a PCL-based copolymer withpendent carboxyl groups. Nuclear magnetic resonance (NMR), Fourier transform infrared(FTIR) spectroscopy, differential scanning calorimetry (DSC) and thermogravimetric analysis(TGA) measurements indicate that cyclic ester and vinyl monomer form a random copolymer.The degradation of the copolymer has also been studied using quartz crystal microbalancewith dissipation (QCM-D).
     2) We have synthesized poly(ε-caprolactone-co-tert-butyl glycidyl ether)(CL-co-BGE)random copolymer with1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)phophoranylidenamino]-2Λ5,4Λ5-catenadi(phosphazene)(t-BuP4) as thecatalyst. The hydrolysis of the resulting polymer yields an amphiphilicpoly(ε-caprolactone-co-glycidol)(CL-co-GD) copolymer. By use of quartz crystalmicrobalance with dissipation (QCM-D), we have investigated the enzymatic degradation ofpolymers in PBS buffer. It shows that the polymeric surface exhibits higher degradation rateas the hydrophilic GD units increase. Laser Light Scattering (LLS) indicates the amphiphiliccopolymer can be self-assemble in water to form nanoparticles.(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide)(MTT) assay experimentsdemonstrate that the CL-co-GD copolymer has a low cytotoxicity.
     3) We have synthesized poly(l-lactide-co-2-(2-methoxyethoxy)ethyl methacrylate)(LA-co-MEO2MA) containing both degradable and protein resistant units via hybrid copolymerization with(1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dimethylamino)phophoranylidenamino]-2Λ5,Λ5-catenadi(phosphazene)(t-BuP4) as the catalyst. Nuclear magnetic resonance (NMR)and differential scanning calorimetry (DSC) show that LA-co-MEO2MA is a randomcopolymer. The studies of quartz crystal microbalance with dissipation (QCM-D) demonstratethat the copolymer enzymaticlly degrades much faster than poly(l-lactide)(PLA)homopolymer due to its lower crystallinity. We have also investigated the adsorption ofbovine serum albumin (BSA), lysozyme or fibrinogen on a LA-co-MEO2MA surface in realtime by use of QCM-D and surface plasmon resonance (SPR). Our studies reveal that thepolymer is protein resistant depending on MEO2MA content.3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay experimentsdemonstrate that the polymer has a low cytotoxicity.
     4) Ring-opening polymerization (ROP) of ε-caprolactone (CL) using salicylic acid (SAA)as the organocatalyst and benzyl alcohol (BnOH) as the initiator in bulk at80°C successfullyproceeded to give a narrowly distributed poly(ε-caprolactone)(PCL). In addition,2-hydroxyethyl methacrylate (HEMA), propargyl alcohol (PGA),6-azido-1-hexanol (AHA)and methoxy poly(ethylene glycol)(mPEG) were also used as functional initiators. The1HNMR, SEC, MALDI-TOF MS measurements of the PCL clearly indicate the presence of theinitiator residue at the chain end, implying that the SAA-catalyzed ROP of CL was throughthe activated monomer mechanism. The kinetic experiments confirmed the controlled/livingnature of the SAA-catalyzed ROP of CL. Furthermore, the block copolymerization of CL andδ-valerolactone (VL) successfully proceeded to give PCL-b-PVL.
     5) Narrowly distributed poly(ε-caprolactone)(PCL) was synthesized by the ring-openingpolymerization (ROP) of ε-caprolactone (CL) using tris(pentafluorophenyl)borane (B(C6F5)3)as acidic catalyst and benzyl alcohol (BnOH) as the initiator in bulk at80°C. The use offunctional initiators such as2-hydroxyethyl methacrylate (HEMA), propargyl alcohol (PGA),6-azido-1-hexanol (AHA) and methoxy poly(ethylene glycol)(mPEG) leads toend-functionalized PCLs.1H NMR, SEC and MALDI-TOF MS measurements clearlyindicate the presence of the initiator residue at the chain end of the obtained PCLhomopolymers. The study on polymerization kinetics confirm the controlled/living nature ofthe B(C6F5)3-catalyzed ROP of CL. Accordingly, the block copolymerization of CL withδ-valerolactone (VL) and trimethylene carbonate (TMC) successfully proceeded to givePCL-b-PVL and PCL-b-PTMC copolymers. Macrocyclic PCL was also prepared by theintramolecular click reaction of the heterotelechelic α-azido,ω-enthynyl-PCL.
引文
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