PLL-b-PLeu两亲性嵌段共聚多肽的合成及其自组装的研究
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摘要
两亲性嵌段共聚多肽由于能形成各种形态的聚集体而可作为药物载体、组织工程支架、基因载体等被广泛应用于生物医学领域。本论文主要分为两个部分对聚氨基酸和两亲性共聚多肽进行了制备及自组装等方面的研究。
第一部分,聚亮氨酸和聚赖氨酸的制备及表征。
分别以L-亮氨酸和L-苄氧羰基赖氨酸为原料,用三光气法合成了L-亮氨酸-NCA和L-苄氧羰基赖氨酸-NCA,再以三乙胺为引发剂,制备了聚L-亮氨酸和聚(L-苄氧羰基赖氨酸)。并用质量分数为33%的溴化氢冰醋酸溶液脱除了PZLL上的苄氧羰基保护基团得到聚L-赖氨酸。利用红外光谱和~1H-NMR证实了产物的组成和化学结构,并用流变的手段研究了聚赖氨酸水溶液的流变特性。
第二部分,两亲性嵌段共聚物PLL-b-PLeu的制备及自组装的研究。
用第一部分相同的方法制备了聚(L-苄氧羰基赖氨酸),并以此为大分子引发剂,合成了聚(L-苄氧羰基赖氨酸)-聚(L-亮氨酸)(PZLL-b-PLeu)。再用溴化氢冰醋酸法脱除了PZLL-b-PLeu上的苄氧羰基保护基团,从而得到了两亲性嵌段聚合多肽聚(L-赖氨酸)-聚(L-亮氨酸)(PLL-b-PLeu)。利用红外光谱和核磁对产物进行了表征,用TEM研究了PLL-b-PLeu在水溶液中自组装。研究结果表明,双亲性嵌段共聚肽在水溶液中可以形成核壳结构的胶束。
Amphiphilic block copolypeptides are able to self-assemble into structured aggregates,so they are used in different biomaterial applications,e.g.carriers for controlled drug release,scaffolds for tissue engineering,vehicles for gene transfer therapy,etc.This paper reported two parts contents.
The first part presented the synthesis and characterization of Poly(L-benzyl -lysine) and Poly(L-leucine).Poly(L-lysine) and Poly(L-leucine) were synthesized by ring opening polymerization of Lys(Z)-NCA and Leu-NCA which were prepared by triphosgene method.Poly(L-lysine) was obtained by removal of protection group in 33%HBr solution in HAc.The two polymers were characterized by FTIR and 1H NMR.We also studied the properties of Poly(L-lysine) solution by the rheological tests.
The second part presented the synthesis of amphiphilic Poly(L-lysine)-b-Poly (L-leucine) and its self-assembly behavior in water.Poly(L-benzyl-lysine) was synthesized by the same way as the first part,which was used as a macroinitiator to initiate ring opening polymerization of Leu-NCA to synthesize diblock copolymer Poly(L-benzyl-lysine)-b-Poly(L-leucine)(PZLL-b-PLeu).Amphiphilic Poly(L-benzyl-lysine)-b-Poly(L-leucine)(PLL-b-PLeu) was obtained by HBr-HAc method. The aggregation morphologies of PLL-b-PLeu in aqueous solution were observed using TEM.It was found that the diblock copolypeptide self-assembles to form micelles in water.
第一部分,聚亮氨酸和聚赖氨酸的制备及表征。
分别以L-亮氨酸和L-苄氧羰基赖氨酸为原料,用三光气法合成了L-亮氨酸-NCA和L-苄氧羰基赖氨酸-NCA,再以三乙胺为引发剂,制备了聚L-亮氨酸和聚(L-苄氧羰基赖氨酸)。并用质量分数为33%的溴化氢冰醋酸溶液脱除了PZLL上的苄氧羰基保护基团得到聚L-赖氨酸。利用红外光谱和~1H-NMR证实了产物的组成和化学结构,并用流变的手段研究了聚赖氨酸水溶液的流变特性。
第二部分,两亲性嵌段共聚物PLL-b-PLeu的制备及自组装的研究。
用第一部分相同的方法制备了聚(L-苄氧羰基赖氨酸),并以此为大分子引发剂,合成了聚(L-苄氧羰基赖氨酸)-聚(L-亮氨酸)(PZLL-b-PLeu)。再用溴化氢冰醋酸法脱除了PZLL-b-PLeu上的苄氧羰基保护基团,从而得到了两亲性嵌段聚合多肽聚(L-赖氨酸)-聚(L-亮氨酸)(PLL-b-PLeu)。利用红外光谱和核磁对产物进行了表征,用TEM研究了PLL-b-PLeu在水溶液中自组装。研究结果表明,双亲性嵌段共聚肽在水溶液中可以形成核壳结构的胶束。
Amphiphilic block copolypeptides are able to self-assemble into structured aggregates,so they are used in different biomaterial applications,e.g.carriers for controlled drug release,scaffolds for tissue engineering,vehicles for gene transfer therapy,etc.This paper reported two parts contents.
The first part presented the synthesis and characterization of Poly(L-benzyl -lysine) and Poly(L-leucine).Poly(L-lysine) and Poly(L-leucine) were synthesized by ring opening polymerization of Lys(Z)-NCA and Leu-NCA which were prepared by triphosgene method.Poly(L-lysine) was obtained by removal of protection group in 33%HBr solution in HAc.The two polymers were characterized by FTIR and 1H NMR.We also studied the properties of Poly(L-lysine) solution by the rheological tests.
The second part presented the synthesis of amphiphilic Poly(L-lysine)-b-Poly (L-leucine) and its self-assembly behavior in water.Poly(L-benzyl-lysine) was synthesized by the same way as the first part,which was used as a macroinitiator to initiate ring opening polymerization of Leu-NCA to synthesize diblock copolymer Poly(L-benzyl-lysine)-b-Poly(L-leucine)(PZLL-b-PLeu).Amphiphilic Poly(L-benzyl-lysine)-b-Poly(L-leucine)(PLL-b-PLeu) was obtained by HBr-HAc method. The aggregation morphologies of PLL-b-PLeu in aqueous solution were observed using TEM.It was found that the diblock copolypeptide self-assembles to form micelles in water.
引文
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[2]吕冬梅,功能性生物医用聚酯-聚氨基酸共聚物的合成及应用[硕士学位论文],北京,北京协和医学院,2006,4-5
[3]Kyoung Tack Kim,Mitchell A.Winnik,and Ian Manners.Synthesis and self-assembly of dendritic-helical block copolymer.The Royal Society of Chemistry,2006,2,957-965
[4]Megeed Zaki,Cappello Joseph,and Ghandehari Hamidresa.Genetically engineered silk-elastinlike protein polymers for concontrolled drug delivery.Advanced Drug Delivery Reviews,2002,54(8),1075-1091
[5]Tirrell J G,and Tirrell D A.Synthesis of biopolymers:polyesters,polysaccharides and polynucleotides.Current Opinion in Solid State & Materials Science,1996,1(3),407-411
[6]McPherson D T,Xu Jie,and Urry D W.Product Purification by Reversible Phase Transition Following Escherichia coil Expression of Genes Encoding up to 251Repeats of the Elastomeric Pentapeptide GVGVP.Protein Expression and Purification,1996,7(1),51-57
[7]V Jarm,and D Fles.Polymerization and properties of optically active α-(p-substituted benzenesulfonamido)-β-lactones.Journal of Polymer Science:Polymer Chemistry Edition,1977,15(5),1061-1071
[8]Qinxin Zhou,and Joachim Kohn.Preparation of poly(L-serine ester):a structural analog of conventional poly(L-serine).Macromolecules,1990,23,3399-3406
[9]Isablelle Fietier,Alain Borgne,and Nicolas Spassky.Synthesis of functional polyestersderived from serine.Polymer Bulletin,1990,24,349-353
[10]Geblin ME,and Kohn J.Synthesis and polymerization of N-Z-L-serine-,betalactone and serine hydroxybenzotriazole active esters.Journal of the American Chemical Society,1992,114,3962-3965
[11]Kazunori Kataoka,Atsushi Ishihara,Atsushi Harada,and Hideki Miyazaki. Effect of the secondary structure of poly(L-lysine) segments on the micellization in aqueous milieu of substituted with a hydrocinnamoyl group at the N-position.Macromolecules,1998,31(18),6071-6076
[12]Chao Deng,Xuesi Chen,Haijun Yu,Jing Sun,Tiancheng Lu,and Xiaobin Jing.A biodegradable triblock copolymer poly(ethylene glycol)-b-poly(L-lactide)-b-Poly (L-lysine):Synthesis,self-assembly,and RGD peptide modification.Polymer,2007,48,139-149
[13]Minglong Yuan,and Xiaomo Deng.Synthesis and characterization of poly(ethylene glycol)-block-poly(amino acid) copolymer.European Polymer Journal.2001,37(9).1907-1912
[14]Junhuang Cheng.and Jichang Feng.Polypeptide diblock copolymers:Synthesis and properties of poly(N-isopropylacrylamide)-b-polylysine.Macromolecules.2008,41(19),7041-7052
[15]潘才元主编,高分子化学 合肥:中国科学技术出版社,1997,265
[16]Kricheldorf H R,α-Amino acid-N-carboxyanhydrides and related heterocycles.Springer,Berlin.1987
[17]Timothy J.Deming,Facile synthesis of block copolypeptides of defined architecture.Nature.1997,390.386-389
[18]Kricheldorf H R,Polypeptides and 100 years of chemistry of chemistry of α-amino acid N-carboxyanhydrides.Macromolecular Chemistry,2006,45.5752-5784
[19]夏咏梅,方云编著,生物表面活性剂的开发和应用.日用化学工业,1999,(1),27-31
[20]任杰编著 可降解与吸收材料.北京:化学工业出版社,2003年,168
[21]张俐娜主编 天然高分子科学与材料.杭州:科学出版社,2007年,74
[22]何忠效主编 生物技术概论.北京:北京师范大学出版社,2002年,29
[23]邓朝阳,宋贵生,一种简单易行的重组方法——三引物PCR法.科学通报,2002,47(16),1247-1249
[24]Halperin A,Tirrell M,and Lodge T P,Tethered chains in polymer microstructures.Advanced Polymer Science.1992,100,31-71
[25]袁建军,李英顺,朱慧光,程时远,江雷,封麟先和范志强,PLA-b-PEO-b-PLA三嵌段共聚物分子聚集体性质的研究.高分子学报,2004,1,1-6
[26]Cameron N S,Corbierre M K,and Eisenberg A,Asymmetric amphiphilic block copolymers in solution:a morphological wonderland.Canadian Journal of Chemistry,1999,77(8),1311-1327
[27]杨子刚,嵌段共聚物的合成及其聚集体行为研究,湖北,湖北大学,2004,6-7
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