壳聚糖-聚乳酸接枝共聚物制备生物可吸收水凝胶药物缓释体系

项目名称： 壳聚糖-聚乳酸接枝共聚物制备生物可吸收水凝胶药物缓释体系

项目编号： No.50873030

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 金属学与金属工艺

项目作者： 李速明

作者单位： 复旦大学

项目金额： 35万元

中文摘要： 深入研究了壳聚糖-聚乳酸（CS-PLA）接枝共聚物水凝胶体系。以低毒性乳酸锌为催化剂，合成了一系列一端含羟基的乳酸低聚物（PLA-OH）和一端含羧基的乳酸低聚物（PLA-COOH）。分别以N,N'-二羰基咪唑和N,N’二环己基碳二亚胺为交联剂，将PLA链段接枝到水溶性壳聚糖的氨基和羟基上，得到壳聚糖-左旋聚乳酸（CS-PLLA）和壳聚糖-右旋聚乳酸（CS-PDLA）。研究表明，壳聚糖C2-NH2反应活性比C6-OH高。调节PLA链段长度和接枝度，控制接枝共聚物的水溶性。MTT细胞毒性实验证明，CS-PLA聚合物都具有良好的细胞相容性。 混合CS-PLLA和CS-PDLA水溶液，利用PLLA和PDLA立体复合作用，制备完全可降解及可注射物理水凝胶体系。CS-PLA取代度越大，凝胶结构越致密，溶胀比越低。以胸腺五肽为模型药物，研究了水凝胶药物缓释体系，探讨了药物释放与凝胶特性之间的关系。致密的水凝胶结构，药物释放速率低。释放量在75%以上。载药量高的凝胶后期释放速率比载药量低的凝胶高。CS-PLA物理水凝胶体系具有优良的药物控制释放性能及生物相容性，在药物控释领域具有广泛的应用前景。

中文关键词： 壳聚糖；聚乳酸；生物可吸收；水凝胶；药物缓释

英文摘要： Biodegradable chitosan-graft-polylactide (CS-PLA) copolymers were prepared by grafting poly(L-lactide) (PLLA) or poly(D-lactide) (PDLA) precursor to the backbone of chitosan, using N,N’carbonyldiimidazole (CDI) or N,N’dicyclohexylcarbodiimide (DCC) as coupling agent. A series of hydroxyl-capped PLA (PLA-OH) were first synthesized using low toxic zinc lactate as initiator, and then activated by CDI to yield PLA-CI intermediate. PLA-CI was finally coupled to the CS backbone to yield CS-PLA, using DMAP as catalyst. Carboxyl-capped PLA (PLA-COOH) was synthesized under similar conditions. Following the activation by DCC, PLA-COOH was attached to C2-NH2 and C6-OH of CS with DMAP as catalyst, thus yielding CS-PLA. Enhanced reactivity of C2-NH2 with respect to C6-OH was observed from 1H-NMR and FT-IR analyses. The degree of substitution of CS-PLA was close to the molar ratio of [CSunit] to [PLA] in the feed, and could be adjusted by varying the feed ratio. The resulting CS-PLA graft copolymers present variable solubility in water and in organic solvents. Comparison of the results obtained from CDI and DCC routes shows that PLA was preferentially attached to C2-NH2 due to the higher reactivity of CS-NH2 as compared to C6-OH, especially when CS was in large excess. Furthermore, the degree of substitution of CS-PLA obtained by DCC route is higher than that by CDI route. Thus the DCC route is preferable for the synthesis of CS-PLA with shorter PLA segments, while the CDI route is preferable with longer PLA segments. The cytocompatibility of CS-PLA was determined via MTT assay. All the copolymers present excellent cytocompatibility. Water soluble CS-PLLA and CS-PDLA were then selected to prepare CS-PLA hydrogels. Swelling, DSC, WAXD, SEM measurements were employed to determine the hydrogel properties. Data showed that the formation of hydrogels results from stereocomplexation between PDLA and PLLA segments of CS-PLA. A three-dimensional network structure is formed with CS as framework and PLLA/PDLA stereocomplex as physical crosslinks. With increasing degree of substitution, the gel structure becomes denser and the swelling ratio decreases. The drug release behavior of the hydrogels was investigated using thymopentin (TP-5) as model drug. A more compact hydrogel structure leads to lower drug release rate and total released ratio. The drug load also affects the release behavior: hydrogels with higher load exhibit an increased release rate at the later stage with respect to those with lower drug load. CS-PLA physical hydrogels are injectable and can be formed at the injection site in situ, which is very promising in the field of controlled drug release.

英文关键词： Chitosan；polylactide；bioreosorbable；hydrogel；drug release.