新型结合阿霉素的聚乙二醇嵌段共聚树枝状聚赖氨酸的合成及其药物缓释行为的研究  

Preparation of New Poly(ethylene glycol)-block-Dendritic Poly(l-lysine)s Conjugated with Doxorubicin and Its Controlled Drug Release

作　　者：夏可嘉[1,2] 盛瑞隆[2] 朱英丹[2] 李慧[2] 罗挺[2] 徐宇虹[1] 曹阿民[2] 

机构地区：[1]上海交通大学药学院,上海200240 [2]中国科学院上海有机化学研究所高分子材料研究室,上海200032

出　　处：《化学学报》2010年第11期1130-1136,共7页Acta Chimica Sinica

基　　金：国家自然科学基金(Nos.20574087;20874114)资助项目

摘　　要：采用液相多肽合成方法,成功制备得到窄分子量分布、结构确定的聚乙二醇嵌段共聚四代树枝状聚赖氨酸(MPEG-block-DPL4).在此基础上,进一步将其DPL4的端氨基转化为端肼基,并通过其与抗肿瘤药物阿霉素(DOX)C=O的反应形成C=N键,实现在DPL4表面的阿霉素药物分子化学结合,最终得到新型pH敏感性的高分子药物MPEG-block-DPL4-CONHN=DOX.运用紫外分光光度(UV-Vis)法,对MPEG-block-DPL4-CONHNH2与阿霉素的负载效率进行了定量分析.高分子药物MPEG-block-DPL4-CONHN=DOX在生理条件(pH=7.4)下相对稳定,而弱酸性条件(pH=4.5,5.5)下,C=N键能较快水解,释放阿霉素药物分子.体外细胞毒性评价结果表明(细胞株SMMC-7721和SPCA-1),所得新型高分子药物MPEG-block-DPL4-CONHN=DOX的细胞毒性显著地低于游离阿霉素药物分子,因此,可进一步研究发展成为新型pH敏感性可控缓释高分子抗肿瘤药物载体体系.Water-soluble methoxy poly（ethylene glycol）-block-dendritic poly（l-lysine） MPEG-block-DPL4 with 4 generation PLL was synthesized with well-defined structure. Further, their PLL dendron surface amino groups were modified by hydrazine, and were succesively conjugated with antitumor doxorubicin via a pH-sensitive N=C hydrazone linkage. UV-Vis spectra were hereby employed for the prepared MPEG-block-DPL4-CONHN=DOX to quantify the efficiencies of transferring dendron surface function groups and newly attaching doxorubicin molecules. Moreover, the new doxorubicin-conjugated polymeric MPEG-block-DPL4-CONHN=DOX was utilized to explore drug release behavior under various pH environments, and indicating that the polymeric drug was quite stable under the physiological condition （pH=7.4） while its DOX drug release was accelerated under acidic condition （pH=4.5, 5.5）. Concerning the cytotoxcity of new synthesized polymeric drug, in-vitro cell toxcity assayed by MTT with human hepatocarcinoma cell-line SMMC-7721 and human lung carcinoma cell-line SPCA-I clearly demonstrated that the new MPEG-block-DPL4-CONHN=DOX showed much lowered cell toxicities than the control of free doxorubicin. Therefore, this low toxcity doxorubicin-conjugated polymeric molecule may be further developed as potential pH-responsive antitumor drug carriar with controlled release ofdoxorubicin.

关 键 词：聚乙二醇嵌段共聚树枝状聚赖氨酸 阿霉素 PH敏感性 可控缓释 

分 类 号：TQ460.1[化学工程—制药化工]