奥曲肽修饰的N-辛基-O,N-羧甲基壳聚糖的合成、表征及其作为阿霉素递送载体的研究  

Octreotide-mediated N-octyl-O,N-carboxymethyl chitosan micelles:preparation,characterization and research as doxorubicin delivery vectors

作　　者：邹爱峰[1] 霍美蓉[1] 周建平[1] 尹晓强[1] 姚成丽[1] 朱钦女[1] 张敏 任金山 

机构地区：[1]中国药科大学药剂学教研室,南京210009 [2]南京威尔曼药物研究所,南京210009

出　　处：《中国药科大学学报》2011年第2期124-130,共7页Journal of China Pharmaceutical University

基　　金：国家"重大新药创制"科技重大专项资助项目(No.2009ZX09310-004);教育部新教师基金资助项目(No.200803161017)~~

摘　　要：以奥曲肽(OCT)为靶基团修饰两亲性壳聚糖衍生物N-辛基-O,N-羧甲基壳聚糖(OCC),并考察其作为抗肿瘤药物阿霉素(DOX)增溶载体的可行性。以聚乙二醇(PEG)为化学连接臂,通过活化酯反应将OCT偶联于OCC上,并通过1H NMR对其进行结构表征;采用透析法制备包载阿霉素(DOX)的主动靶向胶束(DOX-OCT-PEG-OCC),并考察其理化性质;采用透析法研究DOX-OCT-PEG-OCC胶束在不同介质中的释放动力学,并以DOX-OCC为对照,通过MTT试验对DOX-OCT-PEG-OCC胶束的抗肿瘤活性进行了评价。OCT以PEG为连接臂成功偶联于OCC的游离羧基上,该偶联产物在水介质中能自组装形成纳米胶束,对DOX具有优越的增溶效果,载药量高达35.7%,包封率为97.5%,粒径为138.8 nm,多分散系数为0.184,Zeta电位为-34.0 mV,粉末衍射试验证实DOX以无定型或分子分散状态增溶于胶束疏水内核中;DOX-OCT-PEG-OCC胶束体外释放行为呈现非零级释药特征,释放速度具有一定pH依赖性。体外细胞毒实验结果表明:DOX-OCT-PEG-OCC胶束比DOX-OCC胶束对生长抑素受体(SSTR)过度表达的人乳腺细胞MCF-7具有更强的细胞毒性,而对不表达SSTR的人胚肺成纤维细胞WI-38细胞毒性没有显著差异。结果表明:OCT-PEG-OCC是阿霉素优良的增溶和细胞主动靶向递送载体,具有良好的应用前景。The aims of this study were to prepare doxorubicin-loaded N-octyl-O,N-carboxymethyl chitosan（OCC） polymeric micelles modified with octreotide（OCT） and to explore the potential feasibility as doxorubicin（DOX） delivery carrier.OCT-PEG-OCC was synthesized by active ester reaction through polyethylene glycol spacer.The structure of OCT-PEG-OCC was characterized by 1 H NMR.Drug-loaded polymeric micelles were prepared by dialysis.In vitro release of DOX from OCT-PEG-OCC micelles were evaluated using a dialysis method in various buffes.MTT experiments were used to evaluate the cytotoxic effect to MCF-7 cells.It was found that octreotide was conjugated to free carboxy of OCC with polyethylene glycol as spacer successfully.Nanomicelles of OCT-PEG-OCC were self-assembled in water.OCT-PEG-OCC micelles showed excellent drug loading capacites for DOX with drug loading of 35.7% and encapsulation efficiency of 97.5%;the mean size of DOX-OCT-PEG-OCC micelles was 138.8 nm with polydisperse index of 0.184;the Zeta potential was-34.0 mV,X-ray diffraction confirmed that DOX occurs as amorphous or molecular dispersion which could solubilized in the hydrophobic core of micelles.Release behavior of DOX formulated in DOX-OCT-PEG-OCC micelles was best fitted to non-zero-order kinetics and pH-dependent.Compared with DOX-OCC micelles,DOX-OCT-PEG-OCC micelles exhibited stronger cytotoxicity to MCF-7 cells（SSTR-overexpressing） and comparble cytotoxicy to WI-38 cells（no SSTR-expressing）.These results indicated active-targeting delivery in cancer therapy,which has a bright future.

关 键 词：奥曲肽 聚合物胶束 主动靶向 阿霉素 体外释放 

分 类 号：R944[医药卫生—药剂学]