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

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。

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

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.