奥曲肽修饰的PEG隐形脂质体用于改善阿霉素对生长抑素受体II阳性肿瘤的抗癌效果

摘要/Abstract

摘要： 主动靶向给药系统 (targeting drug delivery system, TDDS) 因其能在提高药物疗效的同时降低毒副作用而成为科学研究的焦点, 尤其是在癌症的治疗领域。已经证实隐形脂质体 (sterically stabilized liposome, SSL) 能够延长药物在体内的循环时间, 促进药物在肿瘤部位蓄积, 同时又能够被某些特异性的配体修饰, 实现主动靶向。许多肿瘤细胞表面过度表达生长抑素受体 (somatostatin receptors, SSTRs), 因此, 与生长抑素受体, 特别是亚型II (SSTR2), 具有高亲和力的奥曲肽 (octreotide, OCT), 成为了一个具有应用价值的配体。本研究将奥曲肽与DSPE-PEG₂₀₀₀相连 (DSPE-PEG2000-OCT ), 并制备了含DSPE-PEG2000-OCT 不等的阿霉素 (doxorubicin, DOX) 隐形脂质体 (OCT-SSL-DOX)。所有脂质体粒径约为90 nm, 表面带弱的负电荷, 对阿霉素的包封率均在95%以上。奥曲肽的修饰没有对脂质体的物理性质产生明显的影响。用流式细胞术检测细胞摄取, 优化了脂质体表面奥曲肽密度, 发现脂材中DSPE-PEG2000-OCT 百分数为1.5%时, 主动靶向脂质体促进细胞摄取作用最强。体外释放实验结果表明奥曲肽的修饰没有改变所包载药物阿霉素的释放行为。在SSTR2阳性细胞模型和荷瘤动物模型中, 奥曲肽修饰后的隐形脂质体提高了所包载药物阿霉素对细胞的杀伤作用, 并增强了其体内抗肿瘤疗效。综上, 奥曲肽修饰的隐形脂质体作为抗肿瘤药物的载体, 能够将药物靶向输送到高表达生长抑素受体亚型II的肿瘤细胞内, 提高抗肿瘤疗效。

关键词: 奥曲肽, 隐形脂质体, 阿霉素, 生长抑素受体, MTT, 抗肿瘤活性

Abstract: Active targeting drug delivery systems (TDDS), which could improve drug therapeutic efficacy and reduce toxicity, are still the focus of many scientific researches in cancer therapy. The drug circulation time and tumor accumulation could be significantly increased with the application of sterically stabilized liposome (SSL). SSL could also be modified easily with certain ligands to achieve targeting drug delivery. Because many tumors overexpress somatostatin receptors (SSTRs), octreotide (OCT) becomes a potential targeting ligand due to its high affinity to SSTRs, especially to subtype 2 (SSTR2). In this study, OCT was conjugated to methoxypolyethyleneglycol-distearoyl-phosphatidylethanolamine (DSPE-PEG2000), and doxorubicin (DOX)-loaded SSL with a variable percentage of octreotide-methoxypolyethyleneglycol-distearoyl-phosphatidylethanolamine (DSPE-PEG2000-OCT) were prepared (OCT-SSL-DOX). All liposomes were about 90 nm in diameter and negatively charged on the surface, with DOX encapsulation efficiency at above 95%. OCT modification exhibited little effect on the physicochemical properties of SSL. In this study, cellular delivery efficacy of all prepared liposomes was evaluated in SSTR2-positive cells in vitro by flow cytometry for the optimization of the OCT density on the surface of liposomes. Lipid formulation containing 1.5% DSPE-PEG2000-OCT exhibited the highest efficiency of intracellular drug delivery. The modification of OCT did not alter the release behaviors of liposomal DOX in vitro, but OCT-SSL-DOX increased the cytotoxicity and improved the anti-tumor effect of liposomal DOX in SSTR2-positive cells and tumor-bearing mice models. In summary, OCT-modified SSL succeeded in increasing intracellular delivery and enhancing therapeutic efficacy of encapsulated anticancer agent, suggesting that it might be a promising TDDS for the treatment of SSTR2-overexpressing cancers.

Key words: Octreotide, Sterically stabilized liposomes, Doxorubicin, Somatostatin receptors, MTT, Anti-tumor effect

中图分类号:

R944

Supporting:

Foundation items: National Basic Research Program of China (Grant No. 2009CB930300), State Key Projects (Grant No. 2009ZX09310-001) and the 863 Project of China (Grant No. 2007AA021811).^*Corresponding author. Tel./fax: 86-10-82802791;

章俊麟, 金武, 王学清, 王坚成, 张烜, 张强^*. 奥曲肽修饰的PEG隐形脂质体用于改善阿霉素对生长抑素受体II阳性肿瘤的抗癌效果[J]. .

Jun-Lin Zhang, Wu Jin, Xue-Qing Wang, Jian-Cheng Wang, Xuan Zhang, Qiang Zhang^* . Octreotide modified PEGylated liposomes improved the anticancer efficacy of doxorubicin in somatostatin receptor II positive tumor model [J]. .

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