Cellular uptake and cytotoxicity of shell crosslinked stearic acid-grafted chitosan oligosaccharide micelles encapsulating doxorubicin
Cellular uptake and cytotoxicity of shell crosslinked stearic acid-grafted chitosan oligosaccharide micelles encapsulating doxorubicin
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DOI：
10.1016/j.ejpb.2007.09.018
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发表时间：
2008-05-01
影响因子：
4.9
通讯作者：
Yuan, Hong
中科院分区：
文献类型：
--
作者：
Hu, Fu-Qiang;Wu, Xiu-ling;Yuan, Hong
通过偶联反应合成了氨基取代度(SD%)为3.48%的硬脂酸接枝壳聚糖(CSO-SA)。CSO-SA在水相中能自聚集形成胶束，临界胶束浓度为0.035 mg/mL。CSO-SA自聚集胶束具有多疏水核的空间结构。一条CSO-SA链可以形成2.8个疏水核心。以A549、LLC和SKOV3细胞为模型细胞，CSO-SA胶束的细胞摄取速度明显加快，且CSO-SA胶束在LLC和SKOV3细胞上的摄取高于A549细胞。阿霉素(DOX)作为模型药物被引入CSO-SA胶束中。为了降低载药CSO-SA胶束的初始药物释放(CSO-SA/DOX)，用戊二醛对CSO-SA胶束的壳层进行了交联。CSO-SA胶束的壳层交联减小了胶束的尺寸和表面电位，但对CSO-SA胶束的细胞摄取和药物包封率没有显著影响。细胞抑制实验表明，CSO-SA胶束的包裹提高了DOX的细胞毒性。CSO-SA/DOX在SKOV3细胞中的抗肿瘤效果最好，这是因为CSO-SA胶束的细胞摄取率较高，而游离药物对细胞的敏感性较低。壳层交联型CSO-SA/DOX对所有细胞株的杀伤活性均显著高于未修饰的CSO-SA/DOX。(C)2007 Elsevier B.V.保留所有权利。
Stearic acid-grafted chitosan oligosaccharide (CSO-SA) with 3.48% amino-substituted degree (SD%) was synthesized by coupling reaction. The CSO-SA could self-aggregate to form micelle with a critical micelle concentration (CMC) at 0.035 mg/mL in the aqueous phase. The CSO-SA self-aggregate micelles indicated spatial structure with multi-hydrophobic core. One CSO-SA chain could form 2.8 hydrophobic cores. Cellular uptakes of CSO-SA micelles by using A549, LLC, and SKOV3 cells as model tumor cell lines showed the faster cellular internalization of CSO-SA micelles, and the cellular uptakes on the LLC and SKOV3 cells were higher than that on the A549 cells. Doxorubicin (DOX) was then used as a model drug to incorporate into CSO-SA micelles. To reduce the initial burst drug release from CSO-SA micelles loading DOX (CSO-SA/DOX), the shell of CSO-SA micelles was crosslinked by glutaraldehyde. The shell crosslinking of CSO-SA micelles reduced the micelle size and surface potential, but it did not significantly affect the cellular uptake and drug encapsulation efficiency of CSO-SA micelles. The cellular inhibition experiments demonstrated that the cytotoxicity of DOX was increased by the encapsulation of CSO-SA micelles. CSO-SA/DOX displayed the best antitumor efficacy in SKOV3 cell line due to the higher cellular uptake percentage of CSO-SA micelles and the lower sensitivity of free drug to the cells. The cytotoxicities of shell crosslinked CSO-SA/DOX were highly enhanced in all cell lines than those of unmodified CSO-SA/DOX. (C) 2007 Elsevier B.V. All rights reserved.