Ligand-Directed Stearic Acid Grafted Chitosan Micelles to Increase Therapeutic Efficacy in Hepatic Cancer

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• 作者：Yuan Yang ; Sheng-Xian Yuan ; Ling-Hao Zhao ; Chao Wang ; Jun-Sheng Ni ; Zhen-Guang Wang ; Chuan Lin ; Meng-Chao Wu ; Wei-Ping Zhou
• 刊名：Molecular Pharmaceutics
• 出版年：2015
• 出版时间：February 2, 2015
• 年：2015
• 卷：12
• 期：2
• 页码：644-652
• 全文大小：455K
• ISSN：1543-8392

文摘

Targeted delivery system would be an interesting platform to enhance the therapeutic effect and to reduce the side effects of anticancer drugs. In this study, we have developed lactobionic acid (LA)-modified chitosan鈥搒tearic acid (CS鈥揝A) (CSS鈥揕A) to deliver doxorubicin (DOX) to hepatic cancer cells. The average particle size of CSS鈥揕A/DOX was 鈭?00 nm with a high entrapment efficiency of >95%. Drug release studies showed that DOX release from pH-sensitive micelles is significantly faster at pH 5.0 than at pH 7.4. The LA conjugated micelles showed enhanced cellular uptake in HepG2 and BEL-7402 liver cancer cells than free drug and unconjugated micelles. Consistently, CSS鈥揕A/DOX showed enhanced cell cytotoxicity in these two cell lines. Annexin-V/FITC and PI based apoptosis assay showed that the number of living cells greatly reduced in this group with marked presence of necrotic and apoptotic cells. LA-conjugated carrier induced typical chromatic condensation of cells; membrane blebbing and apoptotic bodies began to appear. In vivo, CSS鈥揕A/DOX showed an excellent tumor regression profile with no toxic side effects. The active targeting moiety, long circulation profile, and EPR effect contributed to its superior anticancer effect in HepG2 based tumor. Our results showed that polymeric micelles conjugated with LA increased the therapeutic availability of DOX in the liver cancer cell based solid tumor without any toxic side effects. The active targeting ligand conjugated nanoparticulate system could be a promising therapeutic strategy in the treatment of hepatic cancers.