文献类型：期刊文献

英文题名：Bufalin-loaded vitamin E succinate-grafted-chitosan oligosaccharide/RGD conjugated TPGS mixed micelles demonstrated improved antitumor activity against drug-resistant colon cancer

作者：Yuan, Zeting[1];Yuan, Yuxia[1];Han, Lin[2];Qiu, Yanyan[1];Huang, Xiaqin[3];Gao, Feng[3];Fan, Guohua[1];Zhang, Yixi[1];Tang, Xueyao[1];He, Xue[1];Xu, Ke[1];Yin, Peihao[1,4,5]

机构：[1]Shanghai Univ Tradit Chinese Med, Intervent Canc Inst Chinese Integrat Med, Putuo Hosp, 164 Lanxi Rd, Shanghai 200062, Peoples R China;[2]Shanghai Univ Tradit Chinese Med, Expt Res Ctr, Putuo Hosp, Shanghai 200062, Peoples R China;[3]East China Univ Sci & Technol, Dept Pharmaceut, Sch Pharm, Shanghai 200237, Peoples R China;[4]Shanghai Univ Tradit Chinese Med, Putuo Hosp, Dept Gen Surg, Shanghai 200062, Peoples R China;[5]Anhui Med Univ, Shanghai Putuo Cent Sch Clin Med, Hefei 230022, Anhui, Peoples R China

年份：2018

卷号：13

起止页码：7533

外文期刊名：INTERNATIONAL JOURNAL OF NANOMEDICINE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000450303600001)】；

基金：This work was supported by the National Natural Science Foundation of China (grant nos. 81473482 and 81603502).

语种：英文

外文关键词：bufalin; colon cancer; multidrug resistance; mixed micelle; tumor targeting; P-gp

摘要：Background: Multidrug resistance (MDR) is the major reason for the failure of chemotherapy in colon cancer. Bufalin (BU) is one of the most effective antitumor active constituents in Chansu. Our previous study found that BU can effectively reverse P-glycoprotein (P-gp)-mediated MDR in colon cancer. However, the clinical application of BU is limited due to its low solubility in water and high toxicity. In the present study, a multifunctional delivery system based on vitamin-E-succinate grafted chitosan oligosaccharide (VES-CSO) and cyclic (arginine-glycine-aspartic acid peptide) (RGD)-modified D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) was prepared by emulsion solvent evaporation method for targeted delivery of BU to improve the efficacy of drug-resistant colon cancer therapy. Methods: The cytotoxicity of BU-loaded micelles against drug-resistant colon cancer LoVo/ADR and HCT116/LOHP cells was measured by CCK-8 assay. The cellular uptake, Rho123 accumulation, and cell apoptosis were determined by flow cytometry. The expression of apoptosis-related protein and P-gp was measured by Western blot assay. The antitumor activity of BU-loaded micelles was evaluated in LoVo/ADR-bearing nude mice. Results: BU-loaded VES-CSO/TPGS-RGD mixed micelles (BU@VeC/T-RGD MM) were 140.3 nm in diameter with zeta potential of 8.66 mV. The BU@VeC/T-RGD MM exhibited good stability, sustained-release pattern, higher intracellular uptake, and greater cytotoxicity in LoVo/ADR cells. Furthermore, the mechanisms of the BU@VeC/T-RGD MM to overcome MDR might be due to enhanced apoptosis rate and P-gp efflux inhibition. Subsequently, in vivo studies confirmed an enhanced therapeutic efficiency and reduced side effects associated with BU@VeC/T-RGD MM compared with free BU, owing to the enhanced permeation and retention effect, improved pharmacokinetic behavior, and tumor targeting, which lead to MDR-inhibiting effect in LoVo/ADR-bearing nude mice. Conclusion: Our results demonstrated that VeC/T-RGD MM could be developed as a potential delivery system for BU to improve its antitumor activity against drug-resistant colon cancer.