Development of liposomal pemetrexed for enhanced therapy against multidrug resistance mediated by ABCC5 in breast cancer

被引:20
作者
Bai, Fang [1 ,3 ]
Yin, You [4 ]
Chen, Ting [1 ]
Chen, Jihui [1 ]
Ge, Meixin [2 ]
Lu, Yunshu [2 ]
Xie, Fangyuan [5 ]
Zhang, Jian [1 ]
Wu, Kejin [3 ]
Liu, Yan [1 ,6 ]
机构
[1] Shanghai Jiao Tong Univ, Xinhua Hosp, Sch Med, Dept Pharm, 1665 Kongjiang Rd, Shanghai, Peoples R China
[2] Shanghai Jiao Tong Univ, Xinhua Hosp, Sch Med, Dept Gen Surg, Shanghai, Peoples R China
[3] Fudan Univ, Obstet & Gynaecol Hosp, Dept Breast Surg, 128 Shenyang Rd, Shanghai, Peoples R China
[4] Second Mil Med Univ, Changzheng Hosp, Dept Neurol, Shanghai, Peoples R China
[5] Shanghai Eastern Hepatobiliary Surg Hosp, Dept Pharm, Shanghai, Peoples R China
[6] Second Mil Med Univ, Changzheng Hosp, Dept Pharm, Shanghai, Peoples R China
基金
中国国家自然科学基金;
关键词
cancer nanotechnology; breast cancer; multidrug resistance; pemetrexed; liposomes; CLINICAL-APPLICATIONS; NANOMEDICINE; TRANSPORTERS; PROTEIN; CELLS;
D O I
10.2147/IJN.S150237
中图分类号
TB3 [工程材料学];
学科分类号
0805 ; 080502 ;
摘要
Purpose: Breast cancer is the most common cancer among women. Pemetrexed, a new generation antifolate drug, is one of the primary treatments for breast cancer. However, multidrug resistance (MDR) in breast cancer greatly hampers the therapeutic efficacy of chemotherapies such as pemetrexed. Nanomedicine is emerging as a promising alternative technique to overcome cancer MDR. Thus, pemetrexed-loaded d-alpha tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) liposomes (liposomal pemetrexed) were developed as a strategy to overcome MDR to pemetrexed in breast cancer. Materials and methods: Liposomal pemetrexed was developed using the calcium acetate gradient method. The cytotoxic effects, apoptosis-inducing activity, in vivo distribution, and antitumor activity of liposomal pemetrexed were investigated. Results: Liposomal pemetrexed was small in size (160.77 nm), with a small polydispersity of <0.1. The encapsulation efficacy of liposomal pemetrexed was 63.5%, which is rather high for water-soluble drugs in liposomes. The IC50 of liposomal pemetrexed following treatment with MDR breast cancer cells (MCF-7 cells overexpressing ABCC5) was 2.6-fold more effective than pemetrexed. The in vivo biodistribution study showed that the liposomes significantly accumulated in tumors 24 h after injection. The antitumor assay in mice bearing MDR breast cancer xenograft tumors confirmed the superior antitumor activity of liposomal pemetrexed over pemetrexed. It was also found that the improved therapeutic effect of liposomal pemetrexed may be attributed to apoptosis through both extrinsic and intrinsic pathways. Conclusion: Liposomal pemetrexed represents a potential therapeutic approach for overcoming breast cancer MDR.
引用
收藏
页码:1327 / 1339
页数:13
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