Department of Pharmacy, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai.
Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai.
Int J Nanomedicine. 2018 Mar 6;13:1327-1339. doi: 10.2147/IJN.S150237. eCollection 2018.
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.
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.
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 IC 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.
Liposomal pemetrexed represents a potential therapeutic approach for overcoming breast cancer MDR.
乳腺癌是女性最常见的癌症。培美曲塞是一种新型的抗叶酸药物，是乳腺癌的主要治疗方法之一。然而，乳腺癌的多药耐药（MDR）极大地阻碍了培美曲塞等化疗药物的治疗效果。纳米医学作为一种有前途的替代技术，正在涌现，以克服癌症 MDR。因此，研制了载有培美曲塞的 d-α生育酚聚乙二醇 1000 琥珀酸酯（维生素 E TPGS）脂质体（脂质体培美曲塞），作为克服乳腺癌中培美曲塞 MDR 的策略。
采用醋酸钙梯度法制备脂质体培美曲塞。研究了脂质体培美曲塞的细胞毒性作用、诱导凋亡活性、体内分布和抗肿瘤活性。
脂质体培美曲塞的粒径较小（160.77nm），多分散性<0.1。脂质体培美曲塞的包封率为 63.5%，对于脂质体中的水溶性药物来说相当高。用 MDR 乳腺癌细胞（过表达 ABCC5 的 MCF-7 细胞）处理后，脂质体培美曲塞的 IC 是培美曲塞的 2.6 倍。体内分布研究表明，脂质体在注射后 24 小时显著聚集在肿瘤中。在携带 MDR 乳腺癌异种移植肿瘤的小鼠中的抗肿瘤试验证实了脂质体培美曲塞优于培美曲塞的抗肿瘤活性。还发现，脂质体培美曲塞改善治疗效果可能归因于通过外在和内在途径的细胞凋亡。
脂质体培美曲塞代表了克服乳腺癌 MDR 的一种潜在的治疗方法。
