Department of Pharmaceutical Technology, Faculty of Pharmacy, Yeditepe University, Istanbul, Turkey.
J Liposome Res. 2009;19(4):322-31. doi: 10.3109/08982100902963043.
Rapamycin (Sirolimus) is a macrolide lactone with antifungal, immunosuppressant, and antiproliferative actions. The mechanism of rapamycin action involves the inhibition of mTOR and subsequent cytostasis. Rapamycin also prevents angiogenesis in tumors and can prevent cancer cells' resistance to other chemotherapeutic agents. However, very poor water solubility, bioavailability, only slight solubility in acceptable parenteral excipients, chemical instability, and major sequestration (95%) of free rapamycin into the erythrocytes have prevented its development as an anticancer drug. To address these problems, it was attempted to develop liposomal rapamycin delivery systems in this study. Conventional and pegylated liposomes were prepared with various lipid and cholesterol ratios. They were then characterized; these liposomes contained 0.68-0.90 mg of rapamycin per milliliter of liposome suspension. Having suitable particle size, these liposomes successfully retained the entrapped drug. Both types of liposomes were found to be effective; however, conventional liposomes showed better antiproliferative activity against MCF-7 cells than pegylated liposomes. But, pegylated liposome showed better stability than conventional liposomes. In conclusion, the enhanced permeability and retention effects of tumors should provide the opportunity for pegylated liposomal rapamycin to be applied as an intravenous drug-delivery system for targeted delivery to cancer cells, avoiding the major sequestration of free rapamycin into the erythrocytes.
雷帕霉素（西罗莫司）是一种具有抗真菌、免疫抑制和抗增殖作用的大环内酯类内酯。雷帕霉素的作用机制涉及到 mTOR 的抑制以及随后的细胞停滞。雷帕霉素还可以防止肿瘤中的血管生成，并可以防止癌细胞对其他化疗药物的耐药性。然而，极差的水溶性、生物利用度、在可接受的注射用赋形剂中仅有轻微的溶解度、化学不稳定性以及游离雷帕霉素主要被红细胞隔离（95%），这些问题阻碍了它作为抗癌药物的发展。为了解决这些问题，本研究试图开发雷帕霉素的脂质体给药系统。用不同的脂质和胆固醇比例制备了常规和聚乙二醇化脂质体，并对其进行了表征；这些脂质体每毫升脂质体悬浮液中含有 0.68-0.90 毫克雷帕霉素。这些脂质体具有合适的粒径，成功地保留了包封的药物。这两种类型的脂质体都被证明是有效的；然而，常规脂质体对 MCF-7 细胞的增殖抑制活性优于聚乙二醇化脂质体。但是，聚乙二醇化脂质体比常规脂质体具有更好的稳定性。总之，肿瘤的增强渗透性和保留效应应该为聚乙二醇化雷帕霉素脂质体作为静脉给药系统用于靶向递送至癌细胞提供机会，避免游离雷帕霉素主要被红细胞隔离。
