Development and characterization of liposomal formulations for rapamycin delivery and investigation of their antiproliferative effect on MCF7 cells

Abstract

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.

Co-loaded paclitaxel/rapamycin liposomes: Development, characterization and in vitro and in vivo evaluation for breast cancer therapy

“…PEGy-lated liposomes containing both PAC and RAP, co-encapsulated or not, presented very slow release, less than 20% of total drug after 72 h (Fig. 4A), indicating that the drugs remained encapsulated within the liposomes, which agreed with other reports on PAC and RAP slow and incomplete release from liposomes [35,48]. PEGylated liposomes were able to retain drugs encapsulated, creating a depot effect, similarly to the observations by Yang et al who studied PAC-loaded liposomes [26].…”

Nanomedicine therapeutic approaches to overcome cancer drug resistance

“…Due to the unpredictability of the EPR effect and the ineffectiveness against non-solid tumors such as leukemia, a greater focus on targeted therapy may be necessary in the future. Despite the fact that the EPR-based targeting is only passive and may be unpredictable, nanodrugs consistently have a better accumulation within a tumor than free drugs including Paclitaxel [80], rapamycin [81], thiostrepton [8], Doxorubicin [82], and Salinomycin [83], among countless others.…”

Nanomicellar Topical Aqueous Drop Formulation of Rapamycin for Back-of-the-Eye Delivery

“…This agent exhibits multiple mechanisms of action other than antiinflammatory property. It also exhibits anti-angiogenic, antifibrotic, antifungal, and antimigratory mechanisms (12,(16)(17)(18)(19). Rapamycin decreases VEGF production and alters the response of endothelial cells to VEGF stimulation (12).…”