The influence of phospholipid on the physicochemical properties and anti-tumor efficacy of liposomes encapsulating cisplatin in mice bearing C26 colon carcinoma

• Published in: International journal of pharmaceutics 2014-10, Vol.473 (1-2), p.326-333
• Main Authors: Alavizadeh, Seyedeh Hoda, Badiee, Ali, Golmohammadzadeh, Shiva, Jaafari, Mahmoud Reza
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - blood; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; C26 colon carcinoma; Cancer treatment; Cell Line, Tumor; Cell Survival - drug effects; Cholesterol - chemistry; Cisplatin; Cisplatin - administration & dosage; Cisplatin - blood; Cisplatin - chemistry; Cisplatin - pharmacokinetics; Colon - pathology; Colonic Neoplasms - drug therapy; Colonic Neoplasms - pathology; Female; Liposome; Liposomes; Mice, Inbred BALB C; Phase Transition; Phase transition temperature; Phospholipids - chemistry; Polyethylene Glycols - chemistry; Tumor Burden - drug effects
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2014.07.020

Our data suggested that physicochemical properties of lipid bilayers including the gel to liquid phase transition temperature will influence the rate of drug release, which in turn, enhances the therapeutic activity of encapsulated cisplatin. Phospholipids with higher temperature of transitions (Tm) (HSPC and DPPC) better retained entrapped cisplatin while in the circulation, whereas those with Tm below the temperature of blood stream (37°C) (DMPC and SPCs), tend to be leakier, thus, decreased the platinum concentration in blood. Our data on murine colon cancer model demonstrated that DPPC and HSPC liposomes significantly decreased tumor size and increased survival compared to cisplatin. We have also observed that the best results were obtained with liposomes having Tm nearly, or close to the body temperature, for instance DPPC (Tm∼41.5°C); with approximately stable bilayer, DPPC liposome well retains the entrapped cisplatin in blood stream and gradually release it in the tumor area even better than HSPC with a greater Tm of 55°C. [Display omitted] SPI-077, cisplatin stealth liposome, is the best illustration of poor cisplatin release from liposomes and the subsequent negligible therapeutic activity. For this reason, optimizing drug release kinetics is desirable. In this report, cisplatin was encapsulated in liposomes composed of different phosphatidylcholines with various phase transition temperatures (Tm) (HSPC, DPPC, DMPC, soy phosphatidylcholine (SPC)), cholesterol and mPEG2000–DSPE. In vitro cytotoxicity studies indicated that lowering Tm of lipids increases cisplatin release; the highest cytotoxicity was observed in SPCs. Cisplatin plasma concentration was also sensitive to the transition temperature. The highest platinum concentration observed after treatment with HSPC and DPPC liposomes, whilst the lowest was observed with SPC. HSPC and DPPC containing liposomes showed the highest therapeutic efficacy and survival with DPPC exhibited better efficacy in mouse model of C26. It seems that DPPC with Tm (41.5°C) nearly, or close to body temperature maintains good drug retention in blood circulation. Upon extravasation through permeable tumor microvasculature, it gradually releases its payload in the tumor area better than HSPC, with a greater Tm of 55°C. Our data suggests, the choice of Tm for lipid mixture directed to a considerable extent the rate of cisplatin elimination from plasma and therapeutic effects.