Liposomal Pemetrexed: Formulation, Characterization and <i>in Vitro</i> Cytotoxicity Studies for Effective Management of Malignant Pleural Mesothelioma

Abstract

Pemetrexed (PMX) is a newly developed multi-targeted anti-folate with promising clinical activity in many solid tumors including malignant pleural mesothelioma (MPM). However, PMX does not show sufficient anti-tumor activity in vivo when used alone either due to inefficient delivery of adequate concentrations to tumor tissue or dose-limiting side effects. In order to overcome these problems and to achieve potent anti-tumor activity, PMX was encapsulated into a liposomal delivery system. In the present study, various formulations of liposomal PMX were prepared. The effect of formulation parameters on the encapsulation efficiency of PMX within liposomes was evaluated. In addition, the influence of drug release rate on the in vitro cytotoxicity was investigated. Encapsulation of PMX within liposomes was remarkably increased by the incorporation of cholesterol within liposomal membranes and by increasing the total lipid concentration. Encapsulation efficiency was found to be unaffected by the type of phospholipid used or the inclusion of a cation lipid, DC-6-14. Interestingly, encapsulation of PMX within "fluid" liposomes was found to allow efficient release of PMX from liposomes resulting in a potent in vitro cytotoxicity against MPM MSTO-211H cell line. On the other hand, entrapment of PMX within "solid" liposomes substantially hindered PMX release from liposomes, and thus PMX failed to exert any in vitro cytotoxicity. These results suggest that encapsulation of PMX within "fluid" liposomes might represent a novel strategy to enhance the therapeutic efficacy of PMX while minimizing the side effect encountered by the non selective delivery of free PMX to various body tissues.Key words liposome; malignant pleural mesothelioma; polyethylene glycol; pemetrexed Pemetrexed (PMX) is a new-generation anti-folate, approved for the treatment of malignant pleural mesothelioma (MPM) and non-small cell lung cancer, currently being evaluated for the treatment of a variety of other solid tumors.

Polymeric films loaded with cisplatin for malignant pleural mesothelioma: a pharmacokinetic study in an ovine model

“…In addition, immuno-chemotherapy resulted in an increased recruitment of inflammatory cells to the site of tumorigenesis and elicited higher level of tumor growth inhibiting cytokines. As mentioned above, intrapleural approaches present the advantage to minimize the adverse effects of chemotherapy, while maximizing its therapeutic efficacy by obtaining high concentrations of the chemotherapeutic drug within the tumor tissue (28). Pemetrexed is currently being used, in combination with cisplatin, as a first-line treatment in patients with MPM.…”

“…This could due to either inadequate delivery of sufficient concentrations to tumor tissue or dose-limiting side effects. Essam Eldin et al, in order to overcome these problems and try to enhance specific anti-tumor activity, encapsulated pemetrexed into a liposomal delivery system (28). They studied different formulations of liposomal pemetrexed and tested their efficacy in vitro on several mesothelioma cell lines.…”

“…They found that, when encapsulated within fluid liposomes, pemetrexed showed a superior in vitro cytotoxic effect against mesothelioma tumor cells, compared to pemetrexed encapsulated within solid liposomes. They concluded that pemetrexed encapsulated within fluid liposomes might exert a potent therapeutic efficacy, superior to that observed with free pemetrexed (28). In our previous experiment, we were also interested in assessing the potential effect of pemetrexed loaded onto our polymeric films (alone and in association with cisplatin) in the rat mesothelioma model (data not published).…”

Liposomal Delivery Systems: Design Optimization and Current Applications

“…39) Drug release from liposomes was demonstrated influenced by liposomal membrane composition and the physicochemical properties of the encapsulated drug. 8,40,41) Inclusion of cholesterol into the liposomal membrane, which has a membrane rigidizing effect, 42,43) and switching from a fluid phase phospholipid bilayer to a solid phase bilayer 42,44) were shown to reduce the release of drugs from liposomes. Drugs with extremely low octanol/buffer partition coefficients exhibited prolonged liposomal retention whereas molecules with partition coefficients ranging from −0.3 to 1.7 were, in contrast, rapidly released.…”

Malign plevral mezotelyomada ilaç taşıyıcı nanosistemler

“…Bunun için insan mezotelyoma hücre dizisi olan MSTO-211H kullanılmıştır. Çalışma sonucunda, sıvı lipozom içerisine kapsüllenmiş ilacın terapötik etkinliğinin serbest pemetreksetten daha yüksek olduğu ve yan etkisinin minimum olduğu belirlenmiştir (78).…”