Encapsulation in a rapid-release liposomal formulation enhances the anti-tumor efficacy of pemetrexed in a murine solid mesothelioma-xenograft model.

We recently developed a PEG-coated liposome encapsulating the anti-folate drug pemetrexed (PMX). Such liposomal formulations have shown potent cytotoxic effects against malignant pleural mesothelioma (MPM) cells in vitro. In the present study, we investigated the pharmacokinetics, bio-distribution and in vivo anti-tumor efficacy of two liposomal PMX formulations with different drug release rates in a murine mesothelioma-xenograft model. Liposomes with different PMX release rates were prepared via manipulating liposomal membrane fluidity through incorporating either a solid-phase (HSPC) or a fluid-phase (POPC) phospholipid. Both liposomal PMX formulations showed prolonged plasma pharmacokinetics and were accumulated to a similar extent in tumors and other tissues, presumably, due to surface modification with polyethylene glycol (PEG). In a murine mesothelioma-xenograft model, interestingly, PMX encapsulated in a fast-release POPC liposome produced superior tumor growth suppression compared with either free PMX or PMX encapsulated in a slow-release HSPC liposome. Such in vivo anti-tumor efficacy was accomplished mainly by a potent induction of apoptosis within tumor tissue by the released PMX from POPC liposomes. Our results clearly emphasize the therapeutic efficacy of liposomal PMX over free PMX in conquering aggressive solid tumors such as malignant mesothelioma. A guarantee of the targeted delivery of PMX to tumor cells helps overcome some of the major shortcomings encountered with the use of free PMX.

Advanced therapeutic approach for the treatment of malignant pleural mesothelioma via the intrapleural administration of liposomal pemetrexed.

Malignant pleural mesothelioma (MPM) is an aggressive cancer that proliferates in the pleural cavity. Pemetrexed (PMX) in combination with cisplatin is currently the approved standard care for MPM, but a dismal response rate persists. Recently, we prepared various liposomal PMX formulations using different lipid compositions and evaluated their in vitro cytotoxicity against human mesothelioma cells (MSTO-211H). In the present study, we investigated the in vivo therapeutic effect of our liposomal PMX formulations using an orthotopic MPM tumor mouse model. PMX encapsulated within either cholesterol-containing (PMX/Chol CL) or cholesterol-free (PMX/Non-Chol CL) cationic liposome was intrapleurally injected into tumor-bearing mice. PMX encapsulated in cholesterol-free liposomes (PMX/Non-Chol CL) drastically inhibited the tumor growth in the pleural cavity, while free PMX and PMX encapsulated in cholesterol-containing liposomes (PMX/Chol CL) barely inhibited the tumor growth. The enhanced in vivo anti-tumor efficacy of PMX/Non-Chol CL was credited, on the one hand, for prolonging the retention of cationic liposomes in the pleural cavity via their electrostatic interaction with the negatively charged membranes of tumor cells, but on the other hand, it was charged with contributing to a higher drug release from the "fluid" liposomal membrane following intrapleural administration. This therapeutic strategy of direct intrapleural administration of liposomal PMX, along with the great advances in CL-guided therapeutics, might be a promising therapeutic approach to conquering the poor prognosis for MPM.

Multiple administration of PEG-coated liposomal oxaliplatin enhances its therapeutic efficacy: a possible mechanism and the potential for clinical application.

We previously developed a PEG-coated cationic liposome that enabled dual targeting delivery of oxaliplatin (l-OHP) to both tumor endothelial cells and tumor cells in a solid tumor. The targeted liposomal l-OHP formulation consequently elicited potent antitumor efficacy in a murine solid tumor model after 3 sequential injections. However, the probable mechanism(s) for this enhanced antitumor activity has not been fully elucidated. In the present study, therefore, the changes in tumor microenvironment induced by sequential administration of liposomal l-OHP were investigated, with emphasis on its impact to the intratumoral localization of the subsequently injected dose. In addition, the potential for anti-PEG IgM production upon repeated administration of liposomal l-OHP-containing PEGylated lipid was clearly revealed. Two sequential injections of liposomal l-OHP induced superior apoptotic activity in tumor tissue and thus resulted in broader intratumor distribution of the subsequent test dose of PEG-coated cationic liposomes, compared with a single injection of liposomal l-OHP. In addition, it was confirmed that repeated administration of liposomal l-OHP did not induce a significant anti-PEG IgM response, indicating that l-OHP encapsulated in PEG-coated liposomes was efficient in abrogating the ABC phenomenon. These results suggest that sequential treatment strategies with liposomal cytotoxic agents might be superior to mono-treatment strategies in achieving alterations in the tumor microenvironment and maintaining/restoring the pharmacokinetics of the formulation, and, therefore, would result in substantial therapeutic efficacy.