title: Advanced therapeutic approach for the treatment of malignant pleural mesothelioma via the intrapleural administration of liposomal pemetrexed.
abstract: 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.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan; Department of Cancer Metabolism and Therapy, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ando
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
authors.forename: Amr S
authors.initials: AS
authors.lastname: Abu Lila
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
authors.forename: Noha Essam
authors.initials: NE
authors.lastname: Eldin
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Kato
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Ukawa
authors.affiliation: Department of Clinical Pharmacy, Institute of Biomedical Sciences, Tokushima University, 2-50-1 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kawazoe
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan; Department of Cancer Metabolism and Therapy, Institute of Biomedical Sciences, Tokushima University, 1-78-1 Sho-machi, Tokushima, 770-8505, Japan. Electronic address: ishida@tokushima-u.ac.jp.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D006801:Humans; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy*; D000086002:Mesothelioma, Malignant; D051379:Mice; D008807:Mice, Inbred BALB C; D000068437:Pemetrexed / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D000068437:Pemetrexed
keywords: Intrapleural administration; Liposomes; Malignant pleural mesothelioma; Orthotopic tumor model; Pemetrexed