title: Systemically Administered RNAi Molecule Sensitizes Malignant Pleural Mesotheliomal Cells to Pemetrexed Therapy.
abstract: Pemetrexed (PMX) is a key drug for the management of malignant pleural mesothelioma (MPM). However, its therapeutic efficacy is cruelly restricted in many clinical settings by the overexpression of thymidylate synthase (TS) gene. Recently, we emphasized the efficacy of locally administered shRNA designed against TS gene in enhancing the cytotoxic effect of PMX against orthotopically implanted MPM cells in tumor xenograft tumor model. Herein, we explored the efficiency of systemic, rather than local, delivery of TS RNAi molecule in sensitizing MPM cells to the cytotoxic effect of PMX. We here designed a PEG-coated TS shRNA-lipoplex (PEG-coated TS shRNA-lipoplex) for systemic injection. PEG modification efficiently delivered TS shRNA in the lipoplex to tumor tissue following intravenous administration as indicated by a significant suppression of TS expression level in tumor tissue. In addition, the combined treatment of PMX with systemic injection of PEG-coated TS shRNA-lipoplex exerted a potent antitumor activity in a s.c. xenograft tumor model, compared to a single treatment with either PMX or PEG-coated TS shRNA-lipoplex. Metastasis, or the spread, of mesothelioma substantially dedicates the effectiveness of treatment options. The systemic, in addition to local, delivery of tumor targeted anti-TS RNAi system we propose in this study might be an effective option to extend the clinical utility of PMX in treating malignant mesothelioma.
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University , Tokushima, Japan.|Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University , Zagazig 44519, Egypt.|Department of Pharmaceutics, Faculty of Pharmacy, Hail University , Hail 2440, Saudi Arabia.
authors.forename: Amr S
authors.initials: AS
authors.lastname: Abu Lila
authors.affiliation: Department of Cancer Metabolism and Therapy, Institute of Biomedical Sciences, Tokushima University , Tokushima 770-8505, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fukushima
authors.affiliation: Department of Thoracic Surgery, Faculty of Medicine, Kyoto University , Kyoto 606-8501, Japan.
authors.forename: Cheng-Long
authors.initials: CL
authors.lastname: Huang
authors.affiliation: Department of Thoracic Surgery, Faculty of Medicine, Kyoto University , Kyoto 606-8501, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Wada
authors.affiliation: Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University , Tokushima, Japan.|Department of Cancer Metabolism and Therapy, Institute of Biomedical Sciences, Tokushima University , Tokushima 770-8505, Japan.
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Ishida
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008081:Liposomes / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000628:therapy*; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics / Q000628:therapy*; D000086002:Mesothelioma, Malignant; D051379:Mice; D008819:Mice, Nude; D000068437:Pemetrexed / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics*; D013940:Thymidylate Synthase / Q000235:genetics; D014162:Transfection
chemical_list: D008081:Liposomes; D034741:RNA, Small Interfering; D000068437:Pemetrexed; D011092:Polyethylene Glycols; D013940:Thymidylate Synthase
keywords: PEG-coated shRNA-lipoplex; malignant pleural mesothelioma; pemetrexed; short hairpin RNA; thymidylate synthase