Systemically administered RNAi molecule sensitizes malignant pleural mesothelioma cells to pemetrexed therapy

Molecular Pharmaceutics 2016 October 14 [Epub ahead of print] [Link]

Abu Lila AS, Fukushima M, Huang CL, Wada H, Ishida T


Pemetrexed (PMX) is a key drug for the treatment of malignant pleural mesothelioma (MPM). However, its therapeutic efficacy is cruelly restricted in many clinical settings by the over-expression 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. In the present study, we investigated the efficacy 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 modifiaction 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 against MSTO-211H xenograft mouse model, compared to a single treatment with either PMX or PEG-coated TS shRNA-lipoplex. Metastasis, or the spread, of mesothelioma plays an important role in 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.