Systemically Administered RNAi Molecule Sensitizes Malignant Pleural Mesotheliomal Cells to Pemetrexed Therapy

Mol Pharm. 2016 Nov 7;13(11):3955-3963. doi: 10.1021/acs.molpharmaceut.6b00728. Epub 2016 Oct 26.

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.

Keywords: PEG-coated shRNA-lipoplex; malignant pleural mesothelioma; pemetrexed; short hairpin RNA; thymidylate synthase.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Humans
  • Liposomes / chemistry
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / therapy*
  • Male
  • Mesothelioma / drug therapy*
  • Mesothelioma / genetics
  • Mesothelioma / therapy*
  • Mesothelioma, Malignant
  • Mice
  • Mice, Nude
  • Pemetrexed / therapeutic use*
  • Polyethylene Glycols / chemistry
  • RNA Interference
  • RNA, Small Interfering / genetics*
  • Thymidylate Synthase / genetics
  • Transfection

Substances

  • Liposomes
  • RNA, Small Interfering
  • Pemetrexed
  • Polyethylene Glycols
  • Thymidylate Synthase