Abu Lila Amr S, Fukushima Masakazu, Huang Cheng-Long, Wada Hiromi, Ishida Tatsuhiro
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.
Mol Pharm. 2016 Nov 7;13(11):3955-3963. doi: 10.1021/acs.molpharmaceut.6b00728. Epub 2016 Oct 26.
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.
培美曲塞（PMX）是治疗恶性胸膜间皮瘤（MPM）的关键药物。然而，在许多临床情况下，胸苷酸合成酶（TS）基因的过表达严重限制了其治疗效果。最近，我们强调了针对TS基因设计的局部给药短发夹RNA（shRNA）在增强PMX对肿瘤异种移植模型中原位植入的MPM细胞的细胞毒性作用方面的效果。在此，我们探讨了全身而非局部递送TS RNA干扰（RNAi）分子使MPM细胞对PMX的细胞毒性作用敏感的效率。我们设计了一种用于全身注射的聚乙二醇（PEG）包被的TS shRNA脂质体复合物（PEG包被的TS shRNA脂质体复合物）。如肿瘤组织中TS表达水平的显著抑制所示，PEG修饰在静脉给药后有效地将脂质体中的TS shRNA递送至肿瘤组织。此外，与单独使用PMX或PEG包被的TS shRNA脂质体复合物治疗相比，PMX与全身注射PEG包被的TS shRNA脂质体复合物联合治疗在皮下异种移植肿瘤模型中发挥了强大的抗肿瘤活性。间皮瘤的转移或扩散极大地影响了治疗方案的有效性。我们在本研究中提出的全身以及局部递送肿瘤靶向抗TS RNAi系统可能是扩展PMX在治疗恶性间皮瘤临床应用的有效选择。
