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ID 115599
Author
Lila, Amr S. Abu Tokushima University|Zagazig University|Hail University
Fukushima, Masakazu Tokushima University
Huang, Cheng-Long Kyoto University
Wada, Hiromi Kyoto University
Keywords
malignant pleural mesothelioma
PEG-coated shRNA-lipoplex
pemetrexed
short hairpin RNA
thymidylate synthase
Content Type
Journal Article
Description
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.
Journal Title
Molecular Pharmaceutics
ISSN
15438384
15438392
NCID
AA11854546
AA12442792
Publisher
ACS Publications
Volume
13
Issue
11
Start Page
3955
End Page
3963
Published Date
2016-10-14
Rights
This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License(https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes.
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DOI (Published Version)
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language
eng
TextVersion
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departments
Pharmaceutical Sciences