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Open AccessArticle

A Unique Gene-Silencing Approach, Using an Intelligent RNA Expression Device (iRed), Results in Minimal Immune Stimulation When Given by Local Intrapleural Injection in Malignant Pleural Mesothelioma

1
Department of Pharmacokinetics and Biopharmaceutics, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan
2
Department of Bioorganic Chemistry, Institute of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima 770-8505, Japan
3
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
4
Department of Pharmaceutics, College of Pharmacy, Hail University, Hail 81442, Saudi Arabia
*
Author to whom correspondence should be addressed.
Academic Editors: Fabio Pastorino, Chiara Brignole and Ildiko Badea
Molecules 2020, 25(7), 1725; https://doi.org/10.3390/molecules25071725
Received: 5 February 2020 / Revised: 7 April 2020 / Accepted: 7 April 2020 / Published: 9 April 2020
(This article belongs to the Special Issue Recent Advances in Precision Nanomedicine for Cancer)
Background: We have recently introduced an intelligent RNA expression device (iRed), comprising the minimum essential components needed to transcribe short hairpin RNA (shRNA) in cells. Use of iRed efficiently produced shRNA molecules after transfection into cells and alleviated the innate immune stimulation following intravenous injection. Methods: To study the usefulness of iRed for local injection, the engineered iRed encoding luciferase shRNA (Luc iRed), complexed with cationic liposomes (Luc iRed/liposome-complexes), was intrapleurally injected into an orthotopic mesothelioma mouse model. Results: Luc iRed/liposome-complexes markedly suppressed the expression of a luciferase marker gene in pleurally disseminated mesothelioma cells. The suppressive efficiency was correlated with the expression level of shRNA within the mesothelioma cells. In addition, intrapleural injection of iRed/liposome-complexes did not induce IL-6 production in the pleural space and consequently in the blood compartment, although plasmid DNA (pDNA) or dsDNA (the natural construct for iRed) in the formulation did. Conclusion: Local delivery of iRed could augment the in vivo gene silencing effect without eliciting pronounced innate immune stimulation. Our results might hold promise for widespread utilization of iRed as an RNAi-based therapeutic for intracelial malignant cancers. View Full-Text
Keywords: cationic liposomes; innate immunity; intelligent RNA expression device (iRed); RNA interference; shRNA cationic liposomes; innate immunity; intelligent RNA expression device (iRed); RNA interference; shRNA
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Ando, H.; Saito-Tarashima, N.; Lila, A.S.A.; Kinjo, N.; Shimizu, T.; Ishima, Y.; Minakawa, N.; Ishida, T. A Unique Gene-Silencing Approach, Using an Intelligent RNA Expression Device (iRed), Results in Minimal Immune Stimulation When Given by Local Intrapleural Injection in Malignant Pleural Mesothelioma. Molecules 2020, 25, 1725.

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