Enhancing Systemic Delivery of Enzymatically Generated RNAi Nanocomplexes for Cancer Therapy

Authors
Nam, H.Ku, S.H.Yoon, H.Y.Kim, K.Kwon, I.C.Kim, S.H.Lee, J.B.
Issue Date
2019-06
Publisher
Blackwell Publishing Ltd
Citation
Advanced Therapeutics, v.2, no.6
Abstract
Despite the superb therapeutic potential of siRNA technology, its clinical application are still limited due to the inherent instability and lack of systemic delivery issues. Recently, the development of long-chain siRNA has been proposed as a strategy to improve in vivo stability, particularly for efficient physical integration of siRNA molecules into gene carriers. Herein, concatemeric siRNAs are enzymatically synthesized through a rolling circle transcription process, and form stable RNA interference (RNAi) nanocomplexes with a redox-sensitive glycol chitosan derivative to systemically deliver the concatemeric siRNAs to tumor tissues. The enzymatically generated RNAi nanocomplexes (RNCs) have higher particle stability and less cytotoxicity than the conventional polyelectrolyte complexes. The therapeutic potential of the RNC formulation is verified in vivo as well as in vitro using VEGF as an antiangiogenic target for RNAi-based anticancer therapy. After systemic administration, RNC is specifically accumulated in tumor tissues and shows a high inhibitory effect on tumor growth. According to the results, the RNC can be considered as a platform technology for efficient tumor-targeted siRNA delivery systems. ? 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Keywords
chitosan derivative; circular DNA; polyelectrolyte; small interfering RNA; vasculotropin; animal experiment; animal model; antineoplastic activity; apoptosis; Article; cancer inhibition; cancer therapy; cell viability; controlled study; cross linking; cytotoxicity; disulfide bond; down regulation; drug delivery system; endocytosis; enzymatic degradation; flow cytometry; fluorescence imaging; gel electrophoresis; gene silencing; human; human cell; intracellular transport; macropinocytosis; male; molecular weight; mouse; nonhuman; particle size; physical chemistry; priority journal; promoter region; prostate cancer; RNA interference; RNAi therapeutics; scanning electron microscopy; static electricity; surface charge; SVEC4-10 cell line; tumor volume; concatemeric siRNA; rolling circle transcription; structural modification; systemic siRNA delivery system; tumor-targeted delivery
ISSN
2366-3987
URI
https://pubs.kist.re.kr/handle/201004/119967
DOI
10.1002/adtp.201900014
Appears in Collections:
KIST Article > 2019
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