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Biomaterials Science

Biomaterials Science

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Bioreducible, arginine-rich polydisulfide-based siRNA nanocomplexes with excellent tumor penetration for efficient gene silencing

Published:11 June 2021 DOI: 10.1039/D1BM00643F PMID: 34180478
Xinyue Zhang, Kai Hong, Qingmei Sun, Yunqing Zhu and Jianzhong Du

Abstract

RNA interference (RNAi) technology has great potential in cancer therapy, e.g., small interfering RNA (siRNA) can be exploited to silence specific oncogenes related to tumor growth and progression. However, it is critical to achieve high transfection efficiency while reducing cytotoxicity. In this paper, we report an siRNA delivery strategy targeting the oncogene KRAS based on arginine-modified poly(disulfide amine)/siRNA nanocomplexes. The poly(disulfide amine) is synthesized via aza-Michael polyaddition followed by the introduction of arginine groups onto its backbone to afford poly((N,N′-bis(acryloyl)cystamine-co-ethylenediamine)-g-Nω-p-tosyl-L-arginine) (PBR) polycations. Thus multiple interactions including electrostatic interaction, hydrogen bonding and a hydrophobic effect are introduced simultaneously between PBR and siRNA or cell membranes to improve transfection efficiency. By optimizing the grafting density of arginine groups, PBR/siRNA nanocomplexes achieve high cellular uptake efficiency, successful endosomal/lysosomal escape, and rapid biodegradation in the presence of high GSH concentration in the cytoplasm, and finally release siRNA to activate the RNAi mechanism. Additionally, compared to commercially available PEI 25K, PBR/siRNA nanocomplexes possess a significantly increased gene silencing effect on human pancreatic cancer cells (PANC-1) with decreased cytotoxicity and enhanced tumor penetration ability in PANC-1 multicellular spheroids in vitro. Overall, with both GSH-responsiveness and excellent tumor penetration, this safe and efficient poly(disulfide amine)-based siRNA delivery system is expected to provide a new strategy for gene therapy of pancreatic cancer and other stromal-rich tumors.

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Genistein 446-72-0 C15H10O5 849 suppliers $10.00-$2658.80
Genistein 446-72-0 C15H10O5 849 suppliers $10.00-$2658.80
Genistein 446-72-0 C15H10O5 849 suppliers $10.00-$2658.80
Genistein 446-72-0 C15H10O5 849 suppliers $10.00-$2658.80
EXO1 75541-83-2 C15H12FNO3 62 suppliers $12.00-$1800.00
EXO1 75541-83-2 C15H12FNO3 62 suppliers $12.00-$1800.00
EXO1 75541-83-2 C15H12FNO3 62 suppliers $12.00-$1800.00
EXO1 75541-83-2 C15H12FNO3 62 suppliers $12.00-$1800.00
Genistein 446-72-0 C15H10O5 - Inquiry
Genistein 446-72-0 C15H10O5 - Inquiry

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