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Direct Comparison of Chol-siRNA Polyplexes and Chol-DsiRNA Polyplexes Targeting STAT3 in a Syngeneic Murine Model of TNBC

Authors :
Joseph A. Vetro
Rakesh Singh
Devendra Kumar
Anthony T. Podany
Don W. Coulter
Zhen Ye
Shetty Ravi Dyavar
Mai Mohamed Abdelmoaty
Stephen M. Curran
Yazen Alnouti
Source :
Non-Coding RNA, Non-Coding RNA; Volume 8; Issue 1; Pages: 8
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

RNA interference (RNAi) molecules have tremendous potential for cancer therapy but are limited by insufficient potency after intravenous (IV) administration. We previously found that polymer complexes (polyplexes) formed between 3′-cholesterol-modified siRNA (Chol-siRNA) or DsiRNA (Chol-DsiRNA) and the cationic diblock copolymer PLL[30]-PEG[5K] greatly increase RNAi potency against stably expressed LUC mRNA in primary syngeneic murine breast tumors after daily IV dosing. Chol-DsiRNA polyplexes, however, maintain LUC mRNA suppression for ~48 h longer after the final dose than Chol-siRNA polyplexes, which suggests that they are the better candidate formulation. Here, we directly compared the activities of Chol-siRNA polyplexes and Chol-DsiRNA polyplexes in primary murine 4T1 breast tumors against STAT3, a therapeutically relevant target gene that is overexpressed in many solid tumors, including breast cancer. We found that Chol-siSTAT3 polyplexes suppressed STAT3 mRNA in 4T1 tumors with similar potency (half-maximal ED50 0.3 mg/kg) and kinetics (over 96 h) as Chol-DsiSTAT3 polyplexes, but with slightly lower activity against total Stat3 protein (29% vs. 42% suppression) and tumor growth (11.5% vs. 8.6% rate-based T/C ratio) after repeated IV administration of equimolar, tumor-saturating doses every other day. Thus, both Chol-siRNA polyplexes and Chol-DsiRNA polyplexes may be suitable clinical candidates for the RNAi therapy of breast cancer and other solid tumors.

Details

Database :
OpenAIRE
Journal :
Non-Coding RNA, Non-Coding RNA; Volume 8; Issue 1; Pages: 8
Accession number :
edsair.doi.dedup.....1b93683aaffd7597bff4f4162a1110b6
Full Text :
https://doi.org/10.20944/preprints202109.0052.v1