Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 2 September 2021 / Approved: 3 September 2021 / Online: 3 September 2021 (08:56:48 CEST)

How to cite: Ye, Z.; Abdelmoaty, M.M.; Curran, S.M.; Dyavar, S.R.; Kumar, D.; Alnouti, Y.; Coulter, D.W.; Podany, A.T.; Singh, R.K.; Vetro, J.A. Direct Comparison of Chol-siRNA Polyplexes and Chol-DsiRNA Polyplexes Targeting STAT3 in a Syngeneic Murine Model of TNBC. Preprints 2021, 2021090052 (doi: 10.20944/preprints202109.0052.v1). Ye, Z.; Abdelmoaty, M.M.; Curran, S.M.; Dyavar, S.R.; Kumar, D.; Alnouti, Y.; Coulter, D.W.; Podany, A.T.; Singh, R.K.; Vetro, J.A. Direct Comparison of Chol-siRNA Polyplexes and Chol-DsiRNA Polyplexes Targeting STAT3 in a Syngeneic Murine Model of TNBC. Preprints 2021, 2021090052 (doi: 10.20944/preprints202109.0052.v1).

Abstract

RNA interference (RNAi) molecules have tremendous potential for cancer therapy but are limited by insufficient potency after i.v. 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 i.v. dosing. Chol-DsiRNA Polyplexes, however, maintain LUC mRNA suppression ~48 h longer after the final dose than Chol-siRNA Polyplexes, suggesting they are a better candidate formulation. Here, we directly compared the activities of Chol-siRNA and Chol-DsiRNA Polyplexes in primary murine 4T1 breast tumors against STAT3, a therapeutically relevant target gene 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 hours 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 i.v. administration of tumor-saturating doses every other day. Thus, both Chol-siRNA Polyplexes and Chol-DsiRNA Polyplexes may be suitable clinical candidates for RNAi therapy of breast cancer and other solid tumors.

Keywords

RNAi; drug delivery; siRNA delivery; DsiRNA delivery; RNAi delivery; Chol-DsiRNA polymer micelles; Chol-siRNA polymer micelles

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