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Direct Comparison of Chol-siRNA Polyplexes and Chol-DsiRNA Polyplexes Targeting STAT3 in a Syngeneic Murine Model of TNBC
| Content Provider | MDPI |
|---|---|
| Author | Ye, Zhen Abdelmoaty, Mai Mohamed Curran, Stephen M. Dyavar, Shetty Ravi Kumar, Devendra Alnouti, Yazen Coulter, Don W. Podany, Anthony T. Singh, Rakesh K. Vetro, Joseph A. |
| Copyright Year | 2022 |
| Description | 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 $ED_{50}$ 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. |
| Starting Page | 8 |
| e-ISSN | 2311553X |
| DOI | 10.3390/ncrna8010008 |
| Journal | Non-Coding RNA |
| Issue Number | 1 |
| Volume Number | 8 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2022-01-13 |
| Access Restriction | Open |
| Subject Keyword | Non-Coding RNA Non-coding Rna Oncology Rnai Drug Delivery Sirna Delivery Dsirna Delivery Rnai Delivery Chol-dsirna Polymer Micelles Chol-sirna Polymer Micelles |
| Content Type | Text |
| Resource Type | Article |
