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Direct Comparison of Chol-siRNA Polyplexes and Chol-DsiRNA Polyplexes Targeting STAT3 in a Syngeneic Murine Model of TNBC
- 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.
- Subjects :
- siRNA delivery
biology
Chemistry
other
technology, industry, and agriculture
Chol-siRNA polymer micelles
RNAi delivery
Biochemistry
Article
RNA interference
Murine model
RNAi
DsiRNA delivery
drug delivery
Drug delivery
Chol-DsiRNA polymer micelles
Genetics
polycyclic compounds
biology.protein
Cancer research
lipids (amino acids, peptides, and proteins)
STAT3
Molecular Biology
Subjects
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