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.