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Abstract：
RNA interference molecules have tremendous potential for cancer therapy but are limited by insufficient potency after i.v. administration. We previously found that Chol-DsiRNA polyplexes formed between cholesterol-modified dicer-substrate siRNA (Chol-DsiRNA) and the cationic diblock copolymer PLL[30]-PEG[5K] greatly increase the activity of Chol-DsiRNA against a stably expressed reporter mRNA in primary murine syngeneic breast tumors after daily i.v. dosing. Here, we provide a more thorough preliminary preclinical study of Chol-DsiRNA polyplexes against the therapeutically relevant target protein, STAT3. We found that Chol-DsiSTAT3 polyplexes greatly increase plasma exposure, distribution, potency, and therapeutic activity of Chol-DsiSTAT3 in primary murine syngeneic 4T1 breast tumors after i.v. administration. Furthermore, inactive Chol-DsiCTRL polyplexes are well tolerated by healthy female BALB/c mice after chronic i.v. administration at 50 mg Chol-DsiCTRL/kg over 28 days. Thus, Chol-DsiRNA polyplexes may be a good candidate for Phase I clinical trials to improve the treatment of breast cancer and other solid tumors.
摘要：
RNA干扰分子具有用于癌症治疗的巨大潜力,但受到静脉内施用后效力不足的限制。我们先前发现，胆固醇修饰的dicer-substratesiRNA（Chol-DsiRNA）和阳离子二嵌段共聚物PLL[30]-PEG[5K]之间形成的Chol-DsiRNA多聚复合物极大地增加了Chol-DsiRNA对稳定表达的活性每日静脉注射后在原发性鼠同系乳腺肿瘤中表达的报告mRNA。这里,我们提供了针对治疗相关靶蛋白的Chol-DsiRNA多聚复合物的更彻底的初步临床前研究，STAT3.我们发现Chol-DsiSTAT3聚合复合物大大增加了等离子体暴露，分布，效力，效力以及在静脉内施用后Chol-DsiSTAT3在原发性鼠同基因4T1乳腺肿瘤中的治疗活性。此外，非活性的Chol-DsiCTRL聚合复合物在28天内以50mgChol-DsiCTRL/kg慢性静脉给药后被健康雌性BALB/c小鼠良好耐受。因此，Chol-DsiRNA复合物可能是I期临床试验的良好候选者，以改善乳腺癌和其他实体瘤的治疗。
