Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA; Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Giza, Egypt.
Nanomedicine. 2021 Apr;33:102363. doi: 10.1016/j.nano.2021.102363. Epub 2021 Feb 3.
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.
RNA 干扰分子在癌症治疗方面具有巨大的潜力，但在静脉注射后，由于效力不足而受到限制。我们之前发现，胆固醇修饰的 Dicer 底物 siRNA（Chol-DsiRNA）与阳离子两亲嵌段共聚物 PLL[30]-PEG[5K] 之间形成的 Chol-DsiRNA 聚合物可大大提高 Chol-DsiRNA 对原发性小鼠同基因乳腺肿瘤中稳定表达的报告 mRNA 的活性，每天静脉注射一次。在这里，我们对 Chol-DsiRNA 聚合物针对治疗相关靶蛋白 STAT3 进行了更全面的初步临床前研究。我们发现，Chol-DsiSTAT3 聚合物可大大提高 Chol-DsiSTAT3 在原发性小鼠同基因 4T1 乳腺肿瘤中的血浆暴露量、分布、效力和治疗活性，静脉注射后。此外，在 28 天内以 50mg Chol-DsiCTRL/kg 的剂量每天静脉给予健康雌性 BALB/c 小鼠时，无活性的 Chol-DsiCTRL 聚合物具有良好的耐受性。因此，Chol-DsiRNA 聚合物可能是 I 期临床试验的良好候选物，可改善乳腺癌和其他实体瘤的治疗。
