Preliminary preclinical study of Chol-DsiRNA polyplexes formed with PLL[30]-PEG[5K] for the RNAi-based therapy of breast cancer

• Published in: Nanomedicine 2021-04, Vol.33, p.102363-102363, Article 102363
• Main Authors: Ye, Zhen, Abdelmoaty, Mai Mohamed, Ambardekar, Vishakha V., Curran, Stephen M., Dyavar, Shetty Ravi, Arnold, Lora L., Cohen, Samuel M., Kumar, Devendra, Alnouti, Yazen, Coulter, Don W., Singh, Rakesh K., Vetro, Joseph A.
• Format: Article
• Language: English
• Subjects: Animals; Breast Neoplasms - therapy; Cell Line, Tumor; Chol-DsiRNA polymer micelles; Chol-siRNA polymer micelles; Cholesterol - chemistry; DEAD-box RNA Helicases - genetics; Drug delivery; DsiRNA; Female; Gene Transfer Techniques; Humans; Mice; Mice, Inbred BALB C; Micelles; Molecular Targeted Therapy; Polyethylene Glycols - chemistry; Polylysine - analogs & derivatives; Polylysine - chemistry; Ribonuclease III - genetics; RNA Interference; RNA, Small Interfering - chemistry; RNAi Therapeutics - methods; STAT3 Transcription Factor - metabolism; Tissue Distribution
• ISSN: 1549-9634; 1549-9642
• DOI: 10.1016/j.nano.2021.102363

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. Chol-DsiRNA polyplexes formed between cholesterol-modified dicer-substrate siRNA (Chol-DsiRNA) and a cationic block copolymer of 30 poly-l-lysine residues and 5 kDa polyethylene glycol (PLL[30]-PEG[5K]) significantly increase the potency and activity of complexed Chol-DsiSTAT3 in primary murine syngeneic breast tumors and are well tolerated by healthy female BALB/c mice after chronic i.v. administration at 50 mg inactive Chol-DsiRNA/kg over 28 days. [Display omitted]