Complexation of Chol-DsiRNA in place of Chol-siRNA greatly increases the duration of mRNA suppression by polyplexes of PLL(30)-PEG(5K) in primary murine syngeneic breast tumors after i.v. administration

• Published in: International journal of pharmaceutics Vol. 543; no. 1-2; pp. 130 - 138
• Main Authors: Ambardekar, Vishakha V., Wakaskar, Rajesh R., Ye, Zhen, Curran, Stephen M., McGuire, Timothy R., Coulter, Don W., Singh, Rakesh K., Vetro, Joseph A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 30.05.2018
• Subjects: Administration, Intravenous; Animals; Cell Line, Tumor; Chol-DsiRNA polymer micelles; Chol-DsiRNA polyplexes; Chol-siRNA polymer micelles; Chol-siRNA polyplexes; Cholesterol - administration & dosage; Cholesterol - chemistry; DEAD-box RNA Helicases; Drug delivery; DsiRNA; Female; Luciferases - genetics; Mammary Neoplasms, Experimental - genetics; Mice, Inbred BALB C; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - chemistry; Polylysine - administration & dosage; Polylysine - analogs & derivatives; Polylysine - chemistry; Ribonuclease III; RNA interference; RNA, Messenger; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - chemistry; RNA interference; Chol-DsiRNA polyplexes; Chol-DsiRNA polymer micelles; DsiRNA; Chol-siRNA polymer micelles; Drug delivery; Chol-siRNA polyplexes
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2018.03.045

[Display omitted] RNA interference has tremendous potential for cancer therapy but is limited by the insufficient potency of RNAi molecules after i.v. administration. We previously found that complexation with PLL(30)-PEG(5K) greatly increases the potency of 3′-cholesterol-modified siRNA [Chol-siRNA] in primary murine syngeneic 4T1 breast tumors after i.v. administration but mRNA suppression decreases 24 h after the final dose. We hypothesized that complexation of cholesterol-modified Dicer-substrate siRNA (Chol-DsiRNA) in place of Chol-siRNA can increase the potency and duration of suppression by polyplexes of PLL(30)-PEG(5K) in solid tumors. We found that replacing Chol-siRNA with Chol-DsiRNA increased polyplex loading and nuclease protection, suppressed stably expressed luciferase to the same extent in primary murine 4T1-Luc breast tumors under the current dosage regimen, but maintained suppression ~72 h after the final dose. The kinetics of suppression in 4T1-Luc over 72 h, however, were similar between DsiLuc and siLuc after electroporation and between polyplexes of Chol-DsiLuc and Chol-siLuc after transfection, suggesting that Chol-DsiRNA polyplexes increase the duration of mRNA suppression through differences in polyplex activities in vivo. Thus, replacing Chol-siRNA with Chol-DsiRNA may significantly increase the duration of mRNA suppression by polyplexes of PLL(30)-PEG(5K) and possibly other PEGylated polycationic polymers in primary tumors and metastases after i.v. administration.