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

Vishakha V. Ambardekar, Rajesh R. Wakaskar, Zhen Ye, Stephen M. Curran, Timothy R McGuire, Donald W Coulter, Rakesh K Singh, Joseph A Vetro

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)130-138
Number of pages9
JournalInternational Journal of Pharmaceutics
Volume543
Issue number1-2
DOIs
StatePublished - May 30 2018

Fingerprint

Small Interfering RNA
Cholesterol
Breast Neoplasms
Messenger RNA
RNA Interference
Neoplasms
Electroporation
Luciferases
Transfection
Polymers
Neoplasm Metastasis

Keywords

  • Chol-DsiRNA polymer micelles
  • Chol-DsiRNA polyplexes
  • Chol-siRNA polymer micelles
  • Chol-siRNA polyplexes
  • Drug delivery
  • DsiRNA
  • RNA interference

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

@article{676e5fbc0eb04480947494ee8c0744d4,
title = "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",
abstract = "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.",
keywords = "Chol-DsiRNA polymer micelles, Chol-DsiRNA polyplexes, Chol-siRNA polymer micelles, Chol-siRNA polyplexes, Drug delivery, DsiRNA, RNA interference",
author = "Ambardekar, {Vishakha V.} and Wakaskar, {Rajesh R.} and Zhen Ye and Curran, {Stephen M.} and McGuire, {Timothy R} and Coulter, {Donald W} and Singh, {Rakesh K} and Vetro, {Joseph A}",
year = "2018",
month = "5",
day = "30",
doi = "10.1016/j.ijpharm.2018.03.045",
language = "English (US)",
volume = "543",
pages = "130--138",
journal = "International Journal of Pharmaceutics",
issn = "0378-5173",
publisher = "Elsevier",
number = "1-2",

}

TY - JOUR

T1 - 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

AU - Ambardekar, Vishakha V.

AU - Wakaskar, Rajesh R.

AU - Ye, Zhen

AU - Curran, Stephen M.

AU - McGuire, Timothy R

AU - Coulter, Donald W

AU - Singh, Rakesh K

AU - Vetro, Joseph A

PY - 2018/5/30

Y1 - 2018/5/30

N2 - 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.

AB - 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.

KW - Chol-DsiRNA polymer micelles

KW - Chol-DsiRNA polyplexes

KW - Chol-siRNA polymer micelles

KW - Chol-siRNA polyplexes

KW - Drug delivery

KW - DsiRNA

KW - RNA interference

UR - http://www.scopus.com/inward/record.url?scp=85044579505&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85044579505&partnerID=8YFLogxK

U2 - 10.1016/j.ijpharm.2018.03.045

DO - 10.1016/j.ijpharm.2018.03.045

M3 - Article

C2 - 29601972

AN - SCOPUS:85044579505

VL - 543

SP - 130

EP - 138

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

SN - 0378-5173

IS - 1-2

ER -