Sustained small interfering RNA delivery by mesoporous silicon particles

Takemi Tanaka, Lingegowda S. Mangala, Pablo E. Vivas-Mejia, René Nieves-Alicea, Aman P. Mann, Edna Mora, Hee Dong Han, Mian M.K. Shahzad, Xuewu Liu, Rohan Bhavane, Jianhua Gu, Jean R. Fakhoury, Ciro Chiappini, Chunhua Lu, Koji Matsuo, Biana Godin, Rebecca L. Stone, Alpa M. Nick, Gabriel Lopez-Berestein, Anil K. SoodMauro Ferrari

Research output: Contribution to journalArticlepeer-review

261 Scopus citations

Abstract

RNA interference (RNAi) is a powerful approach for silencing genes associated with a variety of pathologic conditions; however, in vivo RNAi delivery has remained a major challenge due to lack of safe, efficient, and sustained systemic delivery. Here, we report on a novel approach to overcome these limitations using a multistage vector composed of mesoporous silicon particles (stage 1 microparticles, S1MP) loaded with neutral nanoliposomes (dioleoyl phosphatidylcholine, DOPC) containing small interfering RNA (siRNA) targeted against the EphA2 oncoprotein, which is overexpressed in most cancers, including ovarian. Our delivery methods resulted in sustained EphA2 gene silencing for at least 3 weeks in two independent orthotopic mouse models of ovarian cancer following a single i.v. administration of S1MP loaded with EphA2-siRNA-DOPC. Furthermore, a single administration of S1MP loaded with-EphA2-siRNA-DOPC substantially reduced tumor burden, angiogenesis, and cell proliferation compared with a noncoding control siRNA alone (SKOV3ip1, 54%; HeyA8, 57%), with no significant changes in serum chemistries or in proinflammatory cytokines. In summary, we have provided the first in vivo therapeutic validation of a novel, multistage siRNA delivery system for sustained gene silencing with broad applicability to pathologies beyond ovarian neoplasms.

Original languageEnglish (US)
Pages (from-to)3687-3696
Number of pages10
JournalCancer research
Volume70
Issue number9
DOIs
StatePublished - May 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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