title: Sustained small interfering RNA delivery by mesoporous silicon particles.
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.
authors.affiliation: Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston, Texas, USA.
authors.forename: Takemi
authors.initials: T
authors.lastname: Tanaka
authors.forename: Lingegowda S
authors.initials: LS
authors.lastname: Mangala
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Vivas-Mejia
authors.forename: René
authors.initials: R
authors.lastname: Nieves-Alicea
authors.forename: Aman P
authors.initials: AP
authors.lastname: Mann
authors.forename: Edna
authors.initials: E
authors.lastname: Mora
authors.forename: Hee-Dong
authors.initials: HD
authors.lastname: Han
authors.forename: Mian M K
authors.initials: MM
authors.lastname: Shahzad
authors.forename: Xuewu
authors.initials: X
authors.lastname: Liu
authors.forename: Rohan
authors.initials: R
authors.lastname: Bhavane
authors.forename: Jianhua
authors.initials: J
authors.lastname: Gu
authors.forename: Jean R
authors.initials: JR
authors.lastname: Fakhoury
authors.forename: Ciro
authors.initials: C
authors.lastname: Chiappini
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.forename: Koji
authors.initials: K
authors.lastname: Matsuo
authors.forename: Biana
authors.initials: B
authors.lastname: Godin
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Stone
authors.forename: Alpa M
authors.initials: AM
authors.lastname: Nick
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010051:Ovarian Neoplasms / Q000235:genetics / Q000628:therapy; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics; D036104:Receptor, EphA2 / Q000235:genetics; D012825:Silicon / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D008081:Liposomes; D010713:Phosphatidylcholines; D034741:RNA, Small Interfering; D036104:Receptor, EphA2; C017251:1,2-oleoylphosphatidylcholine; D012825:Silicon