Sustained small interfering RNA delivery by mesoporous silicon particles.
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.
Tanaka
Takemi
T
Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston, Texas, USA.
Mangala
Lingegowda S
LS
Vivas-Mejia
Pablo E
PE
Nieves-Alicea
René
R
Mann
Aman P
AP
Mora
Edna
E
Han
Hee-Dong
HD
Shahzad
Mian M K
MM
Liu
Xuewu
X
Bhavane
Rohan
R
Gu
Jianhua
J
Fakhoury
Jean R
JR
Chiappini
Ciro
C
Lu
Chunhua
C
Matsuo
Koji
K
Godin
Biana
B
Stone
Rebecca L
RL
Nick
Alpa M
AM
Lopez-Berestein
Gabriel
G
Sood
Anil K
AK
Ferrari
Mauro
M
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
D008081:Liposomes; D010713:Phosphatidylcholines; D034741:RNA, Small Interfering; D036104:Receptor, EphA2; C017251:1,2-oleoylphosphatidylcholine; D012825:Silicon