Sustained small interfering RNA delivery by mesoporous silicon particles.
Enviado por Pablo Vivas-Mejia el
Título | Sustained small interfering RNA delivery by mesoporous silicon particles. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Autores | Tanaka, T, Mangala, LS, Vivas-Mejia, P, Nieves-Alicea, R, Mann, AP, Mora, E, Han, H-D, Shahzad, MMK, Liu, X, Bhavane, R, Gu, J, Fakhoury, JR, Chiappini, C, Lu, C, Matsuo, K, Godin, B, Stone, RL, Nick, AM, Lopez-Berestein, G, Sood, AK, Ferrari, M |
Journal | Cancer Res |
Volume | 70 |
Issue | 9 |
Pagination | 3687-96 |
Date Published | 2010 May 1 |
ISSN | 1538-7445 |
Palabras clave | Animals, Cell Line, Tumor, Female, Gene Silencing, Genetic Therapy, Humans, Liposomes, Mice, Mice, Nude, Nanoparticles, Ovarian Neoplasms, Phosphatidylcholines, Receptor, EphA2, RNA, Small Interfering, Silicon, Xenograft Model Antitumor Assays |
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. |
DOI | 10.1158/0008-5472.CAN-09-3931 |
Alternate Journal | Cancer Res. |
PubMed ID | 20430760 |
PubMed Central ID | PMC3202607 |
Grant List | CA109298 / CA / NCI NIH HHS / United States CA110793 / CA / NCI NIH HHS / United States HD050128 / HD / NICHD NIH HHS / United States P50 CA083639 / CA / NCI NIH HHS / United States P50 CA083639 / CA / NCI NIH HHS / United States R01 CA109298 / CA / NCI NIH HHS / United States R01 CA110793 / CA / NCI NIH HHS / United States R01 CA128797 / CA / NCI NIH HHS / United States R01CA128797 / CA / NCI NIH HHS / United States R33 CA122864 / CA / NCI NIH HHS / United States R33CA122864 / CA / NCI NIH HHS / United States |