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Sustained Small Interfering RNA Delivery by Mesoporous Silicon Particles

Takemi TanakaDepartment of Bioengineering, Rice UniversityLingegowda S. MangalaDepartment of Surgery and The University of Puerto Rico Comprehensive Cancer Center, San Juan, Puerto RicoPablo E. Vivas‐MejíaDepartment of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TexasRené Nieves-AliceaDepartment of Bioengineering, Rice UniversityAman P. MannDepartment of Biomedical Engineering, University of Texas Austin, Austin, TexasEdna MoraDepartment of Bioengineering, Rice UniversityHee‐Dong HanDepartment of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TexasMian M.K. ShahzadDepartment of Bioengineering, Rice UniversityXuewu LiuAuthors' Affiliations: 1Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston; Departments of 2Gynecologic Oncology, 3Cancer Biology, 4Experimental Therapeutics, and 5Surgical Oncology, and 6Center for RNA Interference and Non-Coding RNA, University of Texas M.D. Anderson Cancer Center; 7Department of Bioengineering, Rice University; and 8Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas; 9Department of Biomedical Engineering, University of Texas Austin, Austin, Texas; and 10Department of Surgery and 11The University of Puerto Rico Comprehensive Cancer Center, San Juan, Puerto RicoRohan BhavaneDepartment of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TexasJianhua GuAuthors' Affiliations: 1Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston; Departments of 2Gynecologic Oncology, 3Cancer Biology, 4Experimental Therapeutics, and 5Surgical Oncology, and 6Center for RNA Interference and Non-Coding RNA, University of Texas M.D. Anderson Cancer Center; 7Department of Bioengineering, Rice University; and 8Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas; 9Department of Biomedical Engineering, University of Texas Austin, Austin, Texas; and 10Department of Surgery and 11The University of Puerto Rico Comprehensive Cancer Center, San Juan, Puerto RicoJean R. FakhouryAuthors' Affiliations: 1Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston; Departments of 2Gynecologic Oncology, 3Cancer Biology, 4Experimental Therapeutics, and 5Surgical Oncology, and 6Center for RNA Interference and Non-Coding RNA, University of Texas M.D. Anderson Cancer Center; 7Department of Bioengineering, Rice University; and 8Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas; 9Department of Biomedical Engineering, University of Texas Austin, Austin, Texas; and 10Department of Surgery and 11The University of Puerto Rico Comprehensive Cancer Center, San Juan, Puerto RicoCiro ChiappiniAuthors' Affiliations: 1Department of Nanomedicine and Biomedical Engineering, University of Texas Health Science Center at Houston; Departments of 2Gynecologic Oncology, 3Cancer Biology, 4Experimental Therapeutics, and 5Surgical Oncology, and 6Center for RNA Interference and Non-Coding RNA, University of Texas M.D. Anderson Cancer Center; 7Department of Bioengineering, Rice University; and 8Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas; 9Department of Biomedical Engineering, University of Texas Austin, Austin, Texas; and 10Department of Surgery and 11The University of Puerto Rico Comprehensive Cancer Center, San Juan, Puerto RicoChunhua LüDepartment of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TexasKoji MatsuoDepartment of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TexasBiana GodinDepartment of Surgery and The University of Puerto Rico Comprehensive Cancer Center, San Juan, Puerto RicoRebecca L. StoneDepartment of Bioengineering, Rice UniversityAlpa M. NickDepartment of Bioengineering, Rice UniversityGabriel Lopez‐BeresteinRice UniversityAnil K. SoodDepartment of Biomedical Engineering, University of Texas Austin, Austin, TexasMauro FerrariRice University

2010en

ABI

Annotatsiya

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.

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Identifikatorlar

DOI: 10.1158/0008-5472.can-09-3931

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