title: High capacity nanoporous silicon carrier for systemic delivery of gene silencing therapeutics.
abstract: Gene silencing agents such as small interfering RNA (siRNA) and microRNA offer the promise to modulate expression of almost every gene for the treatment of human diseases including cancer. However, lack of vehicles for effective systemic delivery to the disease organs has greatly limited their in vivo applications. In this study, we developed a high capacity polycation-functionalized nanoporous silicon (PCPS) platform comprised of nanoporous silicon microparticles functionalized with arginine-polyethyleneimine inside the nanopores for effective delivery of gene silencing agents. Incubation of MDA-MB-231 human breast cancer cells with PCPS loaded with STAT3 siRNA (PCPS/STAT3) or GRP78 siRNA (PCPS/GRP78) resulted in 91 and 83% reduction of STAT3 and GRP78 gene expression in vitro. Treatment of cells with a microRNA-18a mimic in PCPS (PCPS/miR-18) knocked down 90% expression of the microRNA-18a target gene ATM. Systemic delivery of PCPS/STAT3 siRNA in murine model of MDA-MB-231 breast cancer enriched particles in tumor tissues and reduced STAT3 expression in cancer cells, causing significant reduction of cancer stem cells in the residual tumor tissue. At the therapeutic dosage, PCPS/STAT3 siRNA did not trigger acute immune response in FVB mice, including changes in serum cytokines, chemokines, and colony-stimulating factors. In addition, weekly dosing of PCPS/STAT3 siRNA for four weeks did not cause signs of subacute toxicity based on changes in body weight, hematology, blood chemistry, and major organ histology. Collectively, the results suggest that we have developed a safe vehicle for effective delivery of gene silencing agents.
authors.affiliation: Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, Texas 77030, United States.|MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, 510275, China.
authors.forename: Jianliang
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, Texas 77030, United States.
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, Texas 77030, United States.
authors.forename: Junhua
authors.initials: J
authors.lastname: Mai
authors.affiliation: Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, Texas 77030, United States.
authors.forename: Han-Cheon
authors.initials: HC
authors.lastname: Kim
authors.affiliation: Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, Texas 77030, United States.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, Texas 77030, United States.
authors.forename: Guoting
authors.initials: G
authors.lastname: Qin
authors.affiliation: Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, Texas 77030, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, Texas 77030, United States.
authors.forename: Joy
authors.initials: J
authors.lastname: Wolfram
authors.affiliation: Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, Texas 77030, United States.
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Mu
authors.affiliation: Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, Texas 77030, United States.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Xia
authors.affiliation: Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, Texas 77030, United States.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, Texas 77030, United States.
authors.forename: Xuewu
authors.initials: X
authors.lastname: Liu
authors.affiliation: MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, 510275, China.
authors.forename: Zong-Wan
authors.initials: ZW
authors.lastname: Mao
authors.affiliation: Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, Texas 77030, United States.|Department of Medicine, Weill Cornell Medical College, New York, NY10065, United States.
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.affiliation: Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, Texas 77030, United States.|Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY10065, United States.
authors.forename: Haifa
authors.initials: H
authors.lastname: Shen
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry; D001943:Breast Neoplasms / Q000628:therapy; D045744:Cell Line, Tumor; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental / Q000628:therapy; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008855:Microscopy, Electron, Scanning; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics; D012825:Silicon / Q000737:chemistry
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D035683:MicroRNAs; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D011094:Polyethyleneimine; D001120:Arginine; D012825:Silicon