title: TLR9-Targeted SiRNA Delivery In Vivo.
abstract: The SiRNA strategy is a potent and versatile method for modulating expression of any gene in various species for investigational or therapeutic purposes. Clinical translation of SiRNA-based approaches proved challenging, mainly due to the difficulty of targeted SiRNA delivery into cells of interest and the immunogenic side effects of oligonucleotide reagents. However, the intrinsic sensitivity of immune cells to nucleic acids can be utilized for the delivery of SiRNAs designed for the purpose of cancer immunotherapy. We have demonstrated that synthetic ligands for the intracellular receptor TLR9 can serve as targeting moiety for cell-specific delivery of SiRNAs. Chemically synthesized CpG-SiRNA conjugates are quickly internalized by TLR9-positive cells in the absence of transfection reagents, inducing target gene silencing. The CpG-SiRNA strategy allows for effective targeting of TLR9-positive cells in vivo after local or systemic administration of these oligonucleotides into mice.
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
authors.forename: Dewan Md Sakib
authors.initials: DM
authors.lastname: Hossain
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
authors.forename: Dayson
authors.initials: D
authors.lastname: Moreira
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
authors.forename: Qifang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.|Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute at City of Hope, Duarte, CA, 91010, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Nechaev
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute at City of Hope, Duarte, CA, 91010, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Swiderski
authors.affiliation: Department of Cancer Immunotherapeutics & Tumor Immunology, Beckman Research Institute at City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA. mkortylewski@coh.org.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kortylewski
mesh_terms: D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D045744:Cell Line, Tumor; D002469:Cell Separation; D018899:CpG Islands; D016503:Drug Delivery Systems / Q000379:methods*; D005434:Flow Cytometry; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D009693:Nucleic Acid Hybridization; D009841:Oligonucleotides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: D009841:Oligonucleotides; D034741:RNA, Small Interfering; D051217:Toll-Like Receptor 9
keywords: Cancer; CpG; Leukemia; Myeloid cells; Oligonucleotides; SiRNA; TLR9