title: A robust in vivo positive-readout system for monitoring siRNA delivery to xenograft tumors.
abstract: Delivering small interfering RNA (siRNA) to tumors is the major technical hurdle that prevents the advancement of siRNA-based cancer therapy. One of the difficulties associated with the development of clinically relevant delivery systems is the lack of reliable tools for monitoring siRNA delivery to tumors in vivo. We describe here a novel, positive-readout system where siRNA-mediated target knockdown elicits a rapid and robust increase of reporter activity. Using the positive-readout system, we created (1) β-galactosidase-based tumor models that allow the detection of target knockdown in 1%-2% of tumor cells and can distinguish between tumor areas where effective target knockdown occurs versus tumor areas that are not accessible to delivery, and (2) luciferase-based tumor models that allow the quantitative assessment of a large number of delivery systems. Using these positive-readout models, we screened a number of literature-described siRNA delivery systems and identified lipid nanoparticles as a promising delivery platform for siRNA-based cancer therapy.
authors.affiliation: siRNA Therapeutics, Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Lin
authors.forename: Leiming
authors.initials: L
authors.lastname: Li
authors.forename: Rongqi
authors.initials: R
authors.lastname: Wang
authors.forename: Denise
authors.initials: D
authors.lastname: Wilcox
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Zhao
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Song
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Huang
authors.forename: T Matthew
authors.initials: TM
authors.lastname: Hansen
authors.forename: Prasad
authors.initials: P
authors.lastname: Dande
authors.forename: Carol
authors.initials: C
authors.lastname: Wada
authors.forename: Robert D
authors.initials: RD
authors.lastname: Hubbard
authors.forename: William M
authors.initials: WM
authors.lastname: Kohlbrenner
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Fesik
authors.forename: Yu
authors.initials: Y
authors.lastname: Shen
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D005822:Genetic Vectors; D008081:Liposomes; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D008991:Monitoring, Physiologic / Q000379:methods*; D053758:Nanoparticles / Q000008:administration & dosage; D009369:Neoplasms / Q000628:therapy*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D008081:Liposomes; D034741:RNA, Small Interfering; D001616:beta-Galactosidase