title: Nonadditive Effects of Repetitive Administration of Lipoplexes in Immunocompetent Mice.
abstract: Repetitive administration is routinely used to maintain therapeutic drug levels, but previous studies have documented an accelerated blood clearance of some lipid-based delivery systems under these conditions. To assess the effect of repetitive administration, non-PEGylated lipoplexes (+/-0.5) were administered 4 times via tail vein injection at 3-day intervals to immunocompetent BALB/c mice bearing 4T1 tumors. This study measured the effect of repeat administration of nontargeted lipoplexes on clearance, cytokine/chemokine response, plasmid distribution, reporter gene expression, and liver toxicity. We do not observe a refractory period or a statistically significant difference in blood clearance between the first administration and subsequent injections of this lipoplex formulation, consistent with the absence of a cytokine/chemokine response. However, we do see a significant effect on both plasmid accumulation and expression, an enhancement of 26-fold and 10-fold in tumor plasmid levels and expression, respectively, after 4 injections as compared to that after a single injection. In addition, in vivo imaging suggests that expression in other organs had diminished rapidly 72 h after each administration, in contrast to relatively constant expression in the tumor. Taken together, the findings indicate that gene delivery to tumors can be dramatically enhanced by employing repetitive administration.
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado 80045.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Betker
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado 80045. Electronic address: Tom.Anchordoquy@ucdenver.edu.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Anchordoquy
mesh_terms: D000818:Animals; D004334:Drug Administration Schedule; D007121:Immunocompetence / Q000187:drug effects* / Q000502:physiology; D008055:Lipids / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000378:metabolism*
chemical_list: D008055:Lipids; D011092:Polyethylene Glycols; C000595210:polyethylene glycol 2000
keywords: biodistribution; cholesterol nanodomain; clearance; gene delivery; immunocompetent; lipoplex; liver toxicity; refractory period; repeat dosing; sphingosine