title: HIV TAT peptide modifies the distribution of DNA nanolipoparticles following convection-enhanced delivery.
abstract: We evaluated gene transfer using PEGylated bioresponsive nanolipid particles (NLPs) containing plasmid DNA administered by convection-enhanced delivery (CED) into orthotopically implanted U87-MG tumors in rat brain. We hypothesized that attachment of the human immunodeficiency virus trans-acting transcriptional activator peptide (TATp) to pH-sensitive, reduction-sensitive NLPs would increase gene transfer. TATp was attached either directly to a phospholipid (TATp-lipid) or via a 2-kd polyethylene glycol (PEG) to a lipid (TATp-PEG-lipid). Incorporation of 0.3 mol% TATp-PEG into pH-sensitive NLPs improved transfection 100,000-fold compared to NLPs in culture. In the brain or implanted tumors, the TATp-PEG restricted NLP convection to regions adjacent to the infusion catheter. Gene transfer in the brain from TATp-PEG NLPs, measured by green fluorescent protein (GFP) expression, was substantially greater than from NLPs adjacent to the catheter. Gene transfer using TATp-PEG NLPs, measured by luciferase expression, was 8-12-fold greater than from a 1,2-dioleoyl-3-trimethylammonium-propane/cholesterol cationic lipoplex but 13-27-fold less than from the NLPs. Brain luciferase expression was localized in perivascular macrophages. Thus a cationic ligand, such as the TATp-PEG-lipid, can dramatically increase gene expression in culture, in the normal brain, and in implanted tumors; however, restriction of NLP distribution to the vicinity of the infusion catheter reduces the absolute level of gene transfer.
authors.affiliation: Joint Graduate Group in Bioengineering, University of California at San Francisco, San Francisco, California, USA.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: MacKay
authors.forename: Weijun
authors.initials: W
authors.lastname: Li
authors.forename: Zhaohua
authors.initials: Z
authors.lastname: Huang
authors.forename: Edward E
authors.initials: EE
authors.lastname: Dy
authors.forename: Grace
authors.initials: G
authors.lastname: Huynh
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: Rodney
authors.initials: R
authors.lastname: Collins
authors.forename: Dennis F
authors.initials: DF
authors.lastname: Deen
authors.forename: Francis C
authors.initials: FC
authors.lastname: Szoka
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D015696:Gene Products, tat / Q000235:genetics* / Q000502:physiology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006678:HIV / Q000378:metabolism*; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry*; D009368:Neoplasm Transplantation; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D051381:Rats
chemical_list: D015696:Gene Products, tat; D008081:Liposomes; D010455:Peptides; D004247:DNA