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Mol Ther. 2008 May;16(5):893-900. doi: 10.1038/mt.2008.36. Epub 2008 Mar 11.

HIV TAT peptide modifies the distribution of DNA nanolipoparticles following convection-enhanced delivery.

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Joint Graduate Group in Bioengineering, University of California at San Francisco, San Francisco, California, USA.


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.

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