title: Phospholipid conjugate for intracellular delivery of peptide nucleic acids.
abstract: Peptide nucleic acids (PNAs) have a number of attractive features that have made them an ideal choice for antisense and antigene-based tools, probes, and drugs, but their poor membrane permeability has limited their application as therapeutic or diagnostic agents. Herein, we report a general method for the synthesis of phospholipid-PNAs (LP-PNAs) and compare the effect of noncleavable lipids and bioreductively cleavable lipids (L and LSS) and phospholipid (LP) on the splice-correcting bioactivity of a PNA bearing the cell penetrating Arg9 group (PNA-R9). While the three constructs show similar and increasing bioactivity at 1-3 microM, the activity of LP-PNA-R9 continues to increase from 4-6 microM, while the activity of L-PNA-R9 remains constant and that of LSS-PNA-R9 decreases rapidly in parallel with their relative cytotoxicity. The activity of both LP-PNA-R9 and L-PNA-R9 dramatically increased in the presence of chloroquine, as expected for an endocytotic entry mechanism. The constructs were also found to have CMC values of 1.0 and 4.5 microM, respectively, in 150 mM NaCl, pH 7 water, suggesting that micelle formation may play a hitherto unrecognized role in modulating toxicity and/or facilitating endocytosis.
authors.affiliation: Department of Chemistry, Washington University in St. Louis, St. Louis, Missouri 63130, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Shen
authors.forename: Huafeng
authors.initials: H
authors.lastname: Fang
authors.forename: Yinyin
authors.initials: Y
authors.lastname: Song
authors.forename: Agata A
authors.initials: AA
authors.lastname: Bielska
authors.forename: Zhenghui
authors.initials: Z
authors.lastname: Wang
authors.forename: John-Stephen A
authors.initials: JS
authors.lastname: Taylor
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D002463:Cell Membrane Permeability; D002738:Chloroquine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D006801:Humans; D008823:Micelles; D020135:Peptide Nucleic Acids / Q000737:chemistry* / Q000493:pharmacokinetics; D010743:Phospholipids / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
chemical_list: D004337:Drug Carriers; D008823:Micelles; D020135:Peptide Nucleic Acids; D010743:Phospholipids; D002738:Chloroquine
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