title: Nanoassembly of surfactants with interfacial drug-interactive motifs as tailor-designed drug carriers.
abstract: PEGylated lipopeptide surfactants carrying drug-interactive motifs specific for a peptide-nitroxide antioxidant, JP4-039, were designed and constructed to facilitate the solubilization of this drug candidate as micelles and emulsion nanoparticles. A simple screening process based on the ability that prevents the formation of crystals of JP4-039 in aqueous solution was used to identify agents that have potential drug-interactive activities. Several protected lysine derivatives possessing this activity were identified, of which α-Fmoc-ε-t-Boc lysine is the most potent, followed by α-Cbz- and α-iso-butyloxycarbonyl-ε-t-Boc-lysine. Using a polymer-supported liquid-phase synthesis approach, a series of synthetic lipopeptide surfactants with PEG headgroup, varied numbers and geometries of α-Fmoc or α-Cbz-lysyl groups located at interfacial region as the drug-interactive domains, and oleoyl chains as the hydrophobic tails were synthesized. All α-Fmoc-lysyl-containing lipopeptide surfactants were able to solubilize JP4-039 as micelles, with enhanced solubilizing activity for surfactants with increased numbers of α-Fmoc groups. The PEGylated lipopeptide surfactants with α-Fmoc-lysyl groups alone tend to form filamentous or wormlike micelles. The presence of JP4-039 transformed α-Fmoc-containing filamentous micelles into dots and barlike mixed micelles with substantially reduced sizes. Fluorescence quenching and NMR studies revealed that the drug and surfactant molecules were in close proximity in the complex. JP4-039-loaded emulsion carrying α-Cbz-containing surfactants demonstrated enhanced stability over drug-loaded emulsion without lipopeptide surfactants. JP4-039 emulsion showed a significant mitigation effect on mice exposed to a lethal dose of radiation. PEGylated lipopeptides with an interfacially located drug-interactive domain are therefore tailor-designed formulation materials potentially useful for drug development.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Yixian
authors.initials: Y
authors.lastname: Huang
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Makhov
authors.forename: Michael
authors.initials: M
authors.lastname: Epperly
authors.forename: Jianqin
authors.initials: J
authors.lastname: Lu
authors.forename: Sheila
authors.initials: S
authors.lastname: Grab
authors.forename: Peijun
authors.initials: P
authors.lastname: Zhang
authors.forename: Lisa
authors.initials: L
authors.lastname: Rohan
authors.forename: Xiang-Qun
authors.initials: XQ
authors.lastname: Xie
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.forename: Joel
authors.initials: J
authors.lastname: Greenberger
authors.forename: Song
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004337:Drug Carriers / Q000737:chemistry*; D015195:Drug Design; D004347:Drug Interactions; D004655:Emulsions / Q000737:chemistry; D055666:Lipopeptides / Q000737:chemistry; D008239:Lysine / Q000031:analogs & derivatives / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D051379:Mice; D008823:Micelles; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry*; D009589:Nitrogen Oxides / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry*
chemical_list: D000975:Antioxidants; D004337:Drug Carriers; D004655:Emulsions; C544775:JP4-039; D055666:Lipopeptides; D008823:Micelles; D009589:Nitrogen Oxides; D010455:Peptides; D011108:Polymers; D013501:Surface-Active Agents; C040741:epsilon-tert-butyloxycarbonyl-lysine; D008239:Lysine