title: A multifunctional and reversibly polymerizable carrier for efficient siRNA delivery.
abstract: In this study a multifunctional carrier (MFC), 1,4,7-triazanonylimino-bis[N-(oleicyl-cysteinyl-histinyl)-1-aminoethyl)propionamide] (THCO), containing protonatable amines of different pK(a)s, polymerizable cysteine residues and hydrophobic groups, was designed, synthesized and evaluated for efficient small interfering RNAs (siRNA) delivery. THCO showed pH-sensitive cellular membrane disruption at the endosomal-lysosomal pH to facilitate intracellular siRNA delivery. THCO formed stable and compact nanoparticles with siRNA through charge complexation, hydrophobic condensation and reversible polymerization. The THCO/siRNA nanoparticles were readily modified with PEG-Mal by reacting with remaining thiol groups at the surface. The siRNA delivery efficiency of THCO was comparable to that of Transfast, much higher than that of N-(2,3-dioleoyloxy-1-propyl)trimethylammonium methyl sulphate (DOTAP) in serum-free medium. PEGylated THCO/siRNA nanoparticles resulted in higher transfection efficiency than those of Transfast and DOTAP in the presence of serum. This study demonstrated that the MFC-THCO is promising for efficient siRNA delivery.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 421 Wakara Way, Salt Lake City, UT 84108, USA.
authors.forename: Xu-Li
authors.initials: XL
authors.lastname: Wang
authors.forename: Thanh
authors.initials: T
authors.lastname: Nguyen
authors.forename: David
authors.initials: D
authors.lastname: Gillespie
authors.forename: Randy
authors.initials: R
authors.lastname: Jensen
authors.forename: Zheng-Rong
authors.initials: ZR
authors.lastname: Lu
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004151:Dipeptides / Q000737:chemistry* / Q000633:toxicity; D005029:Ethylenediamines / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011108:Polymers / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000235:genetics*; D014162:Transfection / Q000379:methods*
chemical_list: C526682:1,4,7-triazanonylimino-bis(N-(oleicyl-cysteinyl-histinyl)-1-aminoethyl)propionamide; D004151:Dipeptides; D005029:Ethylenediamines; D011108:Polymers; D034741:RNA, Small Interfering