title: Heterocyclic amine-modified polyethylenimine as gene carriers for transfection of mammalian cells.
abstract: Branched polyethylenimine (PEI) is extensively used as a polycationic non-viral vector for gene delivery. Polyplexes formed with PEI are believed to be released from endocytotic vesicles by the osmotic burst mechanism in the rate-limiting step in transfection. Increasing the buffering capacity of PEI derivatives in the endosomal pH range of 4.5-7.5 should enhance transfection efficiency. In this study, PEI was derivatized by covalently attaching heterocyclic amine moieties (piperazine, pyridine and imidazole rings with pKa values from 5.23 to 6.04) through amide bonds. PEI derivatives with 50% of the primary amines on PEI exhibited increased buffering capacity, increased transfection activity and decreased cytotoxicity in murine neuroblastoma (Neuro-2a) cells. The relative effectiveness in enhancing transfection efficiency was piperazine>pyridine>histidine, but each type of amine was the most effective under a particular set of conditions. Modified vectors could significantly improve transfection efficiency in murine mesenchymal stem cells. PEI25 derivatized at 50% with histidine administered as polyplexes in the tail veins of mice resulted in remarkably enhanced luciferase gene expression in the expected organ distribution and much lower toxicity than underivatized PEI25.
authors.affiliation: Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, P.O. Box 91775-1365, Iran.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Salmasi
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA.
authors.forename: Wayne Thomas
authors.initials: WT
authors.lastname: Shier
authors.affiliation: Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, P.O. Box 91775-1365, Iran.
authors.forename: Maryam
authors.initials: M
authors.lastname: Hashemi
authors.affiliation: Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, P.O. Box 917794-8564, Iran.
authors.forename: Elahe
authors.initials: E
authors.lastname: Mahdipour
authors.affiliation: Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, P.O. Box 91775-1365, Iran.
authors.forename: Hamideh
authors.initials: H
authors.lastname: Parhiz
authors.affiliation: Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, P.O. Box 91775-1365, Iran. Electronic address: abnouskh@mums.ac.ir.
authors.forename: Khalil
authors.initials: K
authors.lastname: Abnous
authors.affiliation: Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, P.O. Box 91775-1365, Iran. Electronic address: ramezanim@mums.ac.ir.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ramezani
mesh_terms: D000588:Amines / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004247:DNA / Q000008:administration & dosage / Q000235:genetics; D004337:Drug Carriers / Q000737:chemistry*; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000008:administration & dosage / Q000235:genetics; D006571:Heterocyclic Compounds / Q000737:chemistry*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D010316:Particle Size; D010957:Plasmids; D011094:Polyethyleneimine / Q000737:chemistry*; D013499:Surface Properties; D014162:Transfection
chemical_list: D000588:Amines; D004337:Drug Carriers; D006571:Heterocyclic Compounds; D049452:Green Fluorescent Proteins; D011094:Polyethyleneimine; D004247:DNA
keywords: Gene delivery; Histidine; Mesenchymal stem cell; Piperazine; Polyethylenimine; Pyridine