title: Synthesis and characterization of a PAMAM dendrimer nanocarrier functionalized by SRL peptide for targeted gene delivery to the brain.
abstract: Blood-brain barrier inhibits most of drugs and genetic materials from reaching the brain. So, developing high efficiency carriers for gene and drug delivery to the brain, is the challenging area in pharmaceutical sciences. This investigation aimed to target DNA to brain using Serine-Arginine-Leucine (SRL) functionalized PAMAM dendrimers as a novel gene delivery system. The SRL peptide was linked on G4 PAMAM dendrimers using bifunctional PEG. DNA was then loaded in these functionalized nanoparticles and their physicochemical properties and cellular uptake/distribution evaluated by AFM, NMR, FTIR and fluorescence and confocal microscopy. Also, biodistribution and brain localization of nanoparticles were studied after IV injection of nanoparticles into rat tail. Unmodified nanoparticles were used as control in all evaluations. In vitro studies showed that SRL-modified nanoparticles have good transfection efficacy and low toxicity. Results also showed that SRL is a LRP ligand and SRL-modified nanoparticles internalized by clathrin/caveolin energy-dependent endocytosis to brain capillary endothelial cells. After intravenous administration, the SRL-modified nanoparticles were able to cross the blood-brain barrier and enter the brain parenchyma. Our result showed that, SRL-modified nanoparticles provide a safe and effective nanocarrier for brain gene delivery.
authors.affiliation: Biomedical Engineering and Medical Physics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Amir
authors.initials: A
authors.lastname: Zarebkohan
authors.affiliation: Department of Resin and Additives, Institute for Color Science and Technology, Tehran, Iran.
authors.forename: Farhood
authors.initials: F
authors.lastname: Najafi
authors.affiliation: School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Hamid Reza
authors.initials: HR
authors.lastname: Moghimi
authors.affiliation: Biomedical Engineering and Medical Physics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hemmati
authors.affiliation: Biomedical Engineering and Medical Physics Department, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Deevband
authors.affiliation: Department of Biotechnology, Faculty of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address: bahram_14@yahoo.com.
authors.forename: Bahram
authors.initials: B
authors.lastname: Kazemi
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D004247:DNA / Q000008:administration & dosage* / Q000737:chemistry; D050091:Dendrimers / Q000008:administration & dosage* / Q000737:chemistry; D042783:Endothelial Cells / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D008297:Male; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009757:Nylons / Q000737:chemistry; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats
chemical_list: D050091:Dendrimers; D009757:Nylons; D009842:Oligopeptides; C520550:PAMAM-G4; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D004247:DNA
keywords: BODIPY fluorophore (PubChem CID: 13007361); Blood–brain barrier; Colchicines (PubChem CID: 6167); Diethuyl ether (PubChem CID: 3283); Ethidiummonoazide bromide (PubChem CID: 2762649); Ethylenediamine (PubChem CID: 3301); Filipin complex (PubChem CID: 6433553); Gene delivery; Methyl acrylate (PubChem CID: 4093); NHS-PEG-MAL (PubChem CID: 51340913); PAMAM dendrimer; Phenylarsine oxide (PubChem CID: 4778); SRL peptide; l-Polylysin (PubChem CID: 162282)