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.
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).
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