title: PEGylated composite nanoparticles of PLGA and polyethylenimine for safe and efficient delivery of pDNA to lungs.
abstract: Achieving stable, efficient and non-toxic pulmonary gene delivery is most challenging requirement for successful gene therapy to lung. Composite nanoparticles (NPs) of the poly(lactic-co-glycolic acid) (PLGA) and cationic polymer polyethyleneimine (PEI) is an efficient alternative to viral and liposomal vectors for the pulmonary delivery of pDNA. NPs with different weight ratios (0-12.5%w/w) of PLGA/PEI were prepared and characterized for size, morphology, surface charge, pDNA loading and in vitro release. The in vitro cell uptake and transfection studies in the CFBE41o-cell line revealed that NPs with 10% w/w PEI were more efficient but they exhibited significant cytotoxicity in MTT assays, challenging the safety of this formulation. Surface modifications of these composite NPs through PEGylation reduced toxicity and enhanced cellular uptake and pDNA expression. PEGylation improved diffusion of NPs through the mucus barrier and prevented uptake by pulmonary macrophages. Finally, PEGylated composite NPs were converted to DPI by lyophilization and combined with lactose carrier particles, which resulted in improved aerosolization properties and lung deposition, without affecting pDNA bioactivity. This study demonstrates that a multidisciplinary approach may enable the local delivery of pDNA to lung tissue for effective treatment of deadly lung diseases.
authors.affiliation: Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, Vadodara, 390001, Gujarat, India; Department of Physiology, McGill University, Montréal, Québec, Canada.
authors.forename: Atul
authors.initials: A
authors.lastname: Kolte
authors.affiliation: Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, Vadodara, 390001, Gujarat, India.
authors.forename: Sushilkumar
authors.initials: S
authors.lastname: Patil
authors.affiliation: Department of Physiology, McGill University, Montréal, Québec, Canada.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lesimple
authors.affiliation: Department of Physiology, McGill University, Montréal, Québec, Canada.
authors.forename: John W
authors.initials: JW
authors.lastname: Hanrahan
authors.affiliation: Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, Vadodara, 390001, Gujarat, India. Electronic address: misraan@hotmail.com.
authors.forename: Ambikanandan
authors.initials: A
authors.lastname: Misra
mesh_terms: D002460:Cell Line; D004247:DNA / Q000008:administration & dosage*; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D008168:Lung / Q000187:drug effects*; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011094:Polyethyleneimine / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D014162:Transfection
chemical_list: D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011094:Polyethyleneimine; D004247:DNA
keywords: Cystic fibrosis; Dry powder inhaler; Gene therapy; Nanoparticles; PEI; PLGA