title: Surface-functionalized nanoparticles for targeted gene delivery across nasal respiratory epithelium.
abstract: The objective of this study was to determine whether surface-modified nanoparticles enhance permeability across nasal mucosa, while retaining the effectiveness of the payload. The uptake and permeability of polystyrene nanoparticles (PS-NPs; FluoSpheres) was evaluated across the various regions of the bovine nasal epithelia following conjugation with deslorelin and transferrin. Uptake and transport of PS-NPs, deslorelin-PS-NPs, and transferrin-PS-NPs exhibited regional differences in the order: inferior turbinate posterior (ITP) > medium turbinate posterior (MTP) > medium turbinate anterior (MTA). Uptake and transport also exhibited directionality and temperature dependence in these tissues. Further, uptake as well as transport of functionalized nanoparticles could be inhibited by excess free functionalizing ligand. Confocal microscopy indicated the presence of functionalized nanoparticles in respiratory epithelial cells, as well as other cell types of the nasal tissue. We chose the ITP region for further studies with deslorelin or transferrin-conjugated poly-l-lactide-co-glycolide nanoparticles (PLGA-NPs) encapsulating an anti-VEGF intraceptor (Flt23k) plasmid. Transport of the nanoparticles, as well as the plasmid from the nanoparticles, exhibited the following order: transferrin-PLGA-NPs > deslorelin-PLGA-NPs > PLGA-NPs >> plasmid. The ability of the nanoparticles transported across the nasal tissue to retain the effectiveness of the Flt23k plasmid was evaluated by measuring transfection efficiency (percentage of cells expressing GFP) and VEGF inhibition in LNCaP and PC-3 prostate cancer cells. Transfection efficiencies and VEGF inhibition in LNCaP and PC-3 cells exhibited the following trend: transferrin-PLGA-NPs >or= deslorelin-PLGA-NPs > PLGA-NPs >> plasmid. Further, functionalized nanoparticles exhibited transfection efficiencies and VEGF inhibition significantly superior compared with the routinely used transfecting agent, lipofectamine. Formulating plasmids into nanoparticulate delivery systems enhances the transnasal delivery and gene therapy at remote target cancer cells, which can be further enhanced by nanoparticle functionalization with deslorelin or transferrin.
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Sneha
authors.initials: S
authors.lastname: Sundaram
authors.forename: Shyamal K
authors.initials: SK
authors.lastname: Roy
authors.forename: Balamurali K
authors.initials: BK
authors.lastname: Ambati
authors.forename: Uday B
authors.initials: UB
authors.lastname: Kompella
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D002417:Cattle; D004337:Drug Carriers / Q000378:metabolism; D016503:Drug Delivery Systems; D019344:Lactic Acid / Q000008:administration & dosage; D053758:Nanoparticles; D009297:Nasal Mucosa / Q000378:metabolism*; D011100:Polyglycolic Acid / Q000008:administration & dosage; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D014168:Transferrin / Q000008:administration & dosage; D017329:Triptorelin Pamoate / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D004337:Drug Carriers; D014168:Transferrin; D017329:Triptorelin Pamoate; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C066438:deslorelin