title: In vitro release characteristics and cellular uptake of poly(D,L-lactic-co-glycolic acid) nanoparticles for topical delivery of antisense oligodeoxynucleotides.
abstract: The efficacy of antisense oligodeoxynucleotides (AsODNs) is compromised by their poor stability in biological fluids and the inefficient cellular uptake due to their size and negative charge. Since chemical modifications of these molecules have resulted in a number of non-antisense activities, incorporation into particulate delivery systems has offered a promising alternative. The aim of this study was to evaluate various poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles for AsODN entrapment and delivery. PLGA nanoparticles were prepared using the double emulsion solvent evaporation method. The influence of formulation parameters such as PLGA concentration and volume ratio of internal aqueous phase volume (Va1) to organic phase volume (Vo) to external aqueous phase volume (Va2) on particle size, polydispersity index (PDI) and zeta potential (ZP) was investigated using a full factorial study. The particle size increased with increasing PLGA concentrations and volume ratios, with an interaction detectable between the two factors. AsODN entrapment efficiencies ranged between 49.97% and 54.95% with no significant difference between various formulations. By fitting the in vitro release profiles to a dual first order release model it was shown that the AsODN release occurred via two processes: a diffusion controlled process in the early phase (25 to 32% within one day) and a PLGA degradation process in the latter (39 to 70% after 14 days). Cellular uptake studies using primary corneal epithelial cells suggested active transport of nanoparticles via endocytosis. PLGA nanoparticles therefore show potential to successfully entrap AsODNs, transport them into cells and release them over time due to polymer erosion.
authors.affiliation: Department of Ophthalmology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
authors.forename: Ying-Shan
authors.initials: YS
authors.lastname: Chen
authors.forename: Raid G
authors.initials: RG
authors.lastname: Alany
authors.forename: Simon A
authors.initials: SA
authors.lastname: Young
authors.forename: Colin R
authors.initials: CR
authors.lastname: Green
authors.forename: Ilva D
authors.initials: ID
authors.lastname: Rupenthal
mesh_terms: D001693:Biological Transport, Active; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D004655:Emulsions; D004705:Endocytosis; D019573:Epithelium, Corneal / Q000378:metabolism*; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D008962:Models, Theoretical; D053758:Nanoparticles; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012997:Solvents / Q000737:chemistry
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D004655:Emulsions; D020319:Oligodeoxyribonucleotides, Antisense; D012997:Solvents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid