title: Degradation kinetics of high molecular weight poly(L-lactide) microspheres and release mechanism of lipid:DNA complexes.
abstract: Plasmid DNA encoding the green lantern protein was ion-paired with 1,2-dioleoyl, 3-trimethylammonium propane (DOTAP) at a (+/-) charge ratio of (1:1) to form a hydrophobic ion-pair (HIP) complex using the Bligh and Dyer method, and transferred into methylene chloride. Precipitation with a compressed antisolvent (PCA) was then employed to encapsulate plasmid DNA into poly(L-lactide) (PLLA) microspheres. The hydrophobicity of DOTAP:DNA complexes allowed consistently high encapsulation efficiencies (>70%) to be achieved. Release of the DOTAP:DNA complex from PLLA microspheres exhibited minimal burst and a short (ca. 1 week) lag phase, followed by sustained release over a 20 week period. Release kinetics were consistent with a simple Fickian diffusion model. No correlation was identified between release rate of soluble poly(L-lactide) species (< or =10 lactate units) from PLLA and the DNA release kinetics. Only approximately 12% of the polymer was degraded into soluble poly(L-lactide) over the time frame where approximately 90% of the plasmid load had been released.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Box C238, 4200 E. Ninth Avenue, Denver, CO 80262, USA. mayank.patel@uchsc.edu
authors.forename: Mayank M
authors.initials: MM
authors.lastname: Patel
authors.forename: Michelle G
authors.initials: MG
authors.lastname: Zeles
authors.forename: Mark C
authors.initials: MC
authors.lastname: Manning
authors.forename: Theodore W
authors.initials: TW
authors.lastname: Randolph
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Anchordoquy
mesh_terms: D000042:Absorption; D002942:Circular Dichroism; D004247:DNA / Q000008:administration & dosage / Q000737:chemistry*; D004355:Drug Stability; D004587:Electrophoresis, Agar Gel; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D019344:Lactic Acid / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D008958:Models, Molecular; D008970:Molecular Weight; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*; D013499:Surface Properties; D013997:Time Factors
chemical_list: D005229:Fatty Acids, Monounsaturated; D011091:Polyesters; D000644:Quaternary Ammonium Compounds; D019344:Lactic Acid; C033616:poly(lactide); D004247:DNA; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane