title: Nanoparticle encapsulation and controlled release of a hydrophobic kinase inhibitor: Three stage mathematical modeling and parametric analysis.
abstract: A mathematical model of drug release that incorporates the simultaneous contributions of initial burst, nanoparticle degradation-relaxation and diffusion was developed and used to effectively describe the release of a kinase inhibitor and anticancer drug, PHT-427. The encapsulation of this drug into PLGA nanoparticles was performed by following the single emulsion-solvent evaporation technique and the release was determined in phosphate buffer pH 7.4 at 37 °C. The size of nanoparticles was obtained in a range of 162-254 nm. The experimental release profiles showed three well defined phases: an initial fast drug release, followed by a nanoparticle degradation-relaxation slower release and then a diffusion release phase. The effects of the controlled release most relevant parameters such as drug diffusivity, initial burst constant, nanoparticle degradation-relaxation constant, and the time to achieve a maximum rate of drug release were evaluated by a parametrical analysis. The theoretical release studies were corroborated experimentally by evaluating the cytotoxicity effectiveness of the inhibitor AKT/PDK1 loaded nanoparticles over BxPC-3 pancreatic cancer cells in vitro. These studies show that the encapsulated inhibitor AKT/PDK1 in the nanoparticles is more accessible and thus more effective when compared with the drug alone, indicating their potential use in chemotherapeutic applications.
authors.affiliation: Department of Chemical and Environmental Engineering, The University of Arizona, Tucson, AZ 85721, USA; Department of Chemical and Metallurgical Engineering, University of Sonora, Hermosillo, SON 83000, Mexico.
authors.forename: Armando
authors.initials: A
authors.lastname: Lucero-Acuña
authors.affiliation: Department of Chemical and Environmental Engineering, The University of Arizona, Tucson, AZ 85721, USA. Electronic address: guzmanr@u.arizona.edu.
authors.forename: Roberto
authors.initials: R
authors.lastname: Guzmán
mesh_terms: D002470:Cell Survival / Q000187:drug effects*; D003692:Delayed-Action Preparations / Q000737:chemistry*; D065546:Drug Liberation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015233:Models, Statistical; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*; D013499:Surface Properties; D013830:Thiadiazoles / Q000737:chemistry* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000096926:Benzenesulfonamides
chemical_list: D003692:Delayed-Action Preparations; D011100:Polyglycolic Acid; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D013830:Thiadiazoles; C550093:4-dodecyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide; D000096926:Benzenesulfonamides
keywords: Controlled release; Mathematical modeling; Nanoparticles; PLGA; Pancreatic cancer; Parametric analysis