PHARMACOKINETIC CHARACTERIZATION AND OPTIMIZATION OF POLY (LACTIDE-CO-GLYCOLIDE) NANOPARTICLES IN VIVO
Rafiei, Pedram 1982-
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To date, nanotechnology is used to modify drug delivery and confer desirable pharmacokinetics to drugs and improve pharmacodynamics. Polymeric nanoparticles of Poly (lactide-co-glycolide) (PLGA) are proposed as suitable vehicles that desirably modify pharmacokinetics. The variability in PLGA and nanoparticle fabrication techniques results in nanoparticles with variable characteristics. It is important to identify factors that significantly influence particle characteristics during nanoparticle preparation to fabricate nanoparticles with the desired properties. Factors like size, zeta potential, and drug loading ability influence fate of nanoparticle and loaded drug in the body. An experimental factorial design based on the Taguchi robust model was used to evaluate the influence of preparation variables on nanoparticle characteristics. Docetaxel, an anticancer agent, was used in the design. Factors affecting nanoparticle properties with statistical significance were identified and models were built to predict particle characteristics. An optimized fabrication method was identified and used to prepare docetaxel-loaded PLGA nanoparticles and docetaxel-loaded PEGylated PLGA nanoparticles. Surface-modification with Poly (ethylene glycol) (PEG) conferred long-circulating properties to PLGA nanoparticles. A mass spectrometric analysis method was developed and partially validated for detection and quantification of docetaxel in biologic/non-biologic samples. Size, zeta potential, Poly-dispersity index, drug release, and cytotoxicity of un-modified and surface-modified nanoparticles were determined. Pharmacokinetics and bio-distribution of docetaxel loaded in nanoparticles and in free solution were evaluated in mice and compared. PLGA and PLGA-PEG nanoparticles had average diameters of around 120 and 180 nm, respectively, with negative zeta potential. They demonstrated a biphasic release profile and were cytotoxic to Hela cells. Nanoparticles modified docetaxel’s bio-distribution by increasing docetaxel’s area under the curve, half-life, and mean residence time in blood while decreasing systemic clearance and apparent volume of distribution. Particle size and surface characteristics likely caused the modifications in docetaxel’s pharmacokinetics. In summary, nanoparticles modified docetaxel’s pharmacokinetics and bio-distribution. The relationship between nanoparticle properties and pharmacokinetic modifications can be established and used to design nanoparticles with intended characteristics that could intentionally change docetaxel’s pharmacokinetics. Models built from the Taguchi design offer suitable means to prepare nanoparticles with predicted characteristics.
DegreeDoctor of Philosophy (Ph.D.)
DepartmentPharmacy and Nutrition
CommitteeBlackburn, David; Alcorn, Jane; El-Anees, Anas; Badea, Ildiko; Harkness, Troy
Copyright DateJune 2017