| This thesis provides a strategy for the formation of stable, controlled size nanoparticle formulations for the controlled release of drugs. The approach detailed in the dissertation involves two main steps. First, the drug of interest is linked to a low solubility molecule to produce a drug conjugate with lower water solubility than the original drug. The second step involves using a fast mixing technique termed Flash NanoPrecipitation, where an amphiphilic diblock copolymer and the drug conjugate are mixed at high velocity in a confined volume to afford nucleation and growth of the solutes and produce nanoparticles. This technique provides high drug contents, high loading efficiencies, controllable sizes, and control of the drug release rates from the nanoparticles through modification of the linker chemistries used to produce the drug conjugate.; The study focused on the anticancer drug paclitaxel, which was conjugated to vitamin E succinate (VES) to produce a paclitaxel-VES conjugate, and was formulated into nanoparticles by Flash NanoPrecipitation using methoxy poly (ethylene glycol)-b-poly (epsilon-caprolactone) (mPEG-PCL) diblock copolymers. The produced nanoparticles were characterized for size by dynamic light scattering (DLS), and showed no change in size or cleavage of paclitaxel from the conjugate in DI water at 4°C for over two weeks. Particle sizes in the range of 53-287 nm were produced by changing the solute concentration in the particle formation process, or through modifying the molecular weight of added poly (epsilon-caprolactone) homopolymer.; Paclitaxel release from paclitaxel conjugate nanoparticles under various conditions of temperature in the range of 4-37°C, and pH of 5.5 to 8, resulted in paclitaxel release half-lives of over 30 days, and the kinetics were attributed mainly to the slower ester cleavage due to the neighboring group effect. The in vivo circulation of the nanoparticles was evaluated in mice, and resulted in plasma circulation half-lives of up to 18 hours, with a clear effect of the copolymer block composition on the nanoparticle circulation profile. The micellization of mPEG-PCL was evaluated using light scattering, and the relative effect of each block revealed in mixtures of water and tetrahydrofuran. |
