Particle fabrication and delivery systems for controlled release of bumped kinase inhibitors (BKIs) for malaria transmission blocking
Yacoob, Christina S.
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The main goal of this research is to successfully fabricate particulate systems for sustained delivery of bumped kinase inhibitors (BKIs) for malaria transmission blocking. The report focuses on optimization of a nanoparticle-based BKI-delivery system and the effects between different fabrication methods and drug hydrophobicity. The first chapters consist of an overview of material/method choices and reviews on both sustained drug delivery systems and nanoparticle fabrication techniques. The middle chapters discuss fabrication and characterization of BKI-loaded particles via emulsification and fluidic nanoprecipitation (fNP). The last chapters compare these two fabrication methods and two BKI molecules for effects on particle characteristics, incorporation, and release. Using the emulsification and fNP fabrication methods we produced BKI-loaded poly (DL-lactide-co-glycolide) (PLGA) particles. BKIs used included RM-1-132 and 1294 (provided by the Van Voorhis and Maly groups, University of Washington). These BKIs are generally amphiphilic, with 1294 displaying a slightly more hydrophobic tendency. The amphiphilic nature of the drug molecule creates a challenge for incorporation into delivery systems, which work optimally with strongly hydrophilic or hydrophobic molecules. Increasing the fabrication pH to a basic pH beyond the molecule's pKa neutralized the molecule and enhanced the incorporation into the PLGA particles. Additional optimization was performed to further increase incorporation. Particles were characterized for size, surface charge, and evaluated for total BKI content and release. Our best systems had ~100% incorporation, and >100ng/hr release (per 25mg particles) up to 4 days (~50ng/hr per 25mg particles up to 4 weeks). Comparisons were made between particle size, fabrication methods and drug hydrophobicity to elucidate fundamentals of amphiphilic drug incorporation. The fNP-fabricated particles displayed >60% incorporation efficiency regardless of drug hydrophobicity, but also displayed higher polydispersity when initial loading or drug hydrophobicity increased. The emulsion system displayed a maximum loading for BKI-loaded particles, which shifted higher as drug hydrophobicity increased. Particle size remained mostly monodisperse except at the highest initial loading. We also examined parallel models to understand the differences between the two fabrication methods and drug molecules, as well as to predict in vivo behavior. Overall, we have successful fabricated a BKI-loaded particulate delivery system which can extend the release on BKIs to help improve malaria transmission blocking and reduce the need for multiple drug administrations. Future directions include increasing and extending the release, testing activity of the released BKI in vivo, and optimizing storage conditions for particles.
- Chemical engineering