Investigation into the Synthesis of Polymeric Core and Shell Nanoparticles for the Controlled Release of Small Hydrophobic Payloads

Abstract

Effective and safe delivery of drugs into the body, where it will provide the maximum benefit to the patient, is the ultimate treatment goal. Factors such as the drug’s bioavailability and pharmacokinetics can lessen efficacy and decrease the safety of these drugs, increasing the cost and potential adverse effects. This is a particular problem for small, hydrophobic drugs, which make up the majority of existing drugs and newly discovered drug candidates. This drug delivery problem is exacerbated for many chemotherapeutics, which have extremely narrow concentration windows where they are safe and effective. This makes delivering these drugs without systemic side effects very challenging. A number of methods and systems have been developed to address this drug delivery limitation, such as controlled release of these drugs from polymeric nanoparticles. These particles are inherently safe, being made of biodegradable, biocompatible, FDA-approved polymers whose release kinetics are well understood and customizable. In addition, more complex designs, such as the core and shell nanoparticle, have allowed greater flexibility and customizability of release without sacrificing size or material. However, clinical translation of these particles has been limited thus far, with some of the main reasons being the lack of control over key performance-defining properties such as size and size distribution. This research explores synthesis conditions, output parameters, and performance of polymeric nanoparticle formation methods. Our goal is to understand synthesis conditions and parameters which will allow us to predict and control the formation of polymeric nanoparticles made of common and safe polymers: poly (D,L) lactic-co-glycolic acid (PLGA) and poly (L) lactic acid (PLLA). To achieve this goal, we analyzed and modeled a common laboratory method for producing PLGA nanoparticle cores. Machine learning and component trend analysis were used to develop a practical, scalable model for best control over particle size and size distribution, before characterizing the effect on release of model, small drugs. We then investigated different methods for coating these cores with a PLLA shell for improved controlled release kinetics and flexibility, attempting to find synthesis parameters which maximize formation efficiency and allow for control of both the core and shell dimensions. Finally, we analyzed the performance of these particles in different formulations of chitosan hydrogel wound dressings. We believe this research sets an important foundation for polymer nanoparticle synthesis and small, hydrophobic drug release by expanding knowledge on the features and performance of these systems and illuminating favorable procedures and methods that optimize their controlled release. This includes the main findings: a practical, scalable power law for dimension control of PLGA nanoparticles, important insights into a modified emulsion method for core/shell nanoparticle production and how it could be further improved for higher formation efficiency, as well as a proof of concept for a hydrogel-PLGA nanoparticle system which showed highly variable release with controlling swelling and structure.