Fabrication of Non-Spherical Biodegradable Particles for Drug Delivery Applications and Studying the Impact of Shape on the Efficacy of Particulate Carriers

Abstract

Biodegradable particles are used to specifically deliver drugs to diseased sites to increase their efficacy and minimize their side effects. Until now, most of the drug delivery platforms have been spherical in their shape due to the ease of fabrication and their well-characterized performance. Recent studies have been shown that shape modifications can be utilized to modulate the performance of particulate carriers to increase their efficacy via changing their immune clearance rate, their circulation time, and their binding to the vascular wall. However, there are still considerable knowledge gaps to understand the impact of the shape of the efficacy of micro/nanoparticles. One of the reasons for the lack of a clear understanding of the impact of shape on the efficacy of biodegradable particles is the absence of a simple and scalable method to fabricate non- spherical particles in large scales. In this thesis, we have developed novel emulsion-based techniques to fabricate non-spherical biodegradable particles in large scales. We first developed a modified two-step emulsion solvent evaporation technique to fabricate ellipsoidal poly(lactic-co-glycolic acid), PLGA, rods. Emulsion droplets were elongated via the application of shear in a system with low interfacial tension. Via this method, we could successfully fabricate PLGA rods with a major axis size as small as 3 micrometers, which is the size range of interest in vascular targeting applications. Our results showed that separation of the droplet formation and stretching steps, and a careful choice of the oil phase solvent and surface-active molecule are the key factors to fabricate rods in the smaller size ranges. We also were able to show these rods were able to successfully bind to an inflamed vasculature both in vitro and in vivo. When the phagocytosis of the particles of various shapes by different phagocyte sub-types was investigated, we showed that contrary to the mononuclear phagocytes, i.e., macrophages and monocytes, neutrophils would preferentially get associated with rod-shaped particles in vitro and in vivo. This opens up the opportunity to selectively target neutrophils in acute inflammation. We next we were able to innovate a metal-assisted gold templating emulsion-based method to fabricate bile salt particles. The composition of these particles and the presence of bile salts as the primary component in their structure were confirmed via different chemical characterization techniques. We also showed that these particles would degrade via surface erosion and release bile salts to the solution. This makes these composite particles suitable candidates as controlled release systems in disease models where the therapeutic benefit of the bile salts is proved to minimize side effects. We demonstrated that these particles could successfully lyse adipocytes and induce apoptosis in cancer cells. Last, we explored the modification of emulsion-based methods via the utilization of a cosolvent to increase the loading efficiency of hydrophilic agents in polymeric nanoparticles. We showed that the utilization of a minimal amount of a polar cosolvent with minimum hydrophilicity, such as ethyl acetate, could be used to stabilize antibodies in the emulsion oil phase and increase their loading efficiency. The methods introduced in this study enable the fabrication of novel drug carriers on a large scale for clinical applications. Overall, the results of this study open up an opportunity for developing new methods for the fabrication of novel biodegradable drug delivery platforms that can be used in the treatment of various disorders.