| dc.description.abstract | Particulate technology has transformed the field of diagnostic and therapeutic medicine due to the ability of particulates to provide better contrast in various imaging modalities and improve the targeting of therapeutic agents to specific tissues in the body. Several nano and micro-particles have found applications in the clinic, and it is expected that many humans are likely to come in contact with such systems in their lifetime. Once administered in vivo, these particulates are captured by phagocytic immune cells, which surveil the host system for foreign substances. The process of recognition and internalization of foreign substances may lead to cellular changes in phagocytic immune cells. A few studies have suggested that based on the physicochemical properties of the diagnostic or therapeutic particles, phagocytic immune cells may be activated towards an inflammatory or anti-inflammatory phenotype. Additionally, uptake of particles may alter cytokine secretion, chemotaxis behavior, oxidative burst, and nitric oxide generation in these cells. However, the effects of particulate uptake on the primary functions of a phagocytic immune cell, which are the internalization of foreign substances and neutralization of pathogens, remains poorly addressed. In this work, we determine how the uptake of particles changes an immune cell’s phagocytic ability and bactericidal activity. Using various phagocytic cell types and cargo-free particles, we demonstrate that particle uptake results in the enhancement of the phagocytic capacity of immune cells. We show that the increased uptake is not a result of cellular activation or cellular heterogeneity; instead, the first phagocytic event appears to prime the cell for subsequent phagocytosis. A consequence of the enhanced uptake ability is that particulate-laden-immune cells show faster clearance of bacteria both in vitro and in vivo. However, in an in vitro infection model involving bacteria with active invasion and replication mechanisms, faster clearance did not occur, suggesting that uptake of particulates could only induce enhanced phagocytosis but not increase the inherent killing capacity of immune cells. In the final part, we explored how surface modification of particulates, a common strategy to impart anti-fouling properties to the particle surface, affects the functional abilities of a phagocytic cell. We decorated the particle surface with polyethylene glycol, the most widely used polymer to reduce immune cell recognition of particulate-based therapeutics. We demonstrate that the effect of PEG-coating in reducing the phagocytosis of particles diminished as the particle size increases and was entirely absent for micrometer-sized particles. While the exact mechanisms of the differences in the interaction of PEG-modified nano and microparticles with phagocytic cells are unclear, we determined that size-based differences are observed even with a dense arrangement of PEG molecules on the surface, appear to be independent of the serum proteins adsorbing on particle surfaces, and are independent of the endocytic uptake pathway. Importantly, uptake of PEG-modified particles enhanced phagocytic rate in immune cells, similar to the observations with non-modified particulates. In summary, this dissertation highlights the importance of evaluating particle-phagocytic cell interaction, which will aid in designing improved particulate systems. The work also provides insights into the use of non-stimulatory cargo-free particles to modulate immune cell functions. | en_US |
