Kinetics of Drug Release from Acetalated Dextran Microparticles and Applications in Immune Engineering

Immune engineering involves the application of immunomodulatory technologies to improve human health. A variety of immune engineering strategies have been employed in the clinic, and the capabilities of immunomodulatory technologies continue to grow. However, one of the challenges of immune engineering is effective delivery of therapeutic compounds in a manner that adequately targets the immune system and creates the necessary context to elicit a desired effect, either by creating or avoiding danger signals to encourage reactive or tolerogenic responses. Drug delivery strategies employing micro/nano-scale technologies can be engineered to address this challenge. Though a wide range of biomedical micro/nanotechnology is discussed in this dissertation, there is a distinct focus on polymeric microparticles (MPs) both with consideration to the immune system and with consideration to formulation, optimization, and manufacturing. The works reported herein are interdisciplinary in nature, but there is an overarching theme focused on the optimization of drug delivery technologies to achieve protective or therapeutic immunomodulatory effects. At the heart of this dissertation is the acetalated dextran (Ace-DEX) MP delivery platform. Machine learning is employed to develop a mathematical model to predict drug release kinetics, which can aid in the future optimization of various Ace-DEX MP formulations. Ace-DEX MPs are also utilized for successful immunomodulation in murine models, both in the context of immune activation and the induction of immune tolerance. In the context of immune activation, merozoite surface protein 2 (MSP2) adsorbed to Ace-DEX MPs elicited enhanced IgG and IgG2a titers in BALB/c mice, outperforming MSP2 adsorbed to FDA-approved alum. The results of this work are promising for the further development of a malaria vaccine to fulfill unmet need in combatting a global health threat. In the context of immune tolerance, tolerogenic Ace-DEX MP formulations were optimized for applications in a murine model of multiple sclerosis, demonstrating significant therapeutic effects at clinically relevant stages of disease. This result is promising and can serve to inform further development of MP therapies to combat autoimmune disease in an antigen-specific manner, without broad immunosuppression. Overall, the work reported herein can inform future development of Ace-DEX MPs with applications in immune engineering.