Date of Award
Spring 5-11-2024
Document Type
Dissertation
Degree Name
Ph.D. in Engineering Science
Department
Chemical Engineering
First Advisor
Thomas Werfel
Second Advisor
Adam Smith
Relational Format
Dissertation/Thesis
Abstract
Tumor-associated macrophages (TAMs) play a substantial role in sculpting the tumor microenvironment (TME) into an immunosuppressive bastion that undermines immune surveillance and enables tumor progression. They therefore represent a promising therapeutic target to make the TME more conducive for anti-tumor immunity and greatly improve treatment outcomes in cancers that are highly resistant to conventional forms of therapy. Several medications have been developed to modulate the activities of TAMs, showing tremendous potential, but these medications lack specificity for TAMs making their use susceptible to adverse side effects that could outweigh prospective benefits. Sophisticated delivery vehicles that can preferentially deliver these medications to TAMs are, therefore, needed to overcome this challenge and maximize the potential of these medications. To address this imperative, we engineered multiple stimuli-responsive glycopolymeric nanoparticles tailored to preferentially deliver drugs to TAMs by taking advantage of distinctive features displayed by these macrophages. Initially, we developed ROS-responsive, glycopolymeric nanoparticles (NPs) made from a diblock copolymer comprising of polypropylene sulfide (PPS) and polymeric glucose (PMAG) which were synthesized through a combination of anionic polymerization and reversible addition-fragmentation chain-transfer (RAFT) polymerization. The NPs exhibited controlled release cargo in response to oxidative species and enhanced internalization in macrophages compared to unglycosylated NPs. The glucose transporter 1 (GLUT 1) was shown to be the underlying mechanism for the enhanced internalization of the glycosylated nanoparticles. Subsequently, we explored polymeric mannose as a ligand to actively target TAMs through the macrophage mannose receptor (MMR). We fabricated glycopolymeric NPs made from diblock copolymers containing poly((2-Diisopropylamino) ethyl methacrylate) (PDPA) and poly (methacrylamido mannose) (PMAM). The NPs displayed pH-responsibility and were tailored for endosomal drug delivery. Moreover, The NPs were capable of targeting TAMs in vitro and in vivo through MMR. More importantly, the targeted blockade of TAM-mediated immunosuppression through these NPs significantly promoted anti-tumor immunity and inhibited breast cancer growth. These studies show that TAM-targeting, glycopolymer-based therapeutics are a promising strategy either as a standalone or in combination with other therapies to drastically improve therapeutic outcomes in hard-to-treat malignancies.
Recommended Citation
Shofolawe-Bakare, Oluwaseyi, "STIMULI-RESPONSIVE GLYCOPOLYMERIC NANOPARTICLES TO BOOST TUMOR IMMUNOGENICITY THROUGH MACROPHAGE-TARGETED THERAPY" (2024). Electronic Theses and Dissertations. 3097.
https://egrove.olemiss.edu/etd/3097
