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Dissertation
IMIDAZOQUINOLINE PRODRUGS AND THEIR POTENTIAL APPLICATIONS FOR IMMUNOTHERAPY
Washington State University
Doctor of Philosophy (PhD), Washington State University
01/2021
DOI:
https://doi.org/10.7273/000005510
Handle:
https://hdl.handle.net/2376/119003
Abstract
Pharmacologic agents for cancer immunotherapy have traditionally been dominated by macromolecules. Developments in the field of immunology around the turn of the century have led to a molecular understanding of the cues involved in the onset of an immune response. Due to this, there has been rapid development of cancer immunotherapeutics in the past decades and the opportunity to design small molecule-based therapies that exhibit robust cell mediated responses. This dissertation presents the development of various prodrug techniques capable of expanding the anti-cancer efficacy of the imidazoquinoline drug class. This is achieved by developing prodrugs that are metabolized to active drug in the tumor microenvironment and in turn limit the release of immunostimulant to malignant tissues, ideally allowing for systemic administration of prodrug with targeted release of active immunostimulant. To this end, the research within this dissertation encompasses the development of Bystander-Assisted Immunotherapy (BAIT) which has been demonstrated in vitro with several variations of hydrolase-directed prodrugs. In the BAIT mechanism of action, an inactive immunostimulant prodrug is directed to the hydrolase enzymes upregulated in cancerous tissues by a pendant saccharide. Selectivity is attributed to the Warburg effect as cancerous tissue displays upregulated hydrolase activity compared to healthy tissues. Cleavage of the saccharide leads to tumor specific prodrug activation, followed by efflux to the extracellular space where quiescent bystander immune cells can be activated by the bioavailable immunostimulant to induce a cell mediated anti-tumor response. More recently, efforts have focused on the development of a novel affinity labeling platform that allows for the formation of in situ protein bioconjugate prodrugs for use in BAIT. This technique was named Ligand-Directed Nitrophenol Carbonate (LDNPC) chemistry and the proof-of-concept work utilized this technique to make avidin directed immunostimulant prodrugs that demonstrated time-dependent release of bioavailable immunostimulant in vitro. Overall, these efforts have created novel lead compounds that utilize unique mechanisms of action and demonstrate potential for use as small-molecule cancer immunotherapeutics.
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Details
- Title
- IMIDAZOQUINOLINE PRODRUGS AND THEIR POTENTIAL APPLICATIONS FOR IMMUNOTHERAPY
- Creators
- Anthony J Burt
- Contributors
- Rock J Mancini (Advisor)Clifford E Berkman (Committee Member)Phil P Garner (Committee Member)Ming Xian (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Department of Chemistry
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 264
- Identifiers
- 99900592258501842
- Language
- English
- Resource Type
- Dissertation