Dissertation
Investigations into Controlled Release Strategies for PSMA-Targeted Therapuetics
Doctor of Philosophy (PhD), Washington State University
01/2019
Handle:
https://hdl.handle.net/2376/118379
Abstract
Prostate cancer (CaP) is the third leading cause of cancer related death in American males. Treatments for CaP have historically suffered from off targeting and lack of specificity which, translate into loss of treatment efficacy and/or quality of life for patients. Efforts in the field of CaP therapy have focused upon the principle of targeted deployment of potent cytotoxic agents to diseased tissues in order to elicit controlled therapeutic responses. Prostate-specific membrane antigen (PSMA) is a cancer associated biomarker, which is restricted to the membrane of cancerous tissue. The selective expression to cancerous cells has made it an ideal biomarker for targeting via various small molecule ligands, anti-bodies, imaging agents, radiotherapeutics, and small-molecule drug conjugates. Current research efforts by our lab and reported herein, outline our efforts to develop a new modular scaffold that contains: 1) a potent cytotoxic agent 2) a novel pH-sensitive linker and 3) a small molecule ligand for PSMA. The Kozikowski and Low groups have spent considerable efforts in developing small-molecule drug conjugate (SMDC) platforms that target PSMA to selectively treat CaP cells with known chemotherapeutics to initiate cell death. Recent works by our group have elucidated the pH-sensitivity the P-N bond of phosphoramidates in proximity of ionizable groups at various pH values relevant to homeostatic and disease states. It was our intent to design a modular prodrug scaffold that allows for ease of synthesis, late stage diversification, and without sacrificing affinity for PSMA. This work demonstrates the selectivity and effectiveness of the first generation of pH-triggered phosphoramidate-based SMDCs against PSMA(+) cell lines, synthesis of a third generation of constrained phosphoramidate-based pH-cleavable linkers, the development of a cell culture model to assess the performance pH-sensitive SMDC candidates at reduced pH, and finally discovery of new targeting moieties for PSMA to extend the application of this platform.
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Details
- Title
- Investigations into Controlled Release Strategies for PSMA-Targeted Therapuetics
- Creators
- Brian S Backer
- Contributors
- Clifford E Berkman (Advisor)Ming Xian (Committee Member)Chulhee Kang (Committee Member)Gregory J Crouch (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Department of Chemistry
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 221
- Identifiers
- 99900581418601842
- Language
- English
- Resource Type
- Dissertation