Dissertation
Controlled-release applications for pH-sensitive phosphoramidates.
Washington State University
Doctor of Philosophy (PhD), Washington State University
01/2021
DOI:
https://doi.org/10.7273/000003115
Handle:
https://hdl.handle.net/2376/121871
Abstract
In 2016, we reported a drug-linking phosphoramidate scaffold that displayed a stability profile that was pH dependent. These pH-triggered phosphoramidate-based linkers were responsive only to pH and did not require intracellular enzymatic action to initiate drug release. Key to the functionality of these linkers were three main components: (1) the pKa of the leaving amine, (2) the proximity of an ionizable group (typically a carboxylate or pyridinium moiety), and (3) the pKa of the ionizable group. Combined, these three moieties allow for exquisite control of this scaffold for the selective release of amine-base payloads in the context of cleavable linkers, which could also be tuned to meet the specific requirements of various controlled-release applications.
Herein, we demonstrate applications of these pH-triggered phosphoramidates-based linkers for payload release in the development of novel therapeutic agents for Parkinson’s disease and cancer. First, we incorporated the linker into a prodrug platform that can be utilized for slow release of L-Dopa in physiological conditions. This has potential implications in ameliorating the undesirable pharmacokinetic profile that is typified by L-Dopa therapy. Furthermore, we optimized the phosphoramidate linker for controlled-release of cytotoxic payloads in the development of small molecule-drug conjugates (SMDCs) for cancer targeted therapeutic applications. The water-soluble linker was designed to release functionally diverse payloads, stable at physiological conditions while rapidly releasing its payload at the mildly acidic pH conditions of the endosome and lysosome. We demonstrated the effectiveness of this linker in-vitro by studying its mechanistic release and intracellular trafficking of fluorogenic payload in PSMA-expressing prostate cancer cells. In-vivo studies displayed exceptional efficacy against PSMAexpressing tumor xenografts in mice. In summary, this work highlights how phosphoramidatebased cleavable linkers can be incorporated into the modular design of new controlled-release therapeutic agents.
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Details
- Title
- Controlled-release applications for pH-sensitive phosphoramidates.
- Creators
- Feyisola Paul Olatunji
- Contributors
- Clifford E Berkman (Advisor)Mary Paine (Committee Member)Ming Xian (Committee Member)Rock J Mancini (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Chemistry, Department of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 317
- Identifiers
- 99900651794401842
- Language
- English
- Resource Type
- Dissertation