Development of Inhibitor-Directed Enzyme Prodrug Therapy
(IDEPT) for Prostate Cancer
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Abstract
Prostate
cancer (PCa) is the second most common cause of cancer
death among American men after lung cancer. Unfortunately, current
therapies do not provide effective treatments for patients with advanced,
metastatic, or hormone refractory disease. Therefore, we seek to generate
therapeutic agents for a novel PCa treatment strategy by delivering
a suicide enzyme (yCD<sub>triple</sub>) to a cell membrane bound biomarker
found on PCa cells (prostate-specific membrane antigen (PSMA)). This
approach has resulted in a new PCa treatment strategy reported here
as inhibitor-directed enzyme prodrug therapy (IDEPT). The therapeutic
agents described were generated using a click chemistry reaction between
the unnatural amino acid (<i>p</i>-azidophenylalanine (<i>p</i>AzF)) incorporated into yCD<sub>triple</sub> and the dibenzylcyclooctyne
moiety of our PSMA targeting agent (DBCO-PEG<sub>4</sub>-AH<sub>2</sub>-TG97). After characterization of the therapeutic agents, we demonstrate
significant PCa cell killing of PSMA-positive cells. Importantly,
we demonstrate that this click chemistry approach can be used to efficiently
couple a therapeutic protein to a targeting agent and may be applicable
to the ablation of other types of cancers and/or malignancies