The disease of >70% of patients with metastatic castration-resistant prostate cancer (mCRPC) has moderate to high nonphysiological levels of a transmembrane protein known as prostate-specific membrane antigen (PSMA) and creates opportunities for precision medicine approaches. Using PSMA as a mechanism of disease selection, I conceptualized, designed, coordinated and contributed to the synthesis of, and tested a precision chemotherapy with on-demand nuclear properties. Conceptually, the strategy fused into a single drug the benefits of microtubule inhibition and theranostics, which are both standard of care in mCRPC. To achieve this, the design of the drug built on the general structure of chelator-containing glutamate-ureido-based radiopharmaceuticals for radioligand therapy. After screening taxanes, auristatins, and maytansinoids as candidates for drug development, I conjugated the next-generation microtubule inhibitor monomethyl auristatin E into glutamate-ureido-based small molecules via a multimodality chelator pioneered in our laboratory. Using a combination of radiopharmaceutical-guided drug development and molecular pharmacology in vitro, I discovered a chemoligand with high affinity to PSMA (Kd = 2.5 [1.5-3.9] nM) that disrupts the mitotic spindle, causes erratic mitosis, and induces cell and clonal death. Image-guided drug development using 68Gallium-positron emission tomography contextualized the accumulation of the chemoligand in PSMA+ C4-2 (7.1 ± 0.9 %ID/g) and 22Rv1 (2.1 ± 0.3 %ID/g) tumors, but not PSMA- PC-3 counterparts (0.2 ± 0.1 %ID/g), relative to its low nonspecific processes and rapid renal excretion. Without exceeding a specificity threshold dosage of 0.5 mg/kg qw x3 (empirically determined in PSMA- PC-3 tumors), the chemoligand more than doubled the median survival (P = 0.04) of male mice bearing PSMAhigh C4-2 tumors at a low cumulative dose (1.5 mg/kg). Using a dosage of 0.125 mg/kg qw x3 in castrated male mice bearing PSMAlow 22Rv1 tumors, the chemoligand caused tumor growth delay and improved the median survival (31 vs. 42 days, P = 0.009) in a manner that correlated with the observed reduction in Ki-67 proliferation index. I termed this therapeutic strategy as chemoligand therapy, a precision medicine that uses an advanced drug design for advanced theranostics.
","abstract_html":"<p>The disease of >70% of patients with metastatic castration-resistant prostate cancer (mCRPC) has moderate to high nonphysiological levels of a transmembrane protein known as prostate-specific membrane antigen (PSMA) and creates opportunities for precision medicine approaches. Using PSMA as a mechanism of disease selection, I conceptualized, designed, coordinated and contributed to the synthesis of, and tested a precision chemotherapy with on-demand nuclear properties. Conceptually, the strategy fused into a single drug the benefits of microtubule inhibition and theranostics, which are both standard of care in mCRPC. To achieve this, the design of the drug built on the general structure of chelator-containing glutamate-ureido-based radiopharmaceuticals for radioligand therapy. After screening taxanes, auristatins, and maytansinoids as candidates for drug development, I conjugated the next-generation microtubule inhibitor monomethyl auristatin E into glutamate-ureido-based small molecules via a multimodality chelator pioneered in our laboratory. Using a combination of radiopharmaceutical-guided drug development and molecular pharmacology <em>in vitro</em>, I discovered a chemoligand with high affinity to PSMA (<em>K</em><sub>d </sub>= 2.5 [1.5-3.9] nM) that disrupts the mitotic spindle, causes erratic mitosis, and induces cell and clonal death. Image-guided drug development using <sup>68</sup>Gallium-positron emission tomography contextualized the accumulation of the chemoligand in PSMA<sup>+ </sup>C4-2 (7.1 ± 0.9 %ID/g) and 22R<em>v</em>1 (2.1 ± 0.3 %ID/g) tumors, but not PSMA<sup>-</sup> PC-3 counterparts (0.2 ± 0.1 %ID/g), relative to its low nonspecific processes and rapid renal excretion. Without exceeding a specificity threshold dosage of 0.5 mg/kg qw x3 (empirically determined in PSMA<sup>-</sup> PC-3 tumors), the chemoligand more than doubled the median survival (<em>P </em>= 0.04) of male mice bearing PSMA<sup>high </sup>C4-2 tumors at a low cumulative dose (1.5 mg/kg). Using a dosage of 0.125 mg/kg qw x3 in castrated male mice bearing PSMA<sup>low </sup>22R<em>v</em>1 tumors, the chemoligand caused tumor growth delay and improved the median survival (31 vs. 42 days, <em>P </em>= 0.009) in a manner that correlated with the observed reduction in Ki-67 proliferation index. I termed this therapeutic strategy as <em>chemoligand therapy</em>, a precision medicine that uses an advanced drug design for advanced theranostics.</p>","abstract_has_math":false,"creators":["Hernandez Vargas, Servando","0000-0003-1614-7966
"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Ali Azhdarinia, Ph.D.","Kendra S. Carmon, Ph.D.","Daniel E. Frigo, Ph.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-12-01T08:00:00Z","date_published":"2025-12-01T08:00:00Z","updated_at":"2026-07-24T05:50:47Z","subjects":["Chemoligand","chemoligand therapy","drug conjugate","image-guided drug development","mCRPC","microtubule inhibition","multimodality chelator","theranostics","PSMA","radiopharmaceutical-guided drug design","specificity threshold","Oncology","Pharmacology","Therapeutics"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1492","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Ali Azhdarinia, Ph.D.","Kendra S. Carmon, Ph.D.","Daniel E. Frigo, Ph.D."]},{"key":"dc:creator","label":"Author","values":["Hernandez Vargas, Servando","0000-0003-1614-7966
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"]},{"key":"dc:title","label":"Title","values":["Chemoligand therapy for metastatic castration-resistant prostate cancer"]}]}],"canonical_facts":{"dc:contributor":["Ali Azhdarinia, Ph.D.","Kendra S. Carmon, Ph.D.","Daniel E. Frigo, Ph.D."],"dc:creator":["Hernandez Vargas, Servando","0000-0003-1614-7966
"],"dc:date.available":["2026-12-04T08:00:00Z"],"dc:description.abstract":["The disease of >70% of patients with metastatic castration-resistant prostate cancer (mCRPC) has moderate to high nonphysiological levels of a transmembrane protein known as prostate-specific membrane antigen (PSMA) and creates opportunities for precision medicine approaches. Using PSMA as a mechanism of disease selection, I conceptualized, designed, coordinated and contributed to the synthesis of, and tested a precision chemotherapy with on-demand nuclear properties. Conceptually, the strategy fused into a single drug the benefits of microtubule inhibition and theranostics, which are both standard of care in mCRPC. To achieve this, the design of the drug built on the general structure of chelator-containing glutamate-ureido-based radiopharmaceuticals for radioligand therapy. After screening taxanes, auristatins, and maytansinoids as candidates for drug development, I conjugated the next-generation microtubule inhibitor monomethyl auristatin E into glutamate-ureido-based small molecules via a multimodality chelator pioneered in our laboratory. Using a combination of radiopharmaceutical-guided drug development and molecular pharmacology in vitro, I discovered a chemoligand with high affinity to PSMA (Kd = 2.5 [1.5-3.9] nM) that disrupts the mitotic spindle, causes erratic mitosis, and induces cell and clonal death. Image-guided drug development using 68Gallium-positron emission tomography contextualized the accumulation of the chemoligand in PSMA+ C4-2 (7.1 ± 0.9 %ID/g) and 22Rv1 (2.1 ± 0.3 %ID/g) tumors, but not PSMA- PC-3 counterparts (0.2 ± 0.1 %ID/g), relative to its low nonspecific processes and rapid renal excretion. Without exceeding a specificity threshold dosage of 0.5 mg/kg qw x3 (empirically determined in PSMA- PC-3 tumors), the chemoligand more than doubled the median survival (P = 0.04) of male mice bearing PSMAhigh C4-2 tumors at a low cumulative dose (1.5 mg/kg). Using a dosage of 0.125 mg/kg qw x3 in castrated male mice bearing PSMAlow 22Rv1 tumors, the chemoligand caused tumor growth delay and improved the median survival (31 vs. 42 days, P = 0.009) in a manner that correlated with the observed reduction in Ki-67 proliferation index. I termed this therapeutic strategy as chemoligand therapy, a precision medicine that uses an advanced drug design for advanced theranostics.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1492"],"dc:subject":["Chemoligand","chemoligand therapy","drug conjugate","image-guided drug development","mCRPC","microtubule inhibition","multimodality chelator","theranostics","PSMA","radiopharmaceutical-guided drug design","specificity threshold","Oncology","Pharmacology","Therapeutics"],"dc:title":["Chemoligand therapy for metastatic castration-resistant prostate cancer"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:50:47Z"}