ORCID ID
Graduation Date
Fall 12-15-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Cancer Research
First Advisor
Jered C Garrison, PhD
Abstract
Small-molecule targeted radionuclide therapeutics (TRTs) have proven effective in several malignancies by combining precise tumor targeting with rapid clearance from non-target tissues. However, many TRTs exhibit poor tumor retention, which directly limits their deliverable therapeutic radiation dose. In response, our laboratory investigated the incorporation of irreversible epoxysuccinyl-based protease inhibitors into TRTs to generate dual-targeted constructs that improve tumor retention through high molecular weight adduct formation via a cysteine protease trapping approach (CPTA).
Neurotensin receptor subtype 1 (NTS1) is a GPCR that promotes cancer cell invasion and survival through upregulation across many malignancies. Its low expression in normal tissues identifies it as a viable target for TRT development. [¹⁷⁷Lu]Lu-3BP-227 is a NTS1-TRT that demonstrated favorable tumor uptake but rapid clearance in clinical trials, motivating its optimization via the CPTA. Preliminary CPTA–NTS1-targeted agents (CPTA-NTS1TAs) achieved two- to threefold increases in tumor retention but exhibited elevated renal uptake. To mitigate off-target toxicity, this work investigated structural modifications to decouple tumor and renal retention of CPTA-NTS1TAs.
In Chapter 2, a structure-activity study evaluated linker composition within CPTA-NTS1TAs, revealing that positively charged ([¹⁷⁷Lu]Lu-8c) or flexible ([¹⁷⁷Lu]Lu-8a) linkers enhanced NTS1 targeting and retention (17.8–28% of initial uptake) compared to [¹⁷⁷Lu]Lu-3BP-227 (13 ± 2%), though renal accumulation remained high. Chapter 3 examined amino acid substitutions at the P2 position of the epoxysuccinyl inhibitor to refine enzymatic specificity and pharmacokinetics. Eight constructs demonstrated preserved NTS1 affinity, efficient internalization, and distinct high–molecular weight adduct profiles. Tyrosine substitution suggested selective cysteine protease interactions and elevated tumor uptake, and sustained retention.
Finally, Chapter 4 extended CPTA utility to a folate receptor 1 (FOLR1)–targeted system for metastatic ovarian cancer, confirming generalizability of the trapping strategy through improved tumor retention and adduct formation relative to a non-trapping control. Collectively, this work establishes the CPTA as a versatile platform for enhancing tumor retention. By bridging the pharmacokinetic gap between small molecules and macromolecular agents, it lays the foundation for developing next-generation TRTs with broader clinical applicability across solid tumors.
Recommended Citation
Klein, Sadie, "Optimizing Small Molecule Targeted Radionuclide Therapeutics for Enhanced Tumor Retention in Ovarian and Colorectal Cancer" (2025). Theses & Dissertations. 1019.
https://digitalcommons.unmc.edu/etd/1019
Comments
2025 Copyright, the authors