Researcher ORCID Identifier
https://orcid.org/0009-0004-0554-2121
Graduation Year
2026
Document Type
Open Access Senior Thesis
Degree Name
Bachelor of Arts
Department
Biophysics
Reader 1
Dr. Naga Vara Kishore Pillarsetty
Reader 2
Dr. Sarah Marzen
Rights Information
© 2025 Gabrielle M Kroepfl
Abstract
Targeted radionuclide therapy (TRT) offers a strategy to deliver cytotoxic radiation selectively to cancer-associated markers, including fibroblast activation protein (FAP), a pan-cancer stromal protein. Although small-molecule FAP radiopharmaceuticals have demonstrated excellent imaging performance, rapid radioligand wash-off has limited therapeutic efficacy by preventing sufficient tumor dose deposition. Next-generation FAP agents—including the covalent-targeted radioligand FAPI-mFS and the macrocyclic peptide FXX489—were developed to address these limitations; however, their off-target interactions and toxicity profiles remain insufficiently characterized. We assessed the pharmacokinetics and specificity of [⁶⁸Ga]Ga-FAPI-mFS in healthy mice and xenograft-bearing mice. Early-time-point PET/CT imaging and ex vivo biodistribution revealed no improvement in tumor uptake relative to [⁶⁸Ga]Ga-FAPI-46 and demonstrated elevated and persistent blood activity. Preliminary SDS-PAGE autoradiography of [⁶⁸Ga]Ga-FAPI-mFS incubated in fresh plasma indicated covalent interactions with non-albumin blood components, pointed to a compromised therapeutic index. We likewise evaluated the therapeutic potential of the macrocyclic peptide [¹⁷⁷Lu]Lu-FXX489 by performing preclinical small-animal and translational dosimetry. Bone marrow dose was estimated using both blood-based scaling and a direct-measurement approach; the latter revealed substantially higher marrow exposures, indicating that standard dosimetry methods markedly underrepresent marrow toxicity risk. The dose-limiting organ of [¹⁷⁷Lu]Lu-FXX489 was determined to be bone marrow. Together, these studies suggest increased FAP affinity alone is insufficient for therapeutic success and may exacerbate off-target toxicity. Future development of FAP-targeted TRT should prioritize tumor-selective retention and incorporate rigorous preclinical marrow dosimetry.
Recommended Citation
Kroepfl, Gabrielle, "Preclinical Evaluation of Next-Generation FAP-Targeted Radionuclide Therapies: Pharmacokinetics, Specificity, and Dosimetry of FAPI-mFS and FXX489" (2026). Scripps Senior Theses. 2906.
https://scholarship.claremont.edu/scripps_theses/2906
Included in
Biological and Chemical Physics Commons, Medical Biophysics Commons, Pharmacy and Pharmaceutical Sciences Commons, Radiochemistry Commons
