Date of Award

2024

Document Type

Thesis (Ph.D.)

Department or Program

Cancer Biology

First Advisor

Kimberley S. Samkoe

Abstract

Accurate assessment of drug receptor occupancy (RO) holds significant importance in both drug development and personalized medicine, as it facilitates quantitative characterization of dose-response relationship for a given drug. This information not only aids appropriate dose selection for clinical trials but also guides personalized dose optimization in precision medicine.

Molecular imaging, utilizing receptor-specific imaging agents for tissue visualization, has emerged as the major option for in vivo measurement of tissue RO. Nonetheless, the abnormal yet complex structure and hemodynamics of tumors often lead to substantial non-specific uptake and retention of imaging agents, thus introducing significant bias to RO measurements. To address the challenge, a quantitative molecular imaging strategy known as near-infrared paired-agent imaging (PAI) has been developed and characterized. PAI employs simultaneous administration of one receptor-specific imaging agent and a pharmacokinetically similar reference agent devoid of receptor specificity. Through quantification of tumor binding potential (BP), a parameter directly proportional to concentration of unbound receptors, PAI holds the potential to accurately measure tumor RO in vivo.

This thesis focuses on the development and characterization of in vivo PAI to measure RO in tumor. By assessing the receptor binding characteristics of ABY-029, an epidermal growth factor receptor (EGFR)-specific imaging agent, the study revealed ABY-029's potential to reflect drug engagement in tumor. Characterization of pre-drug BP in mouse tumor xenografts imaged with different doses of ABY-029 reconfirmed the independence of BP from ABY-029 dosage. Furthermore, in vivo PAI managed to detect dynamic decrease in tumor BP following drug administration. Subsequent in vivo RO dose studies revealed a dose-dependent increase in tumor RO measured by PAI, highlighting its capability to assess RO in tumors. However, overestimation of tumor BP was also observed. To address this issue, a novel assay was developed and employed to characterize tissue biodistribution of the paired agents in response to drug administration. The analysis identified liver as a major body compartment influencing tumor BP. Further refinement of the compartmental modeling for PAI is thus anticipated to allow accurate BP and RO correction. Nevertheless, this study revealed the promising potential of PAI for both future drug development and precision medicine.

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Available for download on Wednesday, July 08, 2026

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