UC Berkeley

Alpha-particle radiopharmaceutical therapy (αRPT) is a cancer treatment modality that aims to minimize toxicity to normal tissues by guiding cytotoxic alpha-emitting radionuclides to cancer cells with biomolecular targeting. The short range of the alpha-particle theoretically allows a perfectly targeted agent to spare healthy tissue, but it can also result in heterogeneous energy deposition in tumors and organs. Data explaining the effect of dose heterogeneity on treatment efficacy and toxicity are still lacking. The ability to predict treatment outcomes and efficiently develop αRPT agents requires clarity in the dose-effect relationship at the microscopic scale and tools to facilitate such investigations.

This dissertation describes the implementation of small-scale dosimetry techniques using an iQID digital autoradiography system and provides three examples of their use in preclinical studies of αRPT agents. Device characterization, quantitative corrections, image processing, Monte Carlo kernel simulations, and histological correlation are discussed. Preclinical imaging throughput is increased through slice minimization algorithms with quantifiable uncertainty costs. These approximations also enable a sampling method for 3D small-scale dosimetry that presents comprehensive views of the absorbed dose distributions within whole organs and tumors. The developed methods are demonstrated in the assessment of At-211 in canine lymph nodes, Ac-225 in murine kidneys and tumor xenografts, and Ac-225 in murine liver micrometastases. These data, which show nonuniform patterns of absorbed dose in tissues and tumors, emphasize that the development of αRPT agents and optimization of tumor and organ doses require consideration of small-scale effects. Finally, progress towards isotope separation in iQID autoradiography using charged particle discrimination or coincident gamma-ray detection is reported. The role of this work is described in the context of growing interest in dosimetry-based, patient-tailored radiopharmaceutical prescriptions.