Microscale Radionuclide S-values for αRPT

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Abstract / Summary – Project 2 Radiopharmaceuticals labeled with alpha-particle emitters (RPT) uniquely satisfy various conditions for therapy of cancer in its advanced stages. Alpha particles have high linear-energy transfer (~100 keV / m) and thus short tissue ranges (~50-80 m). Resultantly, they can sterilize tumor cells with as few as 1-3 particle traversals, in contrast to the requirement of 1000s of beta-particle traversals. Furthermore, they are not susceptible to chemoresistance, and are minimally susceptible to radioresistance. In the development of patient-specific treatment planning for RPT, one primary objective is to ensure that the radiation dose to normal tissues and organs approaches, but remains below, thresholds for toxicity. Assessment of alpha-particle dosimetry of organs at potential toxicity risk can be performed via the MIRD schema, but it ideally must be applied at a spatial scale that is pertinent to the specific cell populations which drive toxicity, and that is relevant to the ranges of the emitted alpha particles. The MIRD schema states that the absorbed dose to a target region may be computed as the product of the time-integrated activity in a source region (i.e., total number of radionuclide decays) and the radionuclide S-value (absorbed dose to the target region per decay in the source region). Traditionally, the MIRD defines source and target regions as whole organs (liver or kidney) or perhaps organ subregions (e.g., liver lobe or renal cortex). Given the ranges of alpha particles, however, source and target regions would ideally be defined at a more microscale level. The main goal of Project 2 is thus to develop a comprehensive library of microscale S-values which will support RPT in the following organs: bone marrow, kidneys, liver, lungs, salivary glands, lacrimal glands, and small intestine. Aim 1 will develop geometric-based models of these tissues in both the human and mouse; we have previously published such models for both bone marrow and kidneys. In Aim 2, we will develop a new generation of 3D tissue models for microscale S-value computation based upon an extensive library of high-quality serial histology images of these same tissues. These models (both mouse and human) will be constructed across multi-ROIs (quantifying intra-organ variability) and multiple individuals (quantifying inter-patient variability). Prior studies have indicated that the laboratory mouse is not a robust pre- clinical model for RPT induced marrow toxicity. Consequently, in Aim 3 studies will focus on microscale bone marrow S-values in the higher-species model of the mini-pig. Also, a microscale model of the porcine kidney will be developed to allow for inter-species extrapolation. Aim 4 studies will focus on validating our Aim 2 and 3 models with respect to tissue volume changes and potential loss of blood in the tissue capillaries. Understanding these changes will allow more accurate modeling of their in-vivo state.