3D Volume Micro-scale 225Ac Dosimetry in Preclinical Prostate Cancer Models

Radiopharmaceutical therapy with alpha particle emitters (αRPT) offers an advantage in the treatment of refractory or metastatic cancers, such as metastatic castration-resistant prostate cancer (mCRPC), by using a precise targeting strategy to exploit the high therapeutic specificity of short-range (40-80 μm) cytotoxic alpha particles.
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Ac-based radiopharmaceuticals have shown high efficacy in several clinical trials, but off-target toxicity suggests that improvements are needed in radiochemistry and progeny radionuclide management. However, the limited availability of data and technologies that quantify dose distribution on spatial scales relevant to the alpha particle range impairs accurate characterization of novel αRPT agents. Here, we demonstrate that 2D digital autoradiography with an ionizing-radiation quantum imaging detector (iQID) can facilitate 3D volumetric dosimetry of targeted and non-targeted tissues. A series of 10-μm cryosections extracted every 200 μm spanning the organ or tumor is measured with the device. These activity maps are used in a previously developed Monte Carlo dose kernel convolution procedure to obtain dose-rate images, which we digitally register into a 3D volume via intensity-maximization rigid-body transformations. The resulting dose-rate organ or tumor volume has an effective voxel size of 39 x 39 x 210 μm. To permit the measurement of only one slice at each position, we validate a digital duplication approximation with a secondary experiment measuring 10 consecutive 10-μmslices in each tissue. We use this technique to sample dose-rate measurements across whole tumors and kidneys from a murine study of
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Ac-MACROPA-YS5, a novel αRPT agent with specificity to CD46-positive tumors. Renal cortical dose rate is over twice that of the medullary region, which suggests that free progeny
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Bi, which is known to collect in the renal cortex, is the source of nephrotoxicity in
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Ac αRPT.