Recent advances in the targeted delivery of radionuclides and the increased availability of -emitters appropriate for clinical use have led to patient trials of multiple α-emitter radiopharmaceutical therapeutics (RPTs). One of these, Xofigo (223RaCl2) was FDA-approved and is in routine clinical practice, with many others likely to follow. One of the stated goals (pillars) of the NIH is a greater level of personalization in medicine. In the realm of radiopharmaceutical therapy (RPT) this translates directly as a need for more accurate personalized dosimetry in order to enable fractionation and administered activity tailored to each patient. However, current dosimetry paradigms are poorly suited to RPT. This reality is reflected by the discrepancies between clinical (or experimental) toxicity and expected toxicity calculated using standard organ-level (or voxel-level) dosimetry, including most notably: (a) hematotoxicity in 223Ra therapy of bone metastases, (b) renal and salivary gland toxicity in pre-clinical models and patients. The objective of this work is to create a dosimetric methodology more suited to αRPT, namely the Macro to micro (M2) methodology, which requires sub-organ activity apportionment factors for organs at risk. This will be accomplished via the following Aims: 1. In murine models, measure αRPT activity concentration in selected whole organs and in relevant organ sub-regions; generate apportionment factor histograms. The translation to human assumes that the link between macroscopic and microscopic spatiotemporal relationship for a given agent measured in a pre-clinical model will apply to the human as the distribution of the agent to the different microscopic compartments should remain the same. We will test and quantify the validity of this assumption and refine the human apportionment factors by introducing a third species, the mini-pig In Aim 2. We will assess apportionment factor transferability, by obtaining corresponding apportionment factor histograms for a porcine model. In Aim 3. We will demonstrate that M2µ predicts toxicity in the porcine model. 4. Apply the M2µ methodology to clinical trial data to quantify the potential benefit of personalized M2µ dosimetry and/or derive dose–response relationships. Successful completion of the proposal will reconcile experimental and clinical results not currently understood and provide a robust standardized dosimetry for personalized dosimetry-based treatment planning of αRPT. Such standardization will enable the dosimetry to be normalized to EQD2, thus enabling rational combinations with other RPTs or external beam therapy as well as relevant absorbed dose reporting. Here we plan to expand this approach to encompass the wide range of RPT/organ combinations that have either been shown to be or are potentially dose-limiting and that require the Macro to micro (M2) methodology to properly correlate dosimetry with toxicity thresholds and provide a deliverable that will allow...