# Macro-to-micro (M2µ) Activity Apportionment for αRPT

> **NIH NIH P01** · JOHNS HOPKINS UNIVERSITY · 2024 · $473,956

## Abstract

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...

## Key facts

- **NIH application ID:** 10931448
- **Project number:** 5P01CA272222-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Robert Francois Hobbs
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $473,956
- **Award type:** 5
- **Project period:** 2023-09-19 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931448

## Citation

> US National Institutes of Health, RePORTER application 10931448, Macro-to-micro (M2µ) Activity Apportionment for αRPT (5P01CA272222-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10931448. Licensed CC0.

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