Evaluation of therapeutic alpha emitters for their potential to be used in FAPI compounds

Introduction: There has been a significant interest in Fibroblast Activation Protein (FAP), which is highly expressed in cancer-associated fibroblasts (CAFs) of the tumor stroma. Recent studies have demonstrated that CAFs have emerged as important regulators of the anti-tumor immune response. Literature suggests that these cells are present in high density at the invasive front of the tumor stroma and have lower expression in the tumor center. The possibility of radiotherapeutic FAP-targeting compounds is being actively investigated. The unique situation where FAP radiotherapeutics target not cancer cells themselves, but CAFs distributed in and around the macroscopic tumor mass, it begs the question as to whether relatively short-range alpha-emitting radioisotopes are an appropriate therapeutic tool. Micro-dosimetric Monte Carlo (MC) simulations were performed to understand the potential of therapeutic effect of α-emitting radionuclides labeled to FAP-targeted compounds using several simplified CAF/tumor geometries.

Methods: We modeled a simple tumor microenvironment of the cubical volume of various sizes 50, 100, 200, 500, and 1000 µm. Three simple source configurations were modeled. α-emitting radionuclides were placed (a) at the edges of the cubical volume, (b) at the edges and placed at the center of the cubical volume, and (c) at the edges of the 3D volume and nine sources were placed in the cubical volume. All volumes were discretized such that each voxel represent a cell of a diameter of 10 µm. First, dose point kernels (DPKs) of therapeutic α-emitting radionuclides such as ²²⁷Th, ²²⁵Ac, ²²⁴Ra, ²²³Ra, ²¹²Pb, ²¹¹At, ²¹³Bi, and ²¹²Bi were simulated in a water phantom. GATE MC simulations were performed by assuming an isotropic point source of radiation at the center of homogeneous water phantom. The particle energy losses were tallied when the complete decay spectra of radionuclide occur, including its descendants. Fifty million decays were simulated to provide sufficient statistical precision in simulated kernels. Second, the DPKs were convolved with the discretized cubical volumes to obtain the absorbed dose distribution. All voxels in the cubical volumes were assessed in MATLAB to create voxelized/per cell dose histograms.

Results: The voxels in the smaller cubical volume geometries (50 and 100 µm) were all irradiated primarily by α-particles from all eight α-emitting radionuclides decay and received a minimal absorbed dose from the daughter β-decay. When simulated CAF sources were more than 200 µm apart, a substantial portion of voxels received minimal and likely non-therapeutic doses, suggesting that a minimal density of CAFs of FAP targets will be necessary for effective α-radiotherapeutics.

Conclusions: We report the assessment of therapeutic α-emitters for their potential to be used in FAP targeting compounds for the treatment of metastatic tumors. MC simulations suggest that α-emitting radionuclides may be useful, but further studies are needed to more accurately simulate the complex distributions of sources in tumor microenvironments based upon actual microscopic distributions of CAFs in various tumor situations. Micro-dosimetric comparison of the dose profiles of the therapeutic radionuclides can be made using the kernels generated in this work.

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