MIRD Pamphlet No. 27: MIRDcell V3, a Revised Software Tool for Multicellular Dosimetry and Bioeffect Modeling

Abstract

Radiopharmaceutical therapy is growing rapidly. However, yet to be addressed is the implementation of methods to plan treatments for circulating tumor cells, disseminated tumor cells, and micrometastases. Given the capacity of radiopharmaceuticals to specifically target and kill single cells and multicellular clusters, a quality not available in chemotherapy and external-beam radiation therapy, it is important to develop dosimetry and bioeffect modeling tools that can inform radiopharmaceutical design and predict their effect on microscopic disease. This pamphlet describes a new version of MIRDcell, a software tool that was initially released by the MIRD committee several years ago. Methods: Version 3 (V3) of MIRDcell uses a combination of analytic and Monte Carlo methods to conduct dosimetry and bioeffect modeling for radiolabeled cells within planar colonies and multicellular clusters. A worked example is provided to assist users to learn old and new features of MIRDcell and test its capacity to recapitulate published responses of tumor cell spheroids to radiopharmaceutical treatments. Prominent capabilities of the new version include radially dependent activity distributions, user-imported activity distributions, cold regions within the cluster, complex bioeffect modeling that accounts for radiation type and subcellular distribution, and a rich table of output data for subsequent analysis. Results: MIRDcell V3 effectively reproduces experimental responses of multicellular spheroids to uniform and nonuniform distributions of therapeutic radiopharmaceuticals. Conclusion: MIRDcell is a versatile software tool that can be used for educational purposes and design of radiopharmaceutical therapies.

Keywords: cell survival; dosimetry; multicellular cluster; nonuniform activity distribution; radionuclide.

Graphical abstract

FIGURE 1.

View of 3 tomographic sections of rod-shaped cluster of cells with cold region in interior. Red cells are labeled with radionuclide. Green cells are unlabeled. Opaque cells are alive, and translucent cells are dead. Blue lines point to tomographic section of corresponding cell layer.

FIGURE 2.

“Source Radiation” tab.

FIGURE 3.

“Cell Source/Target” tab.

FIGURE 4.

Complex radiobiologic parameters.

FIGURE 6.

Tomographic section through center of spherical cell cluster illustrating drug penetration depth, labeled cells (red), unlabeled cells (green), alive cells (opaque), and dead cells (translucent). Only unlabeled cells at center of cluster are alive.

FIGURE 5.

“Multicellular Geometry” tab. SF variation as function of mean activity per cell is shown on right.

FIGURE 7.

Comparison of MIRDcell prediction with experimental observations. Original plots extracted from Kennel et al. (21) have been overlayed with MIRDcell predictions (red). (A) EMT-6 cells. (B) LINE-1 cells. Triangles are data obtained for MAb13A, and circles are those obtained for MAb14, which is nonbinding with tissue. Solid lines are least-squares fits to exponential function provided by Kennel et al. MIRDcell simulation was run for MAb13A cells.