MIRDcell v3.01 Predicts Response of Nonuniform Distribution of Ac-225 labeled Nanocarriers in Multicellular Tumor Spheroids

Introduction: The MIRD Schema can be used to calculate the absorbed dose to tissues from radiopharmaceuticals. MIRDcell v2.17, software released by the MIRD Committee in 2014, implements the Schema to calculate absorbed doses and surviving fractions of cells in multicellular clusters that are labeled with radiopharmaceuticals. The accuracy of the biologic responses predicted with MIRDcell hinges in part on the distribution of cellular activity and corresponding distribution of cellular absorbed dose. In this work, we use experimentally measured activity distributions and a new version (v3.01) of MIRDcell to predict response of ~ 400 micro-meter diameter tumor spheroids to Ac-225 labeled liposome nanocarriers. Predictions are compared with experimental outcomes. Materials and Methods: The experimental data for the spheroids analyzed in this study was provided by the Sofou lab (published and unpublished). The liposomes were prepared with a releasing (R⁺) and a nonreleasing (R⁻) membrane, and an adhesion (A⁺) or no adhesion property (A^-) to increase the exposure times of the tumor cells to the delivered therapeutics. Spheroids were treated with 0 or 9.25 kBq/mL of ²²⁵Ac-labeled nanocarrriers with the properties: R⁻A⁻, R⁻A⁺,R⁺A⁻, and R⁺A⁺. Following the end time at day 20, spheroids were plated for growth. Once the untreated condition reached confluency, the percent outgrowth was calculated as the number of cells counted for each treatment normalized by the number of cells of the untreated condition. The concentration of the nanocarriers as a function of radial position was measured at several times during the uptake and clearance phases. The time-integrated activity per cell was determined as a function of radial position and was estimated using a weighted fit, non-weighted fit and a hybrid of a trapezoidal and an exponential fit to the clearance data beyond the last data point, to uptake and clearance data. This time integrated activity per cell as a function of radial position was used as input data by MIRDcell v3.01, along with the estimated mean activity per cell, and the absorbed dose was calculated for each cell. The surviving fraction of cells in the spheroid was then simulated by MIRDcell for each nanocarrier.

Results: The uptake and clearance of the nanocarriers were best represented by the hybrid fit. Preliminary results of the MIRDcell-predicted surviving fraction for the drugs R⁺A⁺ and R⁻A⁻ are in good agreement with the experimental fractional outgrowths. The results for R-A+ are within reason, however those for R+A- are in poor agreement.

Conclusions: This preliminary work demonstrated the ability of the software tool MIRDcell to predict the outgrowth of tumor cell clusters treated with Ac-225 nanocarriers with satisfactory accuracy in most cases. Further work is needed to improve the predictive accuracy. Acknowledgements: We acknowledge the contribution from all group members of the Sofou lab. This work was supported by the NIH grant number 1R01CA198073 and 1R01CA245139.

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