Predicting response of micrometastases with MIRDcell V3: proof of principle with ²²⁵Ac-DOTA encapsulating liposomes that produce different activity distributions in tumor spheroids.

Abstract

The spatial distribution of radiopharmaceuticals within multicellular clusters is known to have a significant effect on their biological response. Most therapeutic radiopharmaceuticals distribute nonuniformly in tissues which makes predicting responses of micrometastases challenging. The work presented here analyzes published temporally dependent nonuniform activity distributions within tumor spheroids treated with actinium-225-DOTA encapsulating liposomes (²²⁵Ac-liposomes) and uses these data in MIRDcell V3.11 to calculate absorbed dose distributions and predict biological response. The predicted responses are compared with experimental responses. Four types of liposomes were prepared having membranes with different combinations of release (R) and adhesion (A) properties. The combinations were R^-A^-, R^-A⁺, R⁺A^-, and R⁺A⁺. These afford different penetrating properties into tissue. The liposomes were loaded with either carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) or ²²⁵Ac. MDA-MB-231 spheroids were treated with the CFDA-SE-liposomes, harvested at different times, and the time-integrated CFDA-SE concentration at each radial position within the spheroid was determined. This was translated into mean ²²⁵Ac decays/cell versus radial position, uploaded to MIRDcell, and the surviving fraction of cells in spherical multicellular clusters was simulated. The MIRDcell-predicted surviving fractions were compared with experimental fractional-outgrowths of the spheroids following treatment with ²²⁵Ac-liposomes. The biological responses of the multicellular clusters treated with ²²⁵Ac-liposomes with physicochemical properties R⁺A⁺, R^-A⁺, and R^-A^- were predicted by MIRDcell with statistically significant accuracy. The prediction for R⁺A^- was not predicted accurately. In most instances, MIRDcell predicts responses of spheroids treated with ²²⁵Ac-liposomes that result in different tissue-penetrating profiles of the delivered radionuclides.