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

Purpose 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 ( 225 Ac-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. Methods 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 225 Ac. 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 225 Ac 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 225 Ac-liposomes. Results The biological responses of the multicellular clusters treated with 225 Ac-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. Conclusion In most instances, MIRDcell predicts responses of spheroids treated with 225 Ac-liposomes that result in different tissue-penetrating profiles of the delivered radionuclides.