Preirradiation of Spheroids with ²²⁵Ac-Trastuzumab Improves Penetration of ²²⁵Ac-Liposomes and MIRDcell Predictions of Responses to Drug Cocktails.

Abstract

This investigation examined the factors involved in predicting the responses of micrometastases to targeted ²²⁵Ac-based therapies and in optimizing these therapies through the use of cocktails of radiopharmaceuticals (RPTs). <b>Methods:</b> MIRDcell version 4 was used to model the surviving fraction (SF) of cells in multicellular spheroids that were treated with cocktails of ²²⁵Ac RPTs as previously reported by Howe et al. in this journal. Spheroids were treated with varying activity concentrations of [²²⁵Ac]Ac-DOTA-SCN-trastuzumab (²²⁵Ac-trastuzumab) and ²²⁵Ac-DOTA-encapsulating liposomes (²²⁵Ac-liposomes). With the total activity concentration kept constant at 13.75 kBq/mL, 5 different activity distributions among the liposomes and antibodies were evaluated: 0%, 30%, 50%, 70%, and 100% of the total activity on each carrier. Penetration of the ²²⁵Ac-trastuzumab and ²²⁵Ac-liposomes into the spheroids was obtained with fluorescent surrogates in the previous work and remeasured here to determine whether preirradiating the spheroids with ²²⁵Ac-trastuzumab affected the spatiotemporal distribution of the liposomes. These data were used to compare MIRDcell-predicted SFs with experimental spheroid outgrowths. In addition, the artificial intelligence tool in MIRDcell was used to optimize the best cocktail formulation of ²²⁵Ac-antibodies and ²²⁵Ac-liposomes to achieve SFs of less than 0.0001 while minimizing the number of total decays necessary. <b>Results:</b> The penetration profiles of spheroids with 200-µm radii show a 42% increase in the total number of decays attributed to ²²⁵Ac-liposomes between 0 and 100 µm from the centers of spheroids when first pretreated with 6.5 kBq/mL ²²⁵Ac-trastuzumab. The MIRDcell predictions based on liposome penetration data obtained after preirradiation with ²²⁵Ac-trastuzumab also provided a better match to the experimental data. Artificial intelligence optimization found that although ²²⁵Ac-liposomes alone are able to sterilize all the cancer cells in the spheroid, 44% more total decays are required than when using a cocktail of ²²⁵Ac-trastuzumab and ²²⁵Ac-liposomes. <b>Conclusion:</b> Penetration of ²²⁵Ac-liposomes was enhanced by pretreatment with ²²⁵Ac-trastuzumab, and strategies to optimize penetration into micrometastases are important for RPT therapy with carrier cocktails. RPT cocktails, as opposed to single agents, may be required to eliminate circulating tumor cells, disseminated tumor cells, and micrometastases.