The development of targeted alpha particle therapies (TATs) involving actinum-225 is an active area of research. Despite the therapeutic efficacy that has been observed in numerous studies, several challenges need to be overcome before this strategy can be adopted fully. Minimizing kidney toxicity after radiotherapy administration is one issue that still needs to be resolved. To investigate a potential solution to this problem, we prepared a small library of TATs based upon the parent radiopharmaceutical, 225Ac-DOTA-MC1RL, which is under development for the treatment of metastatic melanoma. This library contained radiopharmaceuticals with a range of lipophilicities (log D7.4 values). We conducted biodistribution, pharmacokinetic and radiation dosimetry studies in mice to determine how lipophilicity of the radiopharmaceutical affected these parameters. From these studies, we observed that higher log D7.4 values were associated with decreased kidney uptake, decreased absorbed radiation dose, and decreased kidney toxicity of the TAT, and the inverse was observed for lower log D7.4 values. These findings suggest that tuning radiopharmaceutical lipophilicity can effectively modulate the level of kidney uptake to reduce morbidity and improve both safety and efficacy.

Improving the kidney toxicity profile of actinium-225 radiopharmaceuticals

ACS Spring 2022

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