Enhancing the therapeutic index of [At]YF2 with iodo pseudo carrier: A simple strategy for reducing accumulation in kidneys, salivary and lacrimal glands.

INTRODUCTION

Low-molecular-weight (LMW) PSMA-targeted agents have enjoyed success; however, their off-target toxicity in normal tissues such as kidneys, salivary gland and lacrimal gland can be dose limiting. Herein, we have evaluated the effect of co-administration of the non-radioactive iodo pseudo carrier, iodo YF2, on the normal tissue uptake of [At]YF2 in xenografted mice. The potential implications for clinical translation of these studies were investigated by evaluating the binding of LMW PSMA-targeted agents to murine and human PSMA.

METHODS

[At]YF2 was synthesized following established protocols. Groups of 5 mice bearing subcutaneous PSMA+ PC3 PIP xenografts received [At]YF2 co-injected with varying i.v. doses of iodo YF2 (0-2 nmol), and the biodistribution was evaluated at 1 h post injection (p.i.). In another study, the biodistribution of [At]YF2 alone and [At]YF2 co-administered with 1.5 nmol iodo YF2 was evaluated at 1 and 8 h p.i. Bead-based radioligand binding assays were conducted for [I]YF2 and several other LMW agents to compare their binding to human and murine PSMA.

RESULTS

At 1 h, no significant difference was seen in kidney uptake of [At]YF2 at iodo YF2 concentrations of 0, 0.05 and 0.1 nmol (p > 0.05), but renal accumulations significantly reduced by co-administering 2.0 nmol iodo YF2 (p < 0.0001). Decreases in salivary and lacrimal gland uptake also were observed at 1 h for [At]YF2 co-injected with 0.1 nmol iodo YF2 (p < 0.05). A follow-up study revealed a kidney uptake of 1.8 ± 0.4 % ID/g for [At]YF2 with 1.5 nmol iodo YF2, compared to 46.5 ± 7.7 % ID/g for [At]YF2 alone at 8 h. Tumor uptake showed no significant difference (p > 0.05) between [At]YF2 alone (17.1 ± 8.8 % ID/g at 1 h; 13.6 ± 5.3 % ID/g at 8 h) and [At]YF2 plus 1.5 nmol iodo YF2 (12.8 ± 2.7 % ID/g at 1 h; 14.1 ± 3.2 % ID/g at 8 h). Bead-based radioligand binding assays showed that [I]YF2 has the highest binding fractions to both human PSMA (94.1 ± 0.1 %) and murine PSMA (92.5 ± 0.2 %) with minimal differences between the two, while [Lu]PSMA-617 had the greatest species-dependent disparity with a binding fraction of 90.5 ± 0.3 % to human PSMA and 60.9 ± 1.4 % to murine PSMA.

CONCLUSIONS

Co-administration of iodo YF2 reduced kidney uptake of [At]YF2 and decreased accumulation in normal tissues with no significant change in tumor uptake. In some cases, there was a significant difference in binding to human and murine PSMA among LMW PSMA-targeted agents suggesting that particularly for some agents, applying mouse data to predict human dosimetry must be done with caution.