Abstract A131: Tissue distribution and tumor uptake of novel folate receptor targeted epothilone, BMS-745493 in CD2F1 mice after systemic administration

Abstract

Abstract BMS-753493 is an epothilone folate conjugate targeting folate receptor over-expressing tumor cells. The tissue distribution of radioactivity in tumor bearing mice was studied using quantitative whole body autoradiography (QWBA) after a single intravenous administration of [3H]BMS-753493 or its active epothilone moiety, [3H]BMS-748285, to female CD2F1 mice bearing bilateral tumors: murine lung tumor M109, and its folate receptor expressing variant 98M109. [3H]BMS-753493 derived radioactivity was extensively distributed to tissues. Organs that had the highest radioactivity were gastrointestinal tract and contents, liver, kidney, heart, bone marrow and tumors. In contrast, very little radioactivity was observed in the brain and spinal cord. Folate receptor over-expressing tumor 98M109 had higher radioactivity levels than M109 tumors at all time points, and 98M109 tumor had higher radioactivity than all normal tissues at 24 and 48 h post dose. Similar to [3H]BMS-753493 distribution, [3H]BMS-748285 derived radioactivity was extensively distributed to tissues after IV administration of [3H]BMS-748285. However, no difference in radioactivity was observed between the 98M109 tumor and all normal tissues at 24 and 48 h post dose, although slightly higher radioactivity was observed in 98M109 tumor as compared to M109 tumor. The preferential distribution of BMS-753493-related material to folate receptor expressing tumor 98M109 was further demonstrated in a study with unlabeled materials followed by LC/MS/MS measurement. After administration of BMS-753493, levels of BMS-748285 were much higher in 98M109 tumors than in M109 tumors, while no difference was observed between those two tumors after administration of BMS-748285. Similarly, much lower levels of BMS-748285 were observed in the heart and kidney tissues after administration of BMS-753493 as compared to those observed after dosing of BMS-748285. The relatively lower levels of active epothilone in normal tissues after BMS-753493 dosing suggest a potential wider therapeutic window for BMS-753493. In summary, this study has clearly demonstrated that the epothilone folate conjugate, BMS-753493, enabled the preferentially distribution of the active epothilone to the folate receptor over-expressing 98M109 tumor. This preferential distribution supports targeted delivery of cytotoxics through the folate receptor and correlates well with in vivo antitumor activity observed in mouse xenograft models over-expressing folate receptors. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A131.