Synthesis and biological evaluations of a monomethylauristatin E glucuronide prodrug for selective cancer chemotherapy.
Legigan T, Clarhaut J, Renoux B, Tranoy-Opalinski I, Monvoisin A, Jayle C, Alsarraf J, Thomas M, Papot S.
We developed a glucuronide prodrug of the potent monomethylauristatin E (MMAE). This prodrug is significantly less toxic than the parent drug. However, in the presence of β-glucuronidase the prodrug leads to the efficient release of MMAE thereby triggering a subnanomolar cytotoxic activity against several cancer cell lines. Preliminary in vivo experiments conducted in C57BL/6 mice bearing a subcutaneous murine Lewis Lung Carcinoma (LLC) demonstrated the potential of this targeting system for the selective treatment of solid tumors.