Pharmacokinetic and Biodistribution Studies of [F]-Taccalonolide: A Covalent Microtubule Stabilizer with Antitumor Efficacy.

The taccalonolides are plant-derived microtubule stabilizers that covalently and specifically bind β-tubulin and provide antitumor efficacy in drug-resistant tumor models both in vitro and in vivo. Herein, we report the radiolabeling, in vitro uptake, and in vivo imaging of a F radiolabeled taccalonolide to investigate in vivo biodistribution, including accumulation in TNBC tumors. Biochemical and cellular studies demonstrate that fluorination does not alter biological activity and supports target engagement of the radiolabeled compound. In vivo studies in athymic nude mice bearing TNBC xenografts and healthy control animals show the highest uptake in the gallbladder and intestines with modest uptake in tumors. Unmodified free drug was detected in the gall bladder and intestines, suggesting hepatic transport of the compound prior to metabolism or irreversible target engagement. These results provide a strong rationale for the generation of novel derivatives and formulations to improve serum half-life and tumor targeting of the taccalonolides to ultimately provide new options for drug-resistant TNBC tumors.