Surface Engineering Promoted Insulin‐Sensitizing Activities of Sub‐Nanoscale Vanadate Clusters through Regulated Pharmacokinetics and Bioavailability

Abstract The therapeutic application of vanadium compounds is plagued by their poor bioavailability and potential adverse effects. Herein, 1 nm polyoxovanadate (POV) clusters are functionalized with alkyl chains of various lengths and studied for the effect of surface engineering on their preclinical pharmacokinetics and typical insulin‐sensitizing activity. The concentrations of surface engineered POVs in plasma, urine, and feces are monitored after a single administration to rats. The POVs exhibit a two‐compartment profile of in vivo kinetics, and the surface engineering effect plays an important role in renal clearance of the POVs comparable to small molecules. POVs functionalized with long alkyl chains show much shorter elimination half timet_1/2βand higher elimination fractions (50%) within 48 h than pristine POVs, suggesting favorable elimination kinetics to mitigate the possible side effects of vanadium. Meanwhile, long alkyl chain modification leads to a 76% increment of oral bioavailability in contrast to unmodified POVs. As suggested by glucose tolerance tests and sub‐chronic toxicity tests, the above two factors contribute to the enhanced therapeutic efficacy of POVs while mitigating their adverse effects. The surface engineering protocol provides a feasible approach to the optimization of the bioavailability and pharmacokinetic properties of POVs for promoted insulin‐sensitizing activities.