Employing the intravesical delivery route to target on the kidney

ABSTRACT Background and Objective There is an unmet demand for kidney-targeted non-invasive drug-delivery systems to enhance the therapeutic index and at the same time reduce extrarenal side effects. Here, we performed a proof-of-concept study to evaluate the validity and efficacy of intravesical delivery for kidney targeting in mice. Methods Probes with a wide range of molecular sizes were tested for their efficiency to reach the kidney via intravesical delivery in female mice. The therapeutic efficacy and side effects of pazopanib in treating a renal adenocarcinoma were compared between delivery via intravesical route vs. intraperitoneal route. Intravesical delivery of empagliflozin was tested for its action on the proximal tubules. Finally, intrapelvic infusion was examined as another retrograde route for targeting the kidney. Key findings and limitations Intravesical infusion was valid for a retrograde delivery of molecules up to 500 kDa to the kidney. Empagliflozin, an antagonist of sodium-glucose cotransporter 2 (SGLT2), could efficiently act on the proximal tubules via the intravesical route, and had an action on glucose excretion. In an orthotopic kidney carcinoma model, intravesical delivery of pazopanib was more efficacious in limiting tumor growth, accompanied with much milder adverse effects on extrarenal organs, compared to a systemic delivery when a same dose was administered. This was due to a higher intrarenal drug concentration achieved and a markedly lower level of drug leaked to the blood via intravesical delivery. Conclusions and Clinical Implications The intravesical delivery route has a great potential to benefit kidney therapeutics and research.