A senolysis-based theragnostic prodrug strategy towards chronic renal failure
Yihe Song, Xinming Li, Donglei Shi, Tianyue Sun, Wenwen Liu, Xiaokang Li, Sicong Qiao, Xin Chen, Yuan Guo, Jian Li
Abstract
Selective elimination of senescent cells (senolysis) has become a promising therapeutic strategy for the management of chronic renal failure (CRF), but the senolytic molecular pathways towards CRF therapy are limited. Here, we present for the first time a senescence-associated β-galactosidase (SA-β-gal) activatable theragnostic prodrug strategy to pertinently and effectively treat CRF in mice with the aid of fluorescence-guided senolysis. The signs of premature senescence, including the overexpression of β-gal, have been found in kidneys of mice with CRF, making this enzyme particularly suitable as a trigger of prodrugs for CRF therapy. With this unique design, our pioneering prodrug TSPD achieved the activation of a fluorophore for tracking and the specific release of the parent drug, gemcitabine, in β-gal-enriched cells after activation with SA-β-gal. In mice with CRF, abdominal administration of TSPD was effective for improvement of the kidney functions, supporting the feasibility of the SA-β-gal-dependent senolysis therapy towards CRF.