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A senolysis-based theragnostic prodrug strategy towards chronic renal failure
Yihe Song1, Xinming Li1, Donglei Shi1,2
1State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology Shanghai 200237 China jianli@ecust.edu.cn.
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.
Insights
This study introduces a novel theragnostic prodrug that targets senescent cells in chronic renal failure (CRF). The prodrug, activated by senescence-associated β-galactosidase (SA-β-gal), improves kidney function in mice, offering a new senolysis strategy for CRF.
Area of Science:
- Biomedical Engineering
- Pharmacology
- Gerontology
Background:
- Chronic renal failure (CRF) is associated with premature cellular senescence.
- Existing senolytic therapies for CRF have limited molecular pathways.
- Senescence-associated β-galactosidase (SA-β-gal) is overexpressed in CRF kidneys, presenting a therapeutic target.
Purpose of the Study:
- To develop and evaluate a novel SA-β-gal activatable theragnostic prodrug for CRF treatment.
- To utilize fluorescence-guided senolysis for targeted elimination of senescent cells in CRF.
- To assess the therapeutic efficacy of the prodrug in improving kidney function in a mouse model of CRF.
Main Methods:
- Design of a theragnostic prodrug (TSPD) activated by SA-β-gal.
- In vivo administration of TSPD in a mouse model of CRF.
- Monitoring of prodrug activation, drug release, and kidney function via fluorescence imaging and biochemical assays.
Main Results:
- The prodrug TSPD successfully activated a fluorophore for tracking and released gemcitabine specifically in SA-β-gal-enriched senescent cells.
- Abdominal administration of TSPD led to significant improvement in kidney function in mice with CRF.
- Demonstrated feasibility of SA-β-gal-dependent senolysis for CRF therapy.
Conclusions:
- A novel SA-β-gal activatable theragnostic prodrug strategy offers a promising approach for CRF management.
- Fluorescence-guided senolysis via TSPD effectively targets and eliminates senescent cells, improving renal function.
- This pioneering approach supports the potential of enzyme-activated senolysis in treating chronic renal failure.
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