A senolysis-based theragnostic prodrug strategy towards chronic renal failure,Chemical Science

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A senolysis-based theragnostic prodrug strategy towards chronic renal failure
Chemical Science ( IF 7.6 ) Pub Date : 2022-09-26 , DOI: 10.1039/d2sc03525a
Yihe Song ₁ , Xinming Li ₁ , Donglei Shi _{1,

2} , Tianyue Sun ₁ , Wenwen Liu ₃ , Xiaokang Li ₁ , Sicong Qiao ₁ , Xin Chen ₁ , Yuan Guo ₂ , Jian Li _{1,

3,

4,

5}

Affiliation

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.

中文翻译：

一种针对慢性肾功能衰竭的基于衰老溶解的治疗前药策略

选择性消除衰老细胞 (senolysis) 已成为治疗慢性肾功能衰竭 (CRF) 的一种有前途的治疗策略，但用于 CRF 治疗的衰老细胞分子途径有限。在这里，我们首次提出了一种与衰老相关的 β-半乳糖苷酶 (SA-β-gal) 可激活的治疗前药策略，以借助荧光引导的衰老来有效地治疗小鼠 CRF。在患有 CRF 的小鼠的肾脏中发现了过早衰老的迹象，包括 β-gal 的过度表达，这使得这种酶特别适合作为 CRF 治疗前药的触发剂。凭借这种独特的设计，我们开创性的前药TSPD在用 SA-β-gal 激活后，在富含 β-gal 的细胞中实现了用于跟踪的荧光团的激活和母体药物吉西他滨的特异性释放。在患有 CRF 的小鼠中，腹部给药TSPD可有效改善肾功能，支持 SA-β-gal 依赖性衰老治疗对 CRF 的可行性。

更新日期：2022-09-26

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