Pharmacologically active compounds with preferential cytotoxic activity for senescent cells, known as senolytics, can ameliorate or even revert pathological manifestations of senescence in numerous preclinical mouse disease models, including cancer models. However, translation of senolytic therapies to human disease is hampered by their suboptimal specificity for senescent cells and important toxicities that narrow their therapeutic windows. We have previously shown that the high levels of senescence‐associated lysosomal β‐galactosidase (SA‐β‐gal) found within senescent cells can be exploited to specifically release tracers and cytotoxic cargoes from galactose‐encapsulated nanoparticles within these cells. Here, we show that galacto‐conjugation of the BCL‐2 family inhibitor Navitoclax results in a potent senolytic prodrug (Nav‐Gal), that can be preferentially activated by SA‐β‐gal activity in a wide range of cell types. Nav‐Gal selectively induces senescent cell apoptosis and has a higher senolytic index than Navitoclax (through reduced activation in nonsenescent cells). Nav‐Gal enhances the cytotoxicity of standard senescence‐inducing chemotherapy (cisplatin) in human A549 lung cancer cells. Concomitant treatment with cisplatin and Nav‐Gal in vivo results in the eradication of senescent lung cancer cells and significantly reduces tumour growth. Importantly, galacto‐conjugation reduces Navitoclax‐induced platelet apoptosis in human and murine blood samples treated ex vivo, and thrombocytopenia at therapeutically effective concentrations in murine lung cancer models. Taken together, we provide a potentially versatile strategy for generating effective senolytic prodrugs with reduced toxicities.

中文翻译：

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Navitoclax 的半乳糖结合作为一种有效的策略来增加抗衰老特异性和降低血小板毒性。

对衰老细胞具有优先细胞毒活性的药理活性化合物（称为 senolytics）可以改善甚至逆转许多临床前小鼠疾病模型（包括癌症模型）中衰老的病理表现。然而，senolytic 疗法对人类疾病的转化受到其对衰老细胞的次优特异性和缩小其治疗窗口的重要毒性的阻碍。我们之前已经表明，在衰老细胞中发现的高水平与衰老相关的溶酶体 β-半乳糖苷酶 (SA-β-gal) 可用于从这些细胞内的半乳糖包裹的纳米颗粒中特异性释放示踪剂和细胞毒性物质。在这里，我们表明 BCL-2 家族抑制剂 Navitoclax 的半乳糖共轭产生了一种有效的抗衰老前药 (Nav-Gal)，SA-β-gal 活性可在多种细胞类型中优先激活。Nav-Gal 选择性地诱导衰老细胞凋亡，并且比 Navitoclax 具有更高的衰老指数（通过减少非衰老细胞的活化）。Nav-Gal 增强标准衰老诱导化疗（顺铂）对人 A549 肺癌细胞的细胞毒性。在体内同时使用顺铂和 Nav-Gal 治疗可消灭衰老的肺癌细胞并显着降低肿瘤生长。重要的是，半乳糖结合可减少离体处理的人和小鼠血液样本中 Navitoclax 诱导的血小板凋亡，以及小鼠肺癌模型中治疗有效浓度的血小板减少症。综合起来，