Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity
Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity
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DOI：
10.1111/acel.13142
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发表时间：
2020-03-31
期刊：
影响因子：
7.8
通讯作者：
Munoz-Espin, Daniel
中科院分区：
文献类型：
--
作者：
Gonzalez-Gualda, Estela;Paez-Ribes, Marta;Munoz-Espin, Daniel
对衰老细胞具有优先细胞毒活性的药理活性化合物，称为增龄剂，可以改善甚至逆转包括癌症模型在内的许多临床前小鼠疾病模型的衰老病理表现。然而，由于对衰老细胞的特异性不佳，以及重要的毒性缩小了治疗窗口，使衰老治疗方法转化为人类疾病受到阻碍。我们先前已经证明，在衰老细胞中发现的高水平的衰老相关溶酶体β-半乳糖苷酶(SA-β-GAL)可以被利用来从这些细胞内包裹的半乳糖纳米颗粒中特异性地释放示踪剂和细胞毒性物质。在这里，我们证明了bcl2家族抑制剂Navitoclax的半乳糖偶联导致了一种有效的促衰老前药(Nav-Gal)，它可以在广泛的细胞类型中优先被SA-β-Gal活性激活。NAV-Gal选择性地诱导衰老细胞的凋亡，并且比Navitoclax具有更高的衰老指数(通过减少非衰老细胞的激活)。NAV-Gal增强标准衰老诱导化疗(顺铂)对人A549肺癌细胞的细胞毒作用。顺铂和Nav-Gal同时在体内治疗可以根除衰老的肺癌细胞，并显著减少肿瘤的生长。重要的是，在体外治疗的人和小鼠血液样本中，半乳糖偶联物减少了由奈维他克诱导的血小板凋亡，并在治疗有效浓度的小鼠肺癌模型中减少了血小板减少。综上所述，我们提供了一种潜在的通用策略，用于生产毒性较低的有效的感觉神经前体药物。
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 beta-galactosidase (SA-beta-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-beta-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.