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Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity.
Aging Cell ( IF 8.0 ) Pub Date : 2020-03-31 , DOI: 10.1111/acel.13142 Estela González-Gualda 1 , Marta Pàez-Ribes 1 , Beatriz Lozano-Torres 2, 3, 4, 5 , David Macias 1 , Joseph R Wilson 1 , Cristina González-López 1 , Hui-Ling Ou 1 , Sofía Mirón-Barroso 1 , Zhenguang Zhang 1 , Araceli Lérida-Viso 5 , Juan F Blandez 2 , Andrea Bernardos 2, 3, 4, 6 , Félix Sancenón 2, 3, 4, 5 , Miguel Rovira 7 , Ljiljana Fruk 8 , Carla P Martins 9 , Manuel Serrano 7 , Gary J Doherty 10 , Ramón Martínez-Máñez 2, 3, 4, 5 , Daniel Muñoz-Espín 1
Aging Cell ( IF 8.0 ) Pub Date : 2020-03-31 , DOI: 10.1111/acel.13142 Estela González-Gualda 1 , Marta Pàez-Ribes 1 , Beatriz Lozano-Torres 2, 3, 4, 5 , David Macias 1 , Joseph R Wilson 1 , Cristina González-López 1 , Hui-Ling Ou 1 , Sofía Mirón-Barroso 1 , Zhenguang Zhang 1 , Araceli Lérida-Viso 5 , Juan F Blandez 2 , Andrea Bernardos 2, 3, 4, 6 , Félix Sancenón 2, 3, 4, 5 , Miguel Rovira 7 , Ljiljana Fruk 8 , Carla P Martins 9 , Manuel Serrano 7 , Gary J Doherty 10 , Ramón Martínez-Máñez 2, 3, 4, 5 , Daniel Muñoz-Espín 1
Affiliation
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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：
Navitoclax 的半乳结合是提高 senolytic 特异性并降低血小板毒性的有效策略。
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，衰老溶解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。我们之前已经证明，衰老细胞内发现的高水平的衰老相关溶酶体β-半乳糖苷酶（SA-β-gal）可用于从这些细胞内的半乳糖封装的纳米粒子中特异性释放示踪剂和细胞毒性货物。在这里，我们证明 BCL-2 家族抑制剂 Navitoclax 的半乳结合产生了一种有效的衰老前药 (Nav-Gal)，它可以在多种细胞类型中优先被 SA-β-gal 活性激活。 Nav-Gal 选择性诱导衰老细胞凋亡，并且具有比 Navitoclax 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 肺癌细胞的细胞毒性。体内顺铂和 Nav-Gal 联合治疗可根除衰老肺癌细胞并显着减少肿瘤生长。重要的是，半乳糖结合可减少纳维托克诱导的离体处理的人和小鼠血液样本中的血小板凋亡，以及在小鼠肺癌模型中治疗有效浓度下的血小板减少症。总而言之，我们提供了一种潜在的通用策略，用于生成具有降低毒性的有效的抗衰老前药。
更新日期：2020-03-31
中文翻译：
Navitoclax 的半乳结合是提高 senolytic 特异性并降低血小板毒性的有效策略。
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，衰老溶解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。我们之前已经证明，衰老细胞内发现的高水平的衰老相关溶酶体β-半乳糖苷酶（SA-β-gal）可用于从这些细胞内的半乳糖封装的纳米粒子中特异性释放示踪剂和细胞毒性货物。在这里，我们证明 BCL-2 家族抑制剂 Navitoclax 的半乳结合产生了一种有效的衰老前药 (Nav-Gal)，它可以在多种细胞类型中优先被 SA-β-gal 活性激活。 Nav-Gal 选择性诱导衰老细胞凋亡，并且具有比 Navitoclax 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 肺癌细胞的细胞毒性。体内顺铂和 Nav-Gal 联合治疗可根除衰老肺癌细胞并显着减少肿瘤生长。重要的是，半乳糖结合可减少纳维托克诱导的离体处理的人和小鼠血液样本中的血小板凋亡，以及在小鼠肺癌模型中治疗有效浓度下的血小板减少症。总而言之，我们提供了一种潜在的通用策略，用于生成具有降低毒性的有效的抗衰老前药。
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