Magkouta Sophia, Veroutis Dimitris, Papaspyropoulos Angelos, Georgiou Maria, Lougiakis Nikolaos, Pippa Natassa, Havaki Sophia, Palaiologou Anastasia, Thanos Dimitris-Foivos, Kambas Konstantinos, Lagopati Nefeli, Boukos Nikos, Pouli Nicole, Marakos Panagiotis, Kotsinas Athanassios, Thanos Dimitris, Evangelou Konstantinos, Sampaziotis Fotios, Tamvakopoulos Constantin, Pispas Stergios, Petty Russell, Kotopoulos Nicholas, Gorgoulis Vassilis G
Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Marianthi Simou and G.P. Livanos Labs, 1st Department of Critical Care and Pulmonary Services, School of Medicine, National & Kapodistrian University of Athens,'Evangelismos' Hospital, Athens, Greece.
Nat Aging. 2025 Jan;5(1):162-175. doi: 10.1038/s43587-024-00747-4. Epub 2024 Dec 27.
The emerging field of senolytics is centered on eliminating senescent cells to block their contribution to the progression of age-related diseases, including cancer, and to facilitate healthy aging. Enhancing the selectivity of senolytic treatments toward senescent cells stands to reduce the adverse effects associated with existing senolytic interventions. Taking advantage of lipofuscin accumulation in senescent cells, we describe here the development of a highly efficient senolytic platform consisting of a lipofuscin-binding domain scaffold, which can be conjugated with a senolytic drug via an ester bond. As a proof of concept, we present the generation of GL392, a senolytic compound that carries a dasatinib senolytic moiety. Encapsulation of the GL392 compound in a micelle nanocarrier (termed mGL392) allows for both in vitro and in vivo (in mice) selective elimination of senescent cells via targeted release of the senolytic agent with minimal systemic toxicity. Our findings suggest that this platform could be used to enhance targeting of senotherapeutics toward senescent cells.
衰老细胞溶解剂这一新兴领域的核心是清除衰老细胞，以阻止它们对包括癌症在内的与年龄相关疾病的进展产生影响，并促进健康衰老。提高衰老细胞溶解疗法对衰老细胞的选择性，有望减少与现有衰老细胞溶解干预措施相关的不良反应。利用衰老细胞中脂褐素的积累，我们在此描述了一种高效衰老细胞溶解平台的开发，该平台由一个脂褐素结合域支架组成，它可以通过酯键与一种衰老细胞溶解药物偶联。作为概念验证，我们展示了GL392的产生，这是一种携带达沙替尼衰老细胞溶解部分的衰老细胞溶解化合物。将GL392化合物封装在胶束纳米载体（称为mGL392）中，可通过衰老细胞溶解剂的靶向释放，在体外和体内（在小鼠中）选择性清除衰老细胞，且全身毒性最小。我们的研究结果表明，该平台可用于增强衰老治疗药物对衰老细胞的靶向作用。
