A navitoclax-loaded nanodevice targeting matrix metalloproteinase-3 for the selective elimination of senescent cells
[EN] Cellular senescence is implicated in the occurrence and progression of multiple age-related disorders. In this context, the selective elimination of senescent cells, senolysis, has emerged as an effective therapeu- tic strategy. However, the heterogeneous senescent phenotype hinders the discove...
| Autores: | , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universitat Politècnica de València (UPV) |
| Repositorio: | RiuNet. Repositorio Institucional de la Universitat Politécnica de Valéncia |
| Idioma: | inglés |
| OAI Identifier: | oai:riunet.upv.es:10251/214710 |
| Acceso en línea: | https://riunet.upv.es/handle/10251/214710 |
| Access Level: | acceso abierto |
| Palabra clave: | Matrix metalloproteinase-3 Mesoporous silica nanoparticles Senescence Navitoclax QUIMICA ORGANICA QUIMICA INORGANICA |
| Sumario: | [EN] Cellular senescence is implicated in the occurrence and progression of multiple age-related disorders. In this context, the selective elimination of senescent cells, senolysis, has emerged as an effective therapeu- tic strategy. However, the heterogeneous senescent phenotype hinders the discovery of a universal and robust senescence biomarker that limits the effective of senolytic with off-target toxic effects. Therefore, the development of more selective strategies represents a promising approach to increase the specificity of senolytic therapy. In this study, we have developed an innovative nanodevice for the selective elimi- nation of senescent cells (SCs) based on the specific enzymatic activity of the senescent secretome. The results revealed that when senescence is induced in proliferating WI-38 by ionizing radiation (IR), the cells secrete high levels of matrix metalloproteinase-3 (MMP-3). Based on this result, mesoporous silica nanoparticles (MSNs) were loaded with the senolytic navitoclax (Nav) and coated with a specific peptide which is substrate of MMP-3 (NPs(Nav)@MMP-3). Studies in cells confirmed the preferential release of cargo in IR-induced senescent cells compared to proliferating cells, depending on MMP-3 levels. More- over, treatment with NPs(Nav)@MMP-3 induced a selective decrease in the viability of SCs as well as a protective effect on non-proliferating cells. These results demonstrate the potential use of NPs to develop enhanced senolytic therapies based on specific enzymatic activity in the senescent microenvironment, with potential clinical relevance. |
|---|