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  3. A navitoclax-loaded nanodevice targeting matrix metalloproteinase-3 for the selective elimination of senescent cells

A navitoclax-loaded nanodevice targeting matrix metalloproteinase-3 for the selective elimination of senescent cells

  • Acta Biomater. 2024 Jan 5:S1742-7061(24)00002-3. doi: 10.1016/j.actbio.2024.01.002.
Blanca Escriche-Navarro 1,  Eva Garrido 2,  Félix Sancenon 3,  Alba García-Fernández 4,  Ramón Martínez-Máñez 5
Affiliations

Affiliations

  • 1 Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM) Universitat Politècnica de València, Universitat de València. Camino de Vera, s/n. 46022, Valencia, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN); Unidad Mixta de Investigación en Nanomedicina y Sensores, Universitat Politècnica de València, IIS La Fe. Av. Fernando Abril Martorell, 106 Torre A 7ª planta. 46026, Valencia, Spain.
  • 2 Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM) Universitat Politècnica de València, Universitat de València. Camino de Vera, s/n. 46022, Valencia, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN).
  • 3 Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM) Universitat Politècnica de València, Universitat de València. Camino de Vera, s/n. 46022, Valencia, Spain; Unidad Mixta UPV-CIPF de Investigación en Mecanismos de Enfermedades y Nanomedicina, Universitat Politècnica de València, Centro de Investigación Príncipe Felipe, C/ Eduardo Primo Yúfera 3. 46012, Valencia, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN); Unidad Mixta de Investigación en Nanomedicina y Sensores, Universitat Politècnica de València, IIS La Fe. Av. Fernando Abril Martorell, 106 Torre A 7ª planta. 46026, Valencia, Spain.
  • 4 Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM) Universitat Politècnica de València, Universitat de València. Camino de Vera, s/n. 46022, Valencia, Spain; Unidad Mixta UPV-CIPF de Investigación en Mecanismos de Enfermedades y Nanomedicina, Universitat Politècnica de València, Centro de Investigación Príncipe Felipe, C/ Eduardo Primo Yúfera 3. 46012, Valencia, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN). Electronic address: algarfe4@etsia.upv.es.
  • 5 Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM) Universitat Politècnica de València, Universitat de València. Camino de Vera, s/n. 46022, Valencia, Spain; Unidad Mixta UPV-CIPF de Investigación en Mecanismos de Enfermedades y Nanomedicina, Universitat Politècnica de València, Centro de Investigación Príncipe Felipe, C/ Eduardo Primo Yúfera 3. 46012, Valencia, Spain; CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN); Unidad Mixta de Investigación en Nanomedicina y Sensores, Universitat Politècnica de València, IIS La Fe. Av. Fernando Abril Martorell, 106 Torre A 7ª planta. 46026, Valencia, Spain. Electronic address: rmaez@qim.upv.es.
PMID: 38185231 DOI: 10.1016/j.actbio.2024.01.002
Abstract

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 therapeutic 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 elimination 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. Moreover, 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. STATEMENT OF SIGNIFICANCE: The common β-galactosidase activity has been exploited to develop nanoparticles for the selective elimination of senescent cells. However, the identification of new senescent biomarkers is a key factor for the development of improved strategies. In this scenario, we report for the first time the development of NPs targeting senescent cells based on specific enzymatic activity of the senescent secretome. We report a navitoclax-loaded nanodevice responsive to the matrix metalloproteinase-3 (MMP-3) associated with the senescent phenotype. Our nanosystem achieves the selective release of navitoclax in an MMP-3-dependent manner while limiting off-target effects on non-senescent cells. This opens the possibility of using nanoparticles able to detect an altered senescent environment and selectively release its content, thus enhancing the efficacy of senolytic therapies.

Keywords

Matrix metalloproteinase-3; mesoporous silica nanoparticles; navitoclax; senescence.

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