ß-Galactosidase-Triggered Photodynamic Elimination of Senescent Cells with a Boron Dipyrromethene-Based Photosensitizer.
Por:
Chu JCH, Escriche-Navarro B, Xiong J, García-Fernández A, Martínez-Máñez R and Ng DKP
Publicada:
1 ago 2024
Ahead of Print:
1 jun 2024
Resumen:
Senescence is a cellular response having physiological and reparative functions to preserve tissue homeostasis and suppress tumor growth. However, the accumulation of senescent cells would cause deleterious effects that lead to age-related dysfunctions and cancer progression. Hence, selective detection and elimination of senescent cells are crucial yet remain a challenge. A ß-galactosidase (ß-gal)-activated boron dipyrromethene (BODIPY)-based photosensitizer (compound 1) is reported here that can selectively detect and eradicate senescent cells. It contains a galactose moiety connected to a pyridinium BODIPY via a self-immolative nitrophenylene linker, of which the photoactivity is effectively quenched. Upon interactions with the senescence-associated ß-gal, it undergoes enzymatic hydrolysis followed by self-immolation, leading to the release of an activated BODIPY moiety by which the fluorescence emission and singlet oxygen generation are restored. The ability of 1 to detect and eliminate senescent cells is demonstrated in vitro and in vivo, using SK-Mel-103 tumor-bearing mice treated with senescence-inducing therapy. The results demonstrate that 1 can be selectively activated in senescent cells to trigger a robust senolytic effect upon irradiation. This study breaks new ground in the design and application of new senolytic agents based on photodynamic therapy.
Filiaciones:
Chu JCH:
Department of Chemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
Escriche-Navarro B:
Instituto Interuniversitario de Investigación de Reconocimiento, Molecular y Desarrollo Tecnológico, Universitat Politècnica de València, Universitat de València, Valencia, 46022, Spain
Unidad Mixta de Investigación en Nanomedicina y Sensores, Universitat Politècnica e València, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, 46026, Spain
Unidad Mixta UPV-CIPF de Investigación en Mecanismos de Enfermedades y Nanomedicina, Universitat Politècnica de València, Centro de Investigación Príncipe Felipe, Valencia, 46012, Spain
CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III, Madrid, 28029, Spain
Xiong J:
Department of Chemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
Department of Pharmacy, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, Shenzhen, 518001, China
:
Instituto Interuniversitario de Investigación de Reconocimiento, Molecular y Desarrollo Tecnológico, Universitat Politècnica de València, Universitat de València, Valencia, 46022, Spain
Unidad Mixta UPV-CIPF de Investigación en Mecanismos de Enfermedades y Nanomedicina, Universitat Politècnica de València, Centro de Investigación Príncipe Felipe, Valencia, 46012, Spain
CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III, Madrid, 28029, Spain
:
Instituto Interuniversitario de Investigación de Reconocimiento, Molecular y Desarrollo Tecnológico, Universitat Politècnica de València, Universitat de València, Valencia, 46022, Spain
Unidad Mixta de Investigación en Nanomedicina y Sensores, Universitat Politècnica e València, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, 46026, Spain
Unidad Mixta UPV-CIPF de Investigación en Mecanismos de Enfermedades y Nanomedicina, Universitat Politècnica de València, Centro de Investigación Príncipe Felipe, Valencia, 46012, Spain
CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Instituto de Salud Carlos III, Madrid, 28029, Spain
Ng DKP:
Department of Chemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
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