Inhalation of Acidic Nanoparticles Prevents Doxorubicin Cardiotoxicity Through Improvement of Lysosomal Function

Authors

Yohan Santin, Institute of Metabolic and Cardiovascular Diseases (I2MC), Université de Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Karina Formoso, Institute of Metabolic and Cardiovascular Diseases (I2MC), Université de Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Fraha Haidar, Institute of Metabolic and Cardiovascular Diseases (I2MC), Université de Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Maria Del Fuentes, Institute of Metabolic and Cardiovascular Diseases (I2MC), Université de Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Florence Bourgailh, Center for Electron Microscopy Applied to Biology (CMEAB), Université de Toulouse, Faculté de Médecine, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Nesrine Hifdi, Institute of Metabolic and Cardiovascular Diseases (I2MC), Université de Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Karim Hnia, Institute of Metabolic and Cardiovascular Diseases (I2MC), Université de Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Yosra Doghri, Institute of Metabolic and Cardiovascular Diseases (I2MC), Université de Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Jessica Resta, Institute of Metabolic and Cardiovascular Diseases (I2MC), Université de Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Camille Champigny, Institute of Metabolic and Cardiovascular Diseases (I2MC), Université de Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Séverine Lechevallier, Center for Materials Development and Structural Studies (CEMES), Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Maximin Détrait, Institute of Metabolic and Cardiovascular Diseases (I2MC), Université de Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Grégoire Cousin, Institute of Metabolic and Cardiovascular Diseases (I2MC), Université de Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Malik Bisserier, New York Medical College, New York, Department of Cell Biology and Anatomy, and of Physiology, Valhalla, New York, United States.
Angelo Parini, Institute of Metabolic and Cardiovascular Diseases (I2MC), Université de Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Frank Lezoualc'h, Institute of Metabolic and Cardiovascular Diseases (I2MC), Université de Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Marc Verelst, Center for Materials Development and Structural Studies (CEMES), Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
Jeanne Mialet-Perez, Institute of Metabolic and Cardiovascular Diseases (I2MC), Université de Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.

Author Type(s)

Faculty

Journal Title

Theranostics

First Page

5435

Last Page

5451

Document Type

Article

Publication Date

1-1-2023

Department

Cell Biology and Anatomy

Abstract

Doxorubicin (Dox) is an effective anticancer molecule, but its clinical efficacy is limited by strong cardiotoxic side effects. Lysosomal dysfunction has recently been proposed as a new mechanism of Dox-induced cardiomyopathy. However, to date, there is a paucity of therapeutic approaches capable of restoring lysosomal acidification and function in the heart. We designed novel poly(lactic-co-glycolic acid) (PLGA)-grafted silica nanoparticles (NPs) and investigated their therapeutic potential in the primary prevention of Dox cardiotoxicity in cardiomyocytes and mice. We showed that NPs-PLGA internalized rapidly in cardiomyocytes and accumulated inside the lysosomes. Mechanistically, NPs-PLGA restored lysosomal acidification in the presence of doxorubicin or bafilomycin A1, thereby improving lysosomal function and autophagic flux. Importantly, NPs-PLGA mitigated Dox-related mitochondrial dysfunction and oxidative stress, two main mechanisms of cardiotoxicity. In vivo, inhalation of NPs-PLGA led to effective and rapid targeting of the myocardium, which prevented Dox-induced adverse remodeling and cardiac dysfunction in mice. Our findings demonstrate a pivotal role for lysosomal dysfunction in Dox-induced cardiomyopathy and highlight for the first time that pulmonary-driven NPs-PLGA administration is a promising strategy against anthracycline cardiotoxicity.

Recommended Citation

Santin, Y., Formoso, K., Haidar, F., Fuentes, M. D., Bourgailh, F., Hifdi, N., Hnia, K., Doghri, Y., Resta, J., Champigny, C., Lechevallier, S., Détrait, M., Cousin, G., Bisserier, M., Parini, A., Lezoualc'h, F., Verelst, M., & Mialet-Perez, J. (2023). Inhalation of Acidic Nanoparticles Prevents Doxorubicin Cardiotoxicity Through Improvement of Lysosomal Function. Theranostics, 13 (15), 5435-5451. https://doi.org/10.7150/thno.86310