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Theranostics 2023; 13(15):5435-5451. doi:10.7150/thno.86310 This issue Cite

Research Paper

Inhalation of acidic nanoparticles prevents doxorubicin cardiotoxicity through improvement of lysosomal function

Yohan Santin1, Karina Formoso1, Fraha Haidar1, Maria Del Pilar Oreja Fuentes1, Florence Bourgailh2, Nesrine Hifdi1, Karim Hnia1, Yosra Doghri1, Jessica Resta1, Camille Champigny1, Séverine Lechevallier3, Maximin Détrait1, Grégoire Cousin1,4, Malik Bisserier5, Angelo Parini1, Frank Lezoualc'h1, Marc Verelst3, Jeanne Mialet-Perez1,§,✉

1. Institute of Metabolic and Cardiovascular Diseases (I2MC), Université de Toulouse, INSERM, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
2. Center for Electron Microscopy Applied to Biology (CMEAB), Université de Toulouse, Faculté de Médecine, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
3. Center for Materials Development and Structural Studies (CEMES), Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UPS), Toulouse, France.
4. Department of Cardiology, Rangueil University Hospital, Toulouse, France.
5. New York Medical College, New York, Department of Cell Biology and Anatomy, and of Physiology, Valhalla, New York, United States.
§ Current address: Univ Angers, MitoLab, Unité Mitovasc, CNRS 6015, INSERM U1083, SFR ICAT, Angers, France.

✉ Corresponding author: Jeanne Mialet-Perez, PhD. Email: jeanne.perezfr.

Citation:
Santin Y, Formoso K, Haidar F, Fuentes MDPO, 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. Inhalation of acidic nanoparticles prevents doxorubicin cardiotoxicity through improvement of lysosomal function. Theranostics 2023; 13(15):5435-5451. doi:10.7150/thno.86310. https://www.thno.org/v13p5435.htm
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Abstract

Graphic 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: doxorubicin, lysosomes, nanoparticles, cardiotoxicity, autophagy

Citation styles

APA
Santin, Y., Formoso, K., Haidar, F., Fuentes, M.D.P.O., 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.

ACS
Santin, Y.; Formoso, K.; Haidar, F.; Fuentes, M.D.P.O.; 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. Inhalation of acidic nanoparticles prevents doxorubicin cardiotoxicity through improvement of lysosomal function. Theranostics 2023, 13 (15), 5435-5451. DOI: 10.7150/thno.86310.

NLM
Santin Y, Formoso K, Haidar F, Fuentes MDPO, 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. Inhalation of acidic nanoparticles prevents doxorubicin cardiotoxicity through improvement of lysosomal function. Theranostics 2023; 13(15):5435-5451. doi:10.7150/thno.86310. https://www.thno.org/v13p5435.htm

CSE
Santin Y, Formoso K, Haidar F, Fuentes MDPO, 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.

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