Design and Evaluation of Autophagy-Inducing Particles for the Treatment of Abnormal Lipid Accumulation
Autophagy is a fundamental housekeeping process by which cells degrade their components to maintain homeostasis. Defects in autophagy have been associated with aging, neurodegeneration and metabolic diseases. Non-alcoholic fatty liver diseases (NAFLDs) are characterized by hepatic fat accumulation w...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-06-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/7/1379 |
| _version_ | 1797444397697073152 |
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| author | Stavroula Zagkou Valentine Marais Narimane Zeghoudi Edouard Le Guillou Eeva-Liisa Eskelinen Ganna Panasyuk Bernard Verrier Charlotte Primard |
| author_facet | Stavroula Zagkou Valentine Marais Narimane Zeghoudi Edouard Le Guillou Eeva-Liisa Eskelinen Ganna Panasyuk Bernard Verrier Charlotte Primard |
| author_sort | Stavroula Zagkou |
| collection | DOAJ |
| description | Autophagy is a fundamental housekeeping process by which cells degrade their components to maintain homeostasis. Defects in autophagy have been associated with aging, neurodegeneration and metabolic diseases. Non-alcoholic fatty liver diseases (NAFLDs) are characterized by hepatic fat accumulation with or without inflammation. No treatment for NAFLDs is currently available, but autophagy induction has been proposed as a promising therapeutic strategy. Here, we aimed to design autophagy-inducing particles, using the autophagy-inducing peptide (Tat-Beclin), and achieve liver targeting in vivo, taking NAFLD as a model disease. Polylactic acid (PLA) particles were prepared by nanoprecipitation without any surfactant, followed by surface peptide adsorption. The ability of Tat-Beclin nanoparticles (NP T-B) to modulate autophagy and to decrease intracellular lipid was evaluated in vitro by LC3 immunoblot and using a cellular model of steatosis, respectively. The intracellular localization of particles was evaluated by transmission electron microscopy (TEM). Finally, biodistribution of fluorescent NP T-B was evaluated in vivo using tomography in normal and obese mice. The results showed that NP T-B induce autophagy with a long-lasting and enhanced effect compared to the soluble peptide, and at a ten times lower dose. Intracellular lipid also decreased in a cellular model of NAFLD after treatment with T-B and NP T-B under the same dose conditions. Ultrastructural studies revealed that NP T-B are internalized and located in endosomal, endolysosomal and autolysosomal compartments, while in healthy and obese mice, NP T-B could accumulate for several days in the liver. Given the beneficial effects of autophagy-inducing particles in vitro, and their capacity to target the liver of normal and obese mice, NP T-B could be a promising therapeutic tool for NAFLDs, warranting further in vivo investigation. |
| first_indexed | 2024-03-09T13:12:03Z |
| format | Article |
| id | doaj.art-e4c8754bd500484093a93e1db5bf3379 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T13:12:03Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-e4c8754bd500484093a93e1db5bf33792023-11-30T21:41:31ZengMDPI AGPharmaceutics1999-49232022-06-01147137910.3390/pharmaceutics14071379Design and Evaluation of Autophagy-Inducing Particles for the Treatment of Abnormal Lipid AccumulationStavroula Zagkou0Valentine Marais1Narimane Zeghoudi2Edouard Le Guillou3Eeva-Liisa Eskelinen4Ganna Panasyuk5Bernard Verrier6Charlotte Primard7Adjuvatis, 60 Avenue Rockefeller, 69008 Lyon, FranceAdjuvatis, 60 Avenue Rockefeller, 69008 Lyon, FranceAdjuvatis, 60 Avenue Rockefeller, 69008 Lyon, FranceINSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Université Paris Cité, 75015 Paris, FranceInstitute of Biomedicine, University of Turku, 20520 Turku, FinlandINSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Université Paris Cité, 75015 Paris, FranceAdjuvatis, 60 Avenue Rockefeller, 69008 Lyon, FranceAdjuvatis, 60 Avenue Rockefeller, 69008 Lyon, FranceAutophagy is a fundamental housekeeping process by which cells degrade their components to maintain homeostasis. Defects in autophagy have been associated with aging, neurodegeneration and metabolic diseases. Non-alcoholic fatty liver diseases (NAFLDs) are characterized by hepatic fat accumulation with or without inflammation. No treatment for NAFLDs is currently available, but autophagy induction has been proposed as a promising therapeutic strategy. Here, we aimed to design autophagy-inducing particles, using the autophagy-inducing peptide (Tat-Beclin), and achieve liver targeting in vivo, taking NAFLD as a model disease. Polylactic acid (PLA) particles were prepared by nanoprecipitation without any surfactant, followed by surface peptide adsorption. The ability of Tat-Beclin nanoparticles (NP T-B) to modulate autophagy and to decrease intracellular lipid was evaluated in vitro by LC3 immunoblot and using a cellular model of steatosis, respectively. The intracellular localization of particles was evaluated by transmission electron microscopy (TEM). Finally, biodistribution of fluorescent NP T-B was evaluated in vivo using tomography in normal and obese mice. The results showed that NP T-B induce autophagy with a long-lasting and enhanced effect compared to the soluble peptide, and at a ten times lower dose. Intracellular lipid also decreased in a cellular model of NAFLD after treatment with T-B and NP T-B under the same dose conditions. Ultrastructural studies revealed that NP T-B are internalized and located in endosomal, endolysosomal and autolysosomal compartments, while in healthy and obese mice, NP T-B could accumulate for several days in the liver. Given the beneficial effects of autophagy-inducing particles in vitro, and their capacity to target the liver of normal and obese mice, NP T-B could be a promising therapeutic tool for NAFLDs, warranting further in vivo investigation.https://www.mdpi.com/1999-4923/14/7/1379autophagypolylactic acidpolymeric nanoparticlesliver targetingTat-Beclin peptidenon-alcoholic fatty liver disease |
| spellingShingle | Stavroula Zagkou Valentine Marais Narimane Zeghoudi Edouard Le Guillou Eeva-Liisa Eskelinen Ganna Panasyuk Bernard Verrier Charlotte Primard Design and Evaluation of Autophagy-Inducing Particles for the Treatment of Abnormal Lipid Accumulation Pharmaceutics autophagy polylactic acid polymeric nanoparticles liver targeting Tat-Beclin peptide non-alcoholic fatty liver disease |
| title | Design and Evaluation of Autophagy-Inducing Particles for the Treatment of Abnormal Lipid Accumulation |
| title_full | Design and Evaluation of Autophagy-Inducing Particles for the Treatment of Abnormal Lipid Accumulation |
| title_fullStr | Design and Evaluation of Autophagy-Inducing Particles for the Treatment of Abnormal Lipid Accumulation |
| title_full_unstemmed | Design and Evaluation of Autophagy-Inducing Particles for the Treatment of Abnormal Lipid Accumulation |
| title_short | Design and Evaluation of Autophagy-Inducing Particles for the Treatment of Abnormal Lipid Accumulation |
| title_sort | design and evaluation of autophagy inducing particles for the treatment of abnormal lipid accumulation |
| topic | autophagy polylactic acid polymeric nanoparticles liver targeting Tat-Beclin peptide non-alcoholic fatty liver disease |
| url | https://www.mdpi.com/1999-4923/14/7/1379 |
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