Refereed journal article or data article (A1)

Design and Evaluation of Autophagy-Inducing Particles for the Treatment of Abnormal Lipid Accumulation




List of Authors: Zagkou Stavroula, Marais Valentine, Zeghoudi Narimane, Guillou Edouard Le, Eskelinen EL, Panasyuk Ganna, Verrier Bernard, Primard Charlotte

Publisher: MDPI

Publication year: 2022

Journal: Pharmaceutics

Journal name in source: Pharmaceutics

Journal acronym: Pharmaceutics

Volume number: 14

Issue number: 7

ISSN: 1999-4923

DOI: http://dx.doi.org/10.3390/pharmaceutics14071379

Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/175896553


Abstract
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.

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Last updated on 2022-29-08 at 11:00