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Harnessing Lysosomal pH through PLGA Nanoemulsion as a Treatment of Lysosomal-Related Neurodegenerative Diseases

Abstract : Most neurodegenerative disorders are characterized by deposits of misfolded proteins and neuronal degeneration in specific brain regions. Growing evidence indicates that lysosomal impairment plays a primary pathogenic role in these diseases, in particular, the occurrence of increased lysosomal pH. Thus, therapeutic development aiming at restoring lysosomal function represents a novel, precise, and promising strategy for the treatment of these pathologies. Herein we demonstrate that acidic oil-in-water nanoemulsions loaded with poly(dl-lactide- co-glycolide) (PLGA) are able to rescue impaired lysosomal pH in genetic cellular models of Parkinson's disease. For in vivo assays, nanoemulsions were labeled with an original synthetic hydrophobic far red-emitting dye to allow fluorescence monitoring. Following stereotaxic injection in the mouse brain, widespread diffusion of the nanocarrier was observed, up to 500 μm from the injection site, as well as internalization into the lysosomal compartment in brain cells. Finally, promising preliminary assays of systemic administration demonstrate that a fraction of the formulation crosses the blood brain barrier, penetrates the brain parenchyma, is internalized by cells, and colocalizes with lysosomal markers. Overall, these results suggest the feasibility and the therapeutic potential of this new nanoformulation as an effective drug delivery tool to the brain, with the potential to rescue pathological lysosomal deficits.
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Contributor : Benjamin Dehay Connect in order to contact the contributor
Submitted on : Sunday, March 28, 2021 - 10:43:51 AM
Last modification on : Tuesday, January 4, 2022 - 3:45:11 AM
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Geoffrey Prévot, Federico Soria, Marie-Laure Thiolat, Jonathan Daniel, Jean Baptiste Verlhac, et al.. Harnessing Lysosomal pH through PLGA Nanoemulsion as a Treatment of Lysosomal-Related Neurodegenerative Diseases. Bioconjugate Chemistry, American Chemical Society, 2018, 29 (12), pp.4083-4089. ⟨10.1021/acs.bioconjchem.8b00697⟩. ⟨inserm-02439494⟩



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