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

Geoffrey Prévot, Federico N. Soria, Marie Laure Thiolat, Jonathan Daniel, Jean Baptiste Verlhac, Mireille Blanchard-Desce, Erwan Bezard, Philippe Barthélémy, Sylvie Crauste-Manciet, Benjamin Dehay

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish
Pages (from-to)4083-4089
Number of pages7
JournalBioconjugate Chemistry
Volume29
Issue number12
DOIs
StatePublished - 19 Dec 2018
Externally publishedYes

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