[Epub ahead of


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
Bioconjugate Chem.. 2018-11-13; 29(12): 4083-4089
DOI: 10.1021/acs.bioconjchem.8b00697

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

Prévot G(1), Soria FN(2)(3), Thiolat ML(2)(3), Daniel J(4), Verlhac JB(4),
Blanchard-Desce M(4), Bezard E(2)(3), Barthélémy P(1), Crauste-Manciet S(1),
Dehay B(2)(3).

Author information:
(1)Université de Bordeaux, INSERM, U1212, CNRS UMR 5320, ARNA, ARN: Régulations
Naturelle et Artificielle, ChemBioPharm, F-33000 Bordeaux , France.
(2)Université de Bordeaux , Institut des Maladies Neurodégénératives, UMR 5293 ,
F-33076 Bordeaux , France.
(3)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33076 Bordeaux ,
(4)Université de Bordeaux , Institut des Sciences Moléculaires (CNRS UMR 5255) ,
F-33400 Talence , France.

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.

DOI: 10.1021/acs.bioconjchem.8b00697
PMID: 30424597

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