Lipid Nanoparticles Vectorized with NFL-TBS.40-63 Peptide Target Oligodendrocytes and Promote Neurotrophin-3 Effects Aft
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ORIGINAL PAPER
Lipid Nanoparticles Vectorized with NFL‑TBS.40‑63 Peptide Target Oligodendrocytes and Promote Neurotrophin‑3 Effects After Demyelination In Vitro Catherine Fressinaud1,2 · Olivier Thomas2 · Anita Monika Umerska2 · Patrick Saulnier2 Received: 27 November 2019 / Revised: 1 August 2020 / Accepted: 30 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Promoting remyelination in multiple sclerosis is important to prevent axon degeneration, given the lack of curative treatment. Although some growth factors improve this repair, unspecific delivery to cells and potential side effects limit their therapeutic use. Thus, NFL-TBS.40-63 peptide (NFL)—known to enter specifically myelinating oligodendrocytes (OL)—was used to vectorize 100 nm diameter lipid nanoparticles (LNC), and the ability of NFL-LNC to specifically target OL from newborn rat brain was assessed in vitro. Specific uptake of DiD-labeled NFL-LNC by OL characterized by CNP and myelin basic protein was observed by confocal microscopy, as well as DiD colocalization with NFL and with Rab5—a marker of early endosomes. Unvectorized LNC did not significantly penetrate OL and there was no uptake of NFL-LNC by astrocytes. Canonical maturation of OL which extended compacted myelin-like membranes was observed by transmission electron microscopy in cells grown up to 9 days with NFL-LNC. Endocytosis of NFL-LNC appeared to depend on several pathways, as demonstrated by inhibitors. In addition, vectorized NFL-LNC adsorbed on neurotrophin-3 (NT-3) potentiated the proremyelinating effects of NT-3 after demyelination by lysophosphatidyl choline, allowing noticeably decreasing NT-3 concentration. Our results if they were confirmed in vivo suggest that NFL-vectorized LNC appear safe and could be considered as putative carriers for specific drug delivery to OL in order to increase remyelination. Keywords Lipid nanoparticles · Lysophosphatidyl choline · Neurotrophin-3 · Multiple sclerosis · Oligodendrocyte · Remyelination
Introduction Specific delivery of pharmaceutical or biological components to the desired cellular target is a major concern. It will increase efficacy—and thus decrease the concentrations needed, together with potential side effects. This is an important issue for multiple sclerosis (MS), in which inflammation, oligodendrocyte (OL) death, and insufficient Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11064-020-03122-y) contains supplementary material, which is available to authorized users. * Catherine Fressinaud catherine.fressinaud@univ‑angers.fr 1
Neurology Department, University Hospital, 4 rue Larrey, 49933 Angers Cedex 9, France
MINT, UNIV Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, Angers, France
2
remyelination lead to intractable axon damage and permanent disability. Immunomodulatory or immunosupressive drugs have improved the clinical course of remittingrelapsing MS mainly by reducing the number of relapses and the burden o
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