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Nanomedicine. 2018 Apr;14(3):661-672. doi: 10.1016/j.nano.2018.01.002. Epub 2018 Jan 12.

Uptake and intracellular fate of cholera toxin subunit b-modified mesoporous silica nanoparticle-supported lipid bilayers (aka protocells) in motoneurons.

Author information

1
Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN, United States.
2
Center for Micro-Engineered Materials, University of New, Mexico.
3
Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN, United States; Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, United States.
4
Center for Micro-Engineered Materials, University of New, Mexico; Department of Chemical and Biological Engineering University of New, Mexico; Department of Molecular Genetics and Microbiology University of New, Mexico; Self-Assembled Materials Department, Sandia National Laboratories, Albuquerque, New, Mexico.
5
Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN, United States; Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN, United States. Electronic address: mantilla.carlos@mayo.edu.

Abstract

Cholera toxin B (CTB) modified mesoporous silica nanoparticle supported lipid bilayers (CTB-protocells) are a promising, customizable approach for targeting therapeutic cargo to motoneurons. In the present study, the endocytic mechanism and intracellular fate of CTB-protocells in motoneurons were examined to provide information for the development of therapeutic application and cargo delivery. Pharmacological inhibitors elucidated CTB-protocells endocytosis to be dependent on the integrity of lipid rafts and macropinocytosis. Using immunofluorescence techniques, live confocal and transmission electron microscopy, CTB-protocells were primarily found in the cytosol, membrane lipid domains and Golgi. There was no difference in the amount of motoneuron activity dependent uptake of CTB-protocells in neuromuscular junctions, consistent with clathrin activation at the axon terminals during low frequency activity. In conclusion, CTB-protocells uptake is mediated principally by lipid rafts and macropinocytosis. Once internalized, CTB-protocells escape lysosomal degradation, and engage biological pathways that are not readily accessible by untargeted delivery methods.

KEYWORDS:

Cholera toxin subunit B; Lipid raft endocytosis; Macropinocytosis; Mesoporous silica nanoparticles; Motoneuron; Neuromuscular junction

PMID:
29339186
DOI:
10.1016/j.nano.2018.01.002
[Indexed for MEDLINE]

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