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Sci Rep. 2015 Jul 20;5:11990. doi: 10.1038/srep11990.

LRP-1-mediated intracellular antibody delivery to the Central Nervous System.

Author information

1
1] Department of Chemistry, University College London, London, UK [2] The MRC/UCL Centre for Medical Molecular Virology, University College London, London, UK.
2
1] Department of Biomedical Science [2] Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, UK [3] Department of Neuroscience, University of Sheffield, UK [4] Department of Psychology, University of Sheffield, UK.
3
1] Department of Biomedical Science [2] Department of Chemistry, University of Sheffield, UK.
4
1] Department of Biomedical Science [2] Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, UK [3] Department of Neuroscience, University of Sheffield, UK.
5
Department of Chemistry, University of Sheffield, UK.
6
Department of Psychology, University of Sheffield, UK.
7
1] Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, UK [2] Department of Neuroscience, University of Sheffield, UK.
8
Institute of Pharmaceutical Science, King's College London, UK.

Abstract

The blood-brain barrier (BBB) is by far the most important target in developing new approaches to improve delivery of drugs and diagnostic tools into the Central Nervous System (CNS). Here we report the engineering of pH- sensitive polymersomes (synthetic vesicles formed by amphiphilic copolymers) that exploit endogenous transport mechanisms to traverse the BBB, enabling delivery of large macromolecules into both the CNS parenchyma and CNS cells. We achieve this by targeting the Low Density Lipoprotein Receptor-Related Protein 1 (LRP-1) receptor. We show that LRP-1 is associated with endothelial transcytosis that does not involve acidification of cargo in membrane-trafficking organelles. By contrast, this receptor is also associated with traditional endocytosis in CNS cells, thus aiding the delivery of relevant cargo within their cytosol. We prove this using IgG as a model cargo, thus demonstrating that the combination of appropriate targeting combined with pH-sensitive polymersomes enables the efficient delivery of macromolecules into CNS cells.

PMID:
26189707
PMCID:
PMC4507173
DOI:
10.1038/srep11990
[Indexed for MEDLINE]
Free PMC Article

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