title: LRP-1-mediated intracellular antibody delivery to the Central Nervous System.
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.
authors.affiliation: 1] Department of Chemistry, University College London, London, UK [2] The MRC/UCL Centre for Medical Molecular Virology, University College London, London, UK.
authors.forename: Xiaohe
authors.initials: X
authors.lastname: Tian
authors.affiliation: 1] Department of Chemistry, University College London, London, UK [2] The MRC/UCL Centre for Medical Molecular Virology, University College London, London, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Nyberg
authors.affiliation: 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.
authors.forename: Paul
authors.initials: P
authors.lastname: S Sharp
authors.affiliation: 1] Department of Biomedical Science [2] Department of Chemistry, University of Sheffield, UK.
authors.forename: Jeppe
authors.initials: J
authors.lastname: Madsen
authors.affiliation: 1] Department of Biomedical Science [2] Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, UK [3] Department of Neuroscience, University of Sheffield, UK.
authors.forename: Nooshin
authors.initials: N
authors.lastname: Daneshpour
authors.affiliation: Department of Chemistry, University of Sheffield, UK.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Armes
authors.affiliation: Department of Psychology, University of Sheffield, UK.
authors.forename: Jason
authors.initials: J
authors.lastname: Berwick
authors.affiliation: 1] Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, UK [2] Department of Neuroscience, University of Sheffield, UK.
authors.forename: Mimoun
authors.initials: M
authors.lastname: Azzouz
authors.affiliation: 1] Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, UK [2] Department of Neuroscience, University of Sheffield, UK.
authors.forename: Pamela
authors.initials: P
authors.lastname: Shaw
authors.affiliation: Institute of Pharmaceutical Science, King's College London, UK.
authors.forename: N Joan
authors.initials: NJ
authors.lastname: Abbott
authors.affiliation: 1] Department of Chemistry, University College London, London, UK [2] The MRC/UCL Centre for Medical Molecular Virology, University College London, London, UK.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000378:metabolism*; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D008297:Male; D051379:Mice; D011108:Polymers / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D011973:Receptors, LDL / Q000378:metabolism*; D057900:Transcytosis; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000906:Antibodies; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; D011108:Polymers; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D020691:rab GTP-Binding Proteins