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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / administration & dosage*
  • Antibodies / metabolism*
  • Biological Transport
  • Blood-Brain Barrier / metabolism
  • Central Nervous System / metabolism*
  • Intracellular Space / metabolism
  • Lysosomal-Associated Membrane Protein 1 / metabolism
  • Male
  • Mice
  • Polymers / metabolism
  • Protein Binding
  • Protein Transport
  • Receptors, LDL / metabolism*
  • Transcytosis
  • Tumor Suppressor Proteins / metabolism*
  • rab GTP-Binding Proteins / metabolism

Substances

  • Antibodies
  • Lrp1 protein, mouse
  • Lysosomal-Associated Membrane Protein 1
  • Polymers
  • Receptors, LDL
  • Tumor Suppressor Proteins
  • rab GTP-Binding Proteins