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

Xiaohe Tian, Sophie Nyberg, Paul S. Sharp, Peter Jeppe Madsen, Nooshin Daneshpour, Steven P. Armes, Jason Berwick, Mimoun Azzouz, Pamela Shaw, N. Joan Abbott, Giuseppe Battaglia*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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.

Original languageEnglish
Article number11990
JournalScientific Reports
Volume5
Number of pages14
ISSN2045-2322
DOIs
Publication statusPublished - 2015
Externally publishedYes

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