Internalization of targeted quantum dots by brain capillary endothelial cells in vivo.

TitleInternalization of targeted quantum dots by brain capillary endothelial cells in vivo.
Publication TypeJournal Article
Year of Publication2016
AuteursParis-Robidas, S, Brouard, D, Emond, V, Parent, M, Calon, F
JournalJ Cereb Blood Flow Metab
Volume36
Issue4
Pagination731-42
Date Published2016 Apr
ISSN1559-7016
KeywordsAnimals, Blood-Brain Barrier, Capillaries, Cell Line, Cerebrovascular Circulation, Endocytosis, Endothelial Cells, Endothelium, Vascular, Immunoglobulin G, Male, Mice, Mice, Inbred BALB C, Nanoparticles, Quantum Dots, Rats, Receptors, Transferrin, Tissue Distribution
Abstract

Receptors located on brain capillary endothelial cells forming the blood-brain barrier are the target of most brain drug delivery approaches. Yet, direct subcellular evidence of vectorized transport of nanoformulations into the brain is lacking. To resolve this question, quantum dots were conjugated to monoclonal antibodies (Ri7) targeting the murine transferrin receptor. Specific transferrin receptor-mediated endocytosis of Ri7-quantum dots was first confirmed in N2A and bEnd5 cells. After intravenous injection in mice, Ri7-quantum dots exhibited a fourfold higher volume of distribution in brain tissues, compared to controls. Immunofluorescence analysis showed that Ri7-quantum dots were sequestered throughout the cerebral vasculature 30 min, 1 h, and 4 h post injection, with a decline of signal intensity after 24 h. Transmission electron microscopic studies confirmed that Ri7-quantum dots were massively internalized by brain capillary endothelial cells, averaging 37 ± 4 Ri7-quantum dots/cell 1 h after injection. Most quantum dots within brain capillary endothelial cells were observed in small vesicles (58%), with a smaller proportion detected in tubular structures or in multivesicular bodies. Parenchymal penetration of Ri7-quantum dots was extremely low and comparable to control IgG. Our results show that systemically administered Ri7-quantum dots complexes undergo extensive endocytosis by brain capillary endothelial cells and open the door for novel therapeutic approaches based on brain endothelial cell drug delivery.

DOI10.1177/0271678X15608201
Alternate JournalJ. Cereb. Blood Flow Metab.
PubMed ID26661181
PubMed Central IDPMC4820005
Grant ListCAN76833 / / Canadian Institutes of Health Research / Canada
MOP246453 / / Canadian Institutes of Health Research / Canada
MOP84251 / / Canadian Institutes of Health Research / Canada