High transcytosis of melanotransferrin (P97) across the blood-brain barrier.
The blood-brain barrier (BBB) performs a neuroprotective function by tightly controlling access to the brain; consequently it also impedes access of proteins as well as pharmacological agents to cerebral tissues. We demonstrate here that recombinant human melanotransferrin (P97) is highly accumulated into the mouse brain following intravenous injection and in situ brain perfusion. Moreover, P97 transcytosis across bovine brain capillary endothelial cell (BBCEC) monolayers is at least 14-fold higher than that of holo-transferrin, with no apparent intra-endothelial degradation. This high transcytosis of P97 was not related to changes in the BBCEC monolayer integrity. In addition, the transendothelial transport of P97 was sensitive to temperature and was both concentration- and conformation-dependent, suggesting that the transport of P97 is due to receptor-mediated endocytosis. In spite of the high degree of sequence identity between P97 and transferrin, a different receptor than the one for transferrin is involved in P97 transendothelial transport. A member of the low-density lipoprotein receptor protein family, likely LRP, seems to be involved in P97 transendothelial transport. The brain accumulation, high rate of P97 transcytosis and its very low level in the blood suggest that P97 could be advantageously employed as a new delivery system to target drugs directly to the brain.
Demeule
Michel
M
Laboratoire de Médecine Moléculaire, Département de Chimie-Biochimie, Université du Québec à Montréal-Hôpital Sainte-Justine, Montréal, Québec, Canada.
Poirier
Julie
J
Jodoin
Julie
J
Bertrand
Yanick
Y
Desrosiers
Richard R
RR
Dagenais
Claude
C
Nguyen
Tran
T
Lanthier
Julie
J
Gabathuler
Reinhard
R
Kennard
Malcolm
M
Jefferies
Wilfred A
WA
Karkan
Delara
D
Tsai
Sam
S
Fenart
Laurence
L
Cecchelli
Roméo
R
Béliveau
Richard
R
D000818:Animals; D000951:Antigens, Neoplasm; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D002196:Capillaries / Q000166:cytology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008297:Male; D058950:Melanoma-Specific Antigens; D051379:Mice; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism* / Q000493:pharmacokinetics; D011485:Protein Binding / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D013395:Sucrose / Q000493:pharmacokinetics; D014168:Transferrin / Q000494:pharmacology
D000951:Antigens, Neoplasm; D007457:Iodine Radioisotopes; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins; D014168:Transferrin; D013395:Sucrose