CNS delivery via adsorptive transcytosis.
Adsorptive-mediated transcytosis (AMT) provides a means for brain delivery of medicines across the blood-brain barrier (BBB). The BBB is readily equipped for the AMT process: it provides both the potential for binding and uptake of cationic molecules to the luminal surface of endothelial cells, and then for exocytosis at the abluminal surface. The transcytotic pathways present at the BBB and its morphological and enzymatic properties provide the means for movement of the molecules through the endothelial cytoplasm. AMT-based drug delivery to the brain was performed using cationic proteins and cell-penetrating peptides (CPPs). Protein cationization using either synthetic or natural polyamines is discussed and some examples of diamine/polyamine modified proteins that cross BBB are described. Two main families of CPPs belonging to the Tat-derived peptides and Syn-B vectors have been extensively used in CPP vector-mediated strategies allowing delivery of a large variety of small molecules as well as proteins across cell membranes in vitro and the BBB in vivo. CPP strategy suffers from several limitations such as toxicity and immunogenicity--like the cationization strategy--as well as the instability of peptide vectors in biological media. The review concludes by stressing the need to improve the understanding of AMT mechanisms at BBB and the effectiveness of cationized proteins and CPP-vectorized proteins as neurotherapeutics.
Hervé
Françoise
F
UFR Biomédicale, Université Paris Descartes, CNRS, UPR2228, 45 rue des Saints-Pères, 75270 Paris, France. francoise.herve@univ-paris5.fr
Ghinea
Nicolae
N
Scherrmann
Jean-Michel
JM
D000327:Adsorption; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D002412:Cations; D016503:Drug Delivery Systems; D055724:Electrophysiological Phenomena; D004705:Endocytosis; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D010455:Peptides / Q000008:administration & dosage; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D011506:Proteins / Q000008:administration & dosage
D002412:Cations; D010455:Peptides; D004364:Pharmaceutical Preparations; D011506:Proteins