title: Transthyretin as a new transporter of nanoparticles for receptor-mediated transcytosis in rat brain microvessels.
abstract: Many drugs are unable to breach the blood-brain barrier (BBB). Protein-directed transport of nanomedicine by receptor-mediated transcytosis (RMT) has been investigated as a means to overcome this problem. In this study, we screened transporters using an in vitro transcytosis assay system in rat serum to identify candidates that could guide nanoparticles through the BBB by RMT. The proteins that showed over 5-fold decreases in RMT when treated with chloropromazine, an inhibitor of clathrin-dependent endocytosis, were selected and identified by Maldi-TOF mass spectroscopy. Eleven proteins, including transthyretin (Ttr), and creatine kinase-muscle type (CKM), were identified as being capable of penetrating the endothelial cell layer by RMT. Among them, 10 proteins have not yet been used to transport nanomaterials across the BBB. To validate their activity as nanoparticle transporters in vivo, Ttr and CKM were conjugated to the surface of quantum dot (QD) nanoparticles and administrated intravenously. After 8h, the distribution of Ttr-QDs and CKM-QDs in brain tissue was analyzed. The results showed transcytosis of Ttr-QD conjugates across the BBB in rats as well as in in vitro assays, which was in contrast to the results observed for bare QDs and CKM-QDs. Taken together, these results indicate that Ttr is a new putative transporter for nanomedicines across the BBB.
authors.affiliation: Department of Brain and Cognitive Sciences, DGIST, 711-873, Republic of Korea.
authors.forename: So Yeun
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Division of Nano and Energy Convergence Research, DGIST, 711-873, Republic of Korea.
authors.forename: Eun-Sook
authors.initials: ES
authors.lastname: Choi
authors.affiliation: Division of Nano and Energy Convergence Research, DGIST, 711-873, Republic of Korea.
authors.forename: Hyo-Jung
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Brain and Cognitive Sciences, DGIST, 711-873, Republic of Korea. Electronic address: cmoon@dgist.ac.kr.
authors.forename: Cheil
authors.initials: C
authors.lastname: Moon
authors.affiliation: Division of Nano and Energy Convergence Research, DGIST, 711-873, Republic of Korea. Electronic address: ejkim@dgist.ac.kr.
authors.forename: Eunjoo
authors.initials: E
authors.lastname: Kim
mesh_terms: D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000098:blood supply*; D002478:Cells, Cultured; D008297:Male; D018613:Microscopy, Confocal; D055806:Microvessels / Q000378:metabolism*; D053758:Nanoparticles; D011228:Prealbumin / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D057900:Transcytosis
chemical_list: D011228:Prealbumin
keywords: Blood–brain barrier (BBB); Drug delivery; Nanomedicine; Receptor-mediated transcytosis; Transthyretin