title: Transcytosis and brain uptake of transferrin-containing nanoparticles by tuning avidity to transferrin receptor.
abstract: Receptor-mediated transcytosis across the blood-brain barrier (BBB) may be a useful way to transport therapeutics into the brain. Here we report that transferrin (Tf)-containing gold nanoparticles can reach the brain parenchyma from systemic administration in mice through a receptor-mediated transcytosis pathway. This transport is aided by tuning the nanoparticle avidity to Tf receptor (TfR), which is correlated with nanoparticle size and total amount of Tf decorating the nanoparticle surface. Nanoparticles of both 45 nm and 80 nm diameter reach the brain parenchyma, and their accumulation there (visualized by silver enhancement light microscopy in combination with transmission electron microscopy imaging) is observed to be dependent on Tf content (avidity); nanoparticles with large amounts of Tf remain strongly attached to brain endothelial cells, whereas those with less Tf are capable of both interacting with TfR on the luminal side of the BBB and detaching from TfR on the brain side of the BBB. The requirement of proper avidity for nanoparticles to reach the brain parenchyma is consistent with recent behavior observed with transcytosing antibodies that bind to TfR.
authors: Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
authors: Devin T
authors: DT
authors: Wiley
authors: Paul
authors: P
authors: Webster
authors: Aaron
authors: A
authors: Gale
authors: Mark E
authors: ME
authors: Davis
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000648:ultrastructure; D042783:Endothelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D006046:Gold / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D053768:Metal Nanoparticles; D051379:Mice; D008807:Mice, Inbred BALB C; D011990:Receptors, Transferrin / Q000378:metabolism*; D057900:Transcytosis / Q000187:drug effects*; D014168:Transferrin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D011990:Receptors, Transferrin; D014168:Transferrin; D006046:Gold
references: Biomaterials. 2011 May;32(13):3435-46
references: 21295849
references: Biophys J. 2004 Dec;87(6):4259-70
references: 15361408
references: Nat Rev Drug Discov. 2008 Sep;7(9):771-82
references: 18758474
references: Nat Nanotechnol. 2008 Mar;3(3):145-50
references: 18654486
references: Bioconjug Chem. 2003 Nov-Dec;14(6):1122-32
references: 14624625
references: Anal Chem. 2007 Feb 1;79(3):980-5
references: 17263325
references: Lancet Neurol. 2008 Jan;7(1):84-96
references: 18093565
references: Nature. 2010 Apr 15;464(7291):1067-70
references: 20305636
references: Nano Lett. 2009 May;9(5):1909-15
references: 19344179
references: J Med Chem. 2006 Oct 5;49(20):6087-93
references: 17004722
references: Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):1235-40
references: 20080552
references: Histochem Cell Biol. 2008 Jul;130(1):127-40
references: 18340454
references: Mol Pharm. 2009 May-Jun;6(3):659-68
references: 19267452
references: Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14265-70
references: 18809927
references: Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6656-61
references: 21464325
references: J Pharmacol Exp Ther. 1996 Sep;278(3):1491-8
references: 8819537
references: Sci Transl Med. 2011 May 25;3(84):84ra44
references: 21613623
references: Sci Transl Med. 2012 Aug 29;4(149):149ra119
references: 22932224
references: Proc Natl Acad Sci U S A. 1983 Apr;80(8):2258-62
references: 6300903
references: Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):10963-8
references: 21690358
references: Chem Soc Rev. 2012 Apr 7;41(7):2971-3010
references: 22388185
references: J Drug Target. 2004;12(9-10):635-41
references: 15621689