title: Accumulation of Eu3+ chelates in cells expressing or not P-glycoprotein: implications for blood-brain barrier crossing.
abstract: Alzheimer's disease (AD) is the most commonly form of dementia in the elderly. The development of molecules able to detect biomarkers characteristic of AD is critical to its understanding and treatment. However, such molecules must be able to pass blood-brain barrier (BBB) which is a major impediment to the entry of many therapeutic drugs into the brain. Such a limitation applies to the development of magnetic resonance imaging molecular neuroimaging agents using biomarkers of AD-like beta-amyloid deposits, as the common extracellular contrast agents (CAs) are not able to cross an intact BBB. In this work, we have studied the ability of a series of simple Eu(3+) complexes to enter cells overexpressing or not the ABCB1 (P-gp or P-glycoprotein) protein, which is expressed at the BBB and in human embryonic astrocytes. The intracellular uptake of the Eu(3+) complexes of linear and macrocyclic polyaminocarboxylate ligands with different charges and lipophilicities was followed by atomic absorption spectrometry. Based on biochemical argument, we propose that lipophilic contrast agents can be efficiently taken up by cells and accumulate inside mitochondria when they are positively charged. The important point is that they are not P-gp substrates, which is one of the major obstacles for them to cross the BBB.
authors.affiliation: Laboratoire des Acides Nucléiques et Biophotonique, FRE 3207 CNRS, UMPC Université Paris 6 and Université Paris 13, UFR SMBH, 74 rue Marcel Cachin, 93017 Bobigny, France.
authors.forename: Nacira
authors.initials: N
authors.lastname: Darghal
authors.forename: Arlette
authors.initials: A
authors.lastname: Garnier-Suillerot
authors.forename: Nadia
authors.initials: N
authors.lastname: Bouchemal
authors.forename: Gabriel
authors.initials: G
authors.lastname: Gras
authors.forename: Carlos F G C
authors.initials: CF
authors.lastname: Geraldes
authors.forename: Milena
authors.initials: M
authors.lastname: Salerno
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D003287:Contrast Media / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D005063:Europium / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D008024:Ligands; D008279:Magnetic Resonance Imaging; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002614:Chelating Agents; D003287:Contrast Media; D008024:Ligands; D005063:Europium