title: Effect of lanthanide complex structure on cell viability and association.
abstract: A systematic study of the effect of hydrophobicity and charge on the cell viability and cell association of lanthanide metal complexes is presented. The terbium luminescent probes feature a macrocyclic polyaminocarboxylate ligand (DOTA) in which the hydrophobicity of the antenna and that of the carboxyamide pendant arms are independently varied. Three sensitizing antennas were investigated in terms of their function in vitro: 2-methoxyisophthalamide (IAM(OMe)), 2-hydroxyisophthalamide (IAM), and 6-methylphenanthridine (Phen). Of these complexes, Tb-DOTA-IAM exhibited the highest quantum yield, although the higher cell viability and more facile synthesis of the structurally related Tb-DOTA-IAM(OMe) platform renders it more attractive. Further modification of this latter core structure with carboxyamide arms featuring hydrophobic benzyl, hexyl, and trifluoro groups as well as hydrophilic amino acid based moieties generated a family of complexes that exhibit high cell viability (ED50 > 300 μM) regardless of the lipophilicity or the overall complex charge. Only the hexyl-substituted complex reduced cell viability to 60% in the presence of 100 μM complex. Additionally, cellular association was investigated by ICP-MS and fluorescence microscopy. Surprisingly, the hydrophobic moieties did not increase cell association in comparison to the hydrophilic amino acid derivatives. It is thus postulated that the hydrophilic nature of the 2-methoxyisophthalamide antenna (IAM(OMe)) disfavors the cellular association of these complexes. As such, responsive luminescent probes based on this scaffold would be appropriate for the detection of extracellular species.
authors.affiliation: Department of Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Jonathan V
authors.initials: JV
authors.lastname: Dang
authors.forename: Evan A
authors.initials: EA
authors.lastname: Weitz
authors.forename: Cutler
authors.initials: C
authors.lastname: Lewandowski
authors.forename: Valérie C
authors.initials: VC
authors.lastname: Pierre
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology; D006367:HeLa Cells; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D049408:Luminescent Agents / Q000737:chemistry* / Q000494:pharmacology; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects; D010617:Phenanthridines / Q000737:chemistry / Q000494:pharmacology; D010795:Phthalic Acids / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013725:Terbium / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C516982:2-methoxyisophthalamide; D000577:Amides; D056831:Coordination Complexes; D006573:Heterocyclic Compounds, 1-Ring; D049408:Luminescent Agents; D010617:Phenanthridines; D010795:Phthalic Acids; D013725:Terbium; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid