title: Serum Albumin Binding Inhibits Nuclear Uptake of Luminescent Metal-Complex-Based DNA Imaging Probes.
abstract: The DNA binding and cellular localization properties of a new luminescent heterobimetallic Ir(III) Ru(II) tetrapyridophenazine complex are reported. Surprisingly, in standard cell media, in which its tetracationic, isostructural Ru(II) Ru(II) analogue is localized in the nucleus, the new tricationic complex is poorly taken up by live cells and demonstrates no nuclear staining. Consequent cell-free studies reveal that the Ir(III) Ru(II) complex binds bovine serum albumin, BSA, in Sudlow's Site I with a similar increase in emission and binding affinity to that observed with DNA. Contrastingly, in serum-free conditions the complex is rapidly internalized by live cells, where it localizes in cell nuclei and functions as a DNA imaging agent. The absence of serum proteins also greatly alters the cytotoxicity of the complex, where high levels of oncosis/necrosis are observed due to this enhanced uptake. This suggests that simply increasing the lipophilicity of a DNA imaging probe to enhance cellular uptake can be counterproductive as, due to increased binding to serum albumin protein, this strategy can actually disrupt nuclear targeting.
authors.affiliation: Department of Chemistry, University of Chemistry, Sheffield S3 7HF (UK), Fax: (+44) 114-222-9346.
authors.forename: Ashley
authors.initials: A
authors.lastname: Wragg
authors.affiliation: Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN (UK).
authors.forename: Martin R
authors.initials: MR
authors.lastname: Gill
authors.affiliation: Department of Chemistry, University of Chemistry, Sheffield S3 7HF (UK), Fax: (+44) 114-222-9346.
authors.forename: Luke
authors.initials: L
authors.lastname: McKenzie
authors.affiliation: Department of Chemistry, University of Chemistry, Sheffield S3 7HF (UK), Fax: (+44) 114-222-9346.
authors.forename: Caroline
authors.initials: C
authors.lastname: Glover
authors.affiliation: Department of Chemistry, University of Chemistry, Sheffield S3 7HF (UK), Fax: (+44) 114-222-9346.
authors.forename: Rachel
authors.initials: R
authors.lastname: Mowll
authors.affiliation: Department of Chemistry, University of Chemistry, Sheffield S3 7HF (UK), Fax: (+44) 114-222-9346.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Weinstein
authors.affiliation: Institute of Material Research and Engineering, A*STAR (Agency for Science, Technology and Research), Singapore 117602.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN (UK).
authors.forename: Carl
authors.initials: C
authors.lastname: Smythe
authors.affiliation: Department of Chemistry, University of Chemistry, Sheffield S3 7HF (UK), Fax: (+44) 114-222-9346. james.thomas@sheffield.ac.uk.
authors.forename: Jim A
authors.initials: JA
authors.lastname: Thomas
mesh_terms: D000818:Animals; D002417:Cattle; D056831:Coordination Complexes / Q000737:chemistry*; D015342:DNA Probes / Q000737:chemistry* / Q000378:metabolism*; D003952:Diagnostic Imaging; D007495:Iridium / Q000737:chemistry*; D049449:Luminescence; D011485:Protein Binding; D012428:Ruthenium / Q000737:chemistry*; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism
chemical_list: D056831:Coordination Complexes; D015342:DNA Probes; D012709:Serum Albumin; D012710:Serum Albumin, Bovine; D007495:Iridium; D012428:Ruthenium
keywords: DNA; imaging; iridium; ruthenium polypyridyl; serum albumin