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Cell-specific and nuclear targeting with M(CO)(3)](+) (M=Tc-99m, Re)-based complexes conjugated to acridine orange and bombesin


Agorastos, Nikos; Borsig, Lubor; Renard, Anabelle; Antoni, Philipp; Viola, Giampietro; Spingler, Bernhard; Kurz, Philipp; Alberto, Roger (2007). Cell-specific and nuclear targeting with M(CO)(3)](+) (M=Tc-99m, Re)-based complexes conjugated to acridine orange and bombesin. Chemistry - A European Journal, 13(14):3842-3852.

Abstract

Receptor-specific nuclear targeting requires trifunctional metal complexes. We have synthesized M(L (2)-pept)(L-1-acr)(CO)(3)] (pept = peptide; acr=acridine-based agent) in which the fac-M(CO)(3)](+) moiety (1st function, M=Tc-99m, Re) couples an acridine-based nuclear-targeting agent (2nd function, L-1-acr) and the specific cell-receptor-binding peptide bombesin (3rd function, L-2-pept). The metal-mediated coupling is based on the mixed ligand 2+1] principle. The nuclear targeting agents have been derivatised with an isocyanide group for monodentate (L-1) and bombesin (BBN) with a bidentate ligand (L-2) for complexation to fac-M(CO)(3)](+). For nuclear uptake studies, the model complexes Re(L-2) (C-acr)(CO)(3)] (L-2 = pyridine-2-carboxylic acid and pyridine-2,4-dicarboxylic acid) were synthesized and structurally characterized. We selected acridine derivatives as nuclear-targeting agents, because they are very good nucleus-staining agents and exhibit strong fluorescence. Despite the bulky metal complexes attached to acridine, all Re(L-2) (L-1-acr)(CO)(3)] showed high accumulation in the nuclei of PC3 and B16F1 cells, as evidenced by fluorescence microscopy. For radiopharmaceutical purposes, the Tc-99m analogues have been prepared and radioactivity distribution confirmed the fluorescence results. Coupling of BBN to L-2 gave the receptor-selective complexes M(L-2-BBN)(L-1-acr)(CO)(3)]. Whereas no internalization was found with B16F1 cells, fluorescence microscopy on PC3 cells bearing the BBN receptor showed high and rapid uptake by receptor-mediated endocytosis into the cytoplasm, but not into the nucleus.

Abstract

Receptor-specific nuclear targeting requires trifunctional metal complexes. We have synthesized M(L (2)-pept)(L-1-acr)(CO)(3)] (pept = peptide; acr=acridine-based agent) in which the fac-M(CO)(3)](+) moiety (1st function, M=Tc-99m, Re) couples an acridine-based nuclear-targeting agent (2nd function, L-1-acr) and the specific cell-receptor-binding peptide bombesin (3rd function, L-2-pept). The metal-mediated coupling is based on the mixed ligand 2+1] principle. The nuclear targeting agents have been derivatised with an isocyanide group for monodentate (L-1) and bombesin (BBN) with a bidentate ligand (L-2) for complexation to fac-M(CO)(3)](+). For nuclear uptake studies, the model complexes Re(L-2) (C-acr)(CO)(3)] (L-2 = pyridine-2-carboxylic acid and pyridine-2,4-dicarboxylic acid) were synthesized and structurally characterized. We selected acridine derivatives as nuclear-targeting agents, because they are very good nucleus-staining agents and exhibit strong fluorescence. Despite the bulky metal complexes attached to acridine, all Re(L-2) (L-1-acr)(CO)(3)] showed high accumulation in the nuclei of PC3 and B16F1 cells, as evidenced by fluorescence microscopy. For radiopharmaceutical purposes, the Tc-99m analogues have been prepared and radioactivity distribution confirmed the fluorescence results. Coupling of BBN to L-2 gave the receptor-selective complexes M(L-2-BBN)(L-1-acr)(CO)(3)]. Whereas no internalization was found with B16F1 cells, fluorescence microscopy on PC3 cells bearing the BBN receptor showed high and rapid uptake by receptor-mediated endocytosis into the cytoplasm, but not into the nucleus.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2007
Deposited On:23 Oct 2012 12:49
Last Modified:07 Dec 2017 15:40
Publisher:Wiley-Blackwell
ISSN:0947-6539
Publisher DOI:https://doi.org/10.1002/chem.200700031
Other Identification Number:ISI:000246573200001

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