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Cell‐Specific and Nuclear Targeting with [M(CO) 3 ] + (M= 99m Tc, Re)‐Based Complexes Conjugated to Acridine Orange and Bombesin
Author(s) -
Agorastos Nikos,
Borsig Lubor,
Renard Anabelle,
Antoni Philipp,
Viola Giampietro,
Spingler Bernhard,
Kurz Philipp,
Alberto Roger
Publication year - 2007
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200700031
Subject(s) - acridine orange , acridine , bombesin , chemistry , peptide , fluorescence , ligand (biochemistry) , receptor , stereochemistry , moiety , fluorescence microscope , biochemistry , organic chemistry , apoptosis , physics , quantum mechanics , neuropeptide
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= 99m Tc, 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 )(L 1 ‐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 99m Tc 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.