Spontaneous CO release from Ru(II)(CO)2-protein complexes in aqueous solution, cells, and mice

• Published in: Angewandte Chemie International Edition 2015-01, Vol.54 (4), p.1172
• Main Authors: Chaves-Ferreira, Miguel, Albuquerque, Inês S, Matak-Vinkovic, Dijana, Coelho, Ana C, Carvalho, Sandra M, Saraiva, Lígia M, Romão, Carlos C, Bernardes, Gonçalo J L
• Format: Article
• Language: English
• Subjects: Animals; Carbon Monoxide - analysis; Carbon Monoxide - metabolism; Cattle; Cell Line, Tumor; Female; HeLa Cells; Histidine - chemistry; Humans; Interleukin-10 - metabolism; Interleukin-6 - metabolism; Mass Spectrometry; Mice; Mice, Inbred BALB C; Neoplasms - drug therapy; Organometallic Compounds - chemistry; Prodrugs - chemistry; Prodrugs - metabolism; Prodrugs - therapeutic use; Serum Albumin, Bovine - chemistry; Serum Albumin, Bovine - metabolism; Tissue Distribution; Transplantation, Heterologous; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1521-3773
• DOI: 10.1002/anie.201409344

We demonstrate that Ru(II)(CO)2-protein complexes, formed by the reaction of the hydrolytic decomposition products of [fac-RuCl(κ(2)-H2NCH2CO2)(CO)3] (CORM-3) with histidine residues exposed on the surface of proteins, spontaneously release CO in aqueous solution, cells, and mice. CO release was detected by mass spectrometry (MS) and confocal microscopy using a CO-responsive turn-on fluorescent probe. These findings support our hypothesis that plasma proteins act as CO carriers after in vivo administration of CORM-3. CO released from a synthetic bovine serum albumin (BSA)-Ru(II)(CO)2 complex leads to downregulation of the cytokines interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α in cancer cells. Finally, administration of BSA-Ru(II)(CO)2 in mice bearing a colon carcinoma tumor results in enhanced CO accumulation at the tumor. Our data suggest the use of Ru(II)(CO)2-protein complexes as viable alternatives for the safe and spatially controlled delivery of therapeutic CO in vivo.