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

Abstract

We demonstrate that Ru II (CO) 2 -protein complexes, formed by the reaction of the hydrolytic decomposition products of [fac-RuCl(κ 2 -H 2 NCH 2 CO 2 )(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.