title: 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)-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.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa (Portugal).
authors.forename: Miguel
authors.initials: M
authors.lastname: Chaves-Ferreira
authors.forename: Inês S
authors.initials: IS
authors.lastname: Albuquerque
authors.forename: Dijana
authors.initials: D
authors.lastname: Matak-Vinkovic
authors.forename: Ana C
authors.initials: AC
authors.lastname: Coelho
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Carvalho
authors.forename: Lígia M
authors.initials: LM
authors.lastname: Saraiva
authors.forename: Carlos C
authors.initials: CC
authors.lastname: Romão
authors.forename: Gonçalo J L
authors.initials: GJ
authors.lastname: Bernardes
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000032:analysis / Q000378:metabolism; D002417:Cattle; D045744:Cell Line, Tumor; D005260:Female; D006367:HeLa Cells; D006639:Histidine / Q000737:chemistry; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000188:drug therapy; D009942:Organometallic Compounds / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D012710:Serum Albumin, Bovine / Q000737:chemistry* / Q000378:metabolism; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D009942:Organometallic Compounds; D011355:Prodrugs; D014409:Tumor Necrosis Factor-alpha; C476530:tricarbonylchloro(glycinato)ruthenium(II); D016753:Interleukin-10; D012710:Serum Albumin, Bovine; D006639:Histidine; D002248:Carbon Monoxide
keywords: CORM; albumin; carbon monoxide; metalloproteins; prodrugs