Carbon monoxide (CO), the physiological product of heme oxygenase during catabolic breakdown of heme, has versatile functions and fulfills major anti-oxidative and anti-apoptotic roles in cell systems. Administration of CO is thus thought to be a reasonable therapeutic approach in diseases-such as inflammatory bowel disease-that are induced by reactive oxygen species (ROS). Tricarbonyldichlororuthenium(II) dimer (CORM2) is a commonly used CO donor, but it has poor aqueous solubility and a very short CO-releasing half-life (t1/2). In the present study, we prepared micelles consisting of water-soluble styrene-maleic acid copolymer (SMA) encapsulating CORM2 (SMA/CORM2) that had a hydrodynamic size of 165.3nm. Compared with free CORM2, SMA/CORM2 demonstrated better water solubility (>50mg/ml in a physiological water solution). Moreover, because of micelle formation in an aqueous environment, the CO release rate was slow and sustained. These properties resulted in much longer in vivo bioactivity of SMA/CORM2 compared with that of free CORM2, i.e. the t1/2 in blood of SMA/CORM2 in mice after intravenous (i.v.) injection was about 35 times longer than that of free CORM2. We then evaluated the therapeutic potential of SMA/CORM2 in a murine model of inflammatory colitis induced by dextran sulfate sodium (DSS). Administration (either i.v. or oral) of SMA/CORM2 once at the beginning of colitis, 3days after DSS treatment, significantly improved colitis symptoms-loss of body weight, diarrhea, and hematochezia-as well as histopathological colonic changes-shortening of the colon and necrosis or ulcers in the colonic mucosa. Up-regulation of inflammatory cytokines including monocyte chemotactic protein-1, tumor necrosis factor-α, and interleukin-6 in this DSS-induced colitis was significantly suppressed in SMA/CORM2-treated mice. SMA/CORM2 may thus be a superior CO donor and may be a candidate drug, which involves cytokine suppression, for ROS-related diseases including inflammatory bowel disease.
Keywords: Carbon monoxide; Inflammation; Inflammatory bowel disease; Micelles; Reactive oxygen species; Styrene-maleic acid copolymer.
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