Intercalation Of CORM-2 Into Pharmaceutical Clay Montmorillonite(MMT)for Therapeutic CO Release

In recent years,Carbon Monoxide Releasing Molecules(CORM)have been widely used in the therapeutic application of carbon monoxide,which has been successfully simulated the physiological therapeutic functions of endogenous carbon monoxide,such as organ protection,cardiovascular dilatation,antipyretic,anti-inflammatory,anti-bacterial and anti-cancer,etc.The research of therapeutic CORM has laid a solid theoretical and experimental foundation for clinical application of CO therapy.However,the release of carbon monoxide from these molecules is accompanied by transition metal residues,and its intrinsic metal toxicity seriously restricts the development of related therapeutic applications.Montmorillonite has high ion exchange capacity and unique swelling property,which can not only effectively regulate the drug release,but also effectively enhance the solubility of targeted drugs.In this dissertation,a new carbon monoxide release material with well-controlled release kinetics and low metal leaching was designed and synthesized by using montmorillonite as carrier and transition metal carbonyl complex as coordination intercalation layer.The CO release experiments under physiological environment shows that the hydrophilicity,swelling properties,especially the adsorption characteristics of heavy metals of montmorillonite are essential to inhibit the leaching of heavy metal ions.This study provides a new strategy for the design of therapeutic carbon monoxide release materials.The main contents of this dissertation are included as follows:Firstly,the research progress of carbon monoxide and transition metal carbonyl complex carbon monoxide release molecule and related release materials is reviewed,and the design principles,preparation methods and biological activities of various slow-release systems are systematically evaluated;furthermore,to replace CORM-02,the in-situ carbonylation reaction of Ru-MMT is developed for carbonyl ruthenium release system.As a result,two carbon monoxide-releasing montmorillonites loaded with ruthenium carbonyl,Product 1 and Product 2,were successfully prepared by the intercalation of MMT from ruthenium carbonyl species.The infrared spectroscopy(IR)confirmed the existence of ruthenium coordinated carbonyl ligand in MMT layer.The Energy-dispersive X-ray spectroscopy(EDX)analysis showed that ruthenium element in this material was about 5%.The Scanning electron microscopy(SEM)and Transmission electron microscope(TEM)graphs showed that the layer-structure of MMT has been maintained after loaded the ruthenium carbonyl.And the space of layers has been stretched,which was confirmed by X-Ray diffraction(XRD)analyses.Thermogravimetric(TG)curves with huge weight loss around 100-200℃ were attributed to the CO hot-release of ruthenium carbonyl as well as the loss of the adsorped solvent molecules and water molecules between the layers.The horse myoglobin test showed that the material could hydrolyze and slow release carbon monoxide in physiological environment The half-life of CO release was much longer than that of CORM-2,and it has an excellent environmental tolerance and slow release effect,Finally,this dissertation summarized the characteristies of carbon monoxide release precursors,carbon monoxide detection devices,carbon monoxide release kinetics,cytotoxicity and organ accumulation,which provided the literature support for the research of CO therapy.