Magnetic iron oxide, maghemite (Fe2O3) nanoparticles with covalent surface-bound CO-releasing molecules (CORMs) can be triggered to release CO through heating in an alternating magnetic field. In the proof-of-concept study the rate of CO-release from [RuCl(CO3)(μ-DOPA)]@maghemite nanoparticles was doubled upon exposure to an external alternating magnetic field (31.7 kAm(-1), 247 kHz, 25 °C, 39.9 mTesla, DOPA = dioxyphenyl-alaninato).

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The development of CORMs (CO-releasing molecules) as a prodrug for CO administration in living organisms has attracted significant attention. CORMs offer the promising possibility of a safe and controllable release of CO in low amounts triggered by light, ligands, enzymes, etc. For the targeting of specific tissues or diseases and to prevent possible side effects from metals and other residues after CO release, these CORMs are attached to biocompatible systems, like peptides, polymers, nanoparticles, dendrimers, protein cages, non-wovens, tablets, and metal-organic frameworks. We discuss in this review the known CORM carrier conjugates, in short CORM conjugates, with covalently-bound or incorporated CORMs for medicinal and therapeutic applications. Most conjugates are nontoxic, show increasing half-lives of CO release, and make use of the EPR-effect, but still show problems because of a continuous background of CO release and the absence of an on/off-switch for the CO release.

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Keywords: Carbon monoxide / Carbonyl ligands / Polymer conjugates / Manganese / EPR effect / Cytotoxicity CO-releasing molecules (CORMs) were coordinated to polymeric carrier systems for passive transport to tumour tissue or sites of inflammation, as described by the enhanced permeability and retention (EPR) effect. The developed conjugates consist of an organometallic fac-Mn(CO) 3 fragment, which is bound to a methacrylate or methacrylamide polymer backbone by bis(pyridylmethyl)amine-type ligands. The resulting Mn(CO) 3 -polymer conjugates were investigated as photoinducible CO-releasing molecules (photoCORMs). Furthermore, three model complexes [LMn(CO) 3 ]O 2 SCF 3

Gold(I) complexes of imidazole and thiazole-based diphos type ligands were prepared and their potential as chemotherapeutics investigated. Depending on the ligands employed and the reaction conditions complexes [L(AuCl)(2)] and [L(2)Au]X (X = Cl, PF(6)) are obtained. The ligands used are diphosphanes with azoyl substituents R(2)P(CH(2))(2)PR(2) {R = 1-methylimidazol-2-yl (1), 1-methylbenzimidazol-2-yl (4), thiazol-2-yl (5) and benzthiazol-2-yl (6)} as well as the novel ligands RPhP(CH(2))(2)PRPh {R = 1-methylimidazol-2-yl (3)} and R(2)P(CH(2))(3)PR(2) {R = 1-methylimidazol-2-yl (2)}. The cytotoxic activity of the complexes was assessed against three human cancer cell lines and a rat hepatoma cell line and correlated to the lipophilicity of the compounds. The tetrahedral gold complexes [(3)(2)Au]PF(6) and [(5)(2)Au]PF(6) with intermediate lipophilicity (logD(7.4) = 0.21 and 0.25) showed significant cytotoxic activity in different cell lines. Both compounds induce apoptosis and inhibit the enzymes thioredoxin reductase and glutathione reductase.

Maghemite (Fe2O3) iron oxide nanoparticles (IONPs) were synthesized, modified with covalent surface-bound CO-releasing molecules of a tri(carbonyl)-chlorido-phenylalaninato-ruthenium(II) complex (CORM), and coated with a dextran polymer. The time- and temperature-dependent CO release from this CORM-3 analogue was followed by a myoglobin assay. A new measurement method for the myoglobin assay was developed, based on confining "water-soluble" polymer-coated Dextran500k@CORM@IONP particles in hollow spheres of nontoxic and easily prepared calcium alginate. Dropping a mixture of Dextran500k@CORM@IONP and sodium alginate into a CaCl2 solution leads to stable hollow spheres of Ca(2+) cross-linked alginate which contain the Dextran500k@CORM@IONP particles. This "alginate-method" (i) protects CORM-3 analogues from rapid CO-displacement reactions with a protein, (ii) enables a spatial separation of the CORM from its surrounding myoglobin assay with the alginate acting as a CO-permeable membrane, and (iii) allows the use of substances with high absorptivity (such as iron oxide nanoparticles) in the myoglobin assay without interference in the optical path of the UV cell. Embedding the CORM@IONP nanoparticles in the alginate vessel represents a compartmentation of the reactive component and allows for close contact with, yet facile separation from, the surrounding myoglobin assay. The half-life of the CO release from Dextran500k@CORM@IONP particles surrounded by alginate was determined to be 890 ± 70 min at 20 °C. An acceleration of the CO release occurs at higher temperature with a half-life of 172 ± 27 min at 37 °C and 45 ± 7 min at 50 °C. The CO release can be triggered in an alternating current magnetic field (31.7 kA m(-1), 247 kHz, 39.9 mT) through local magnetic heating of the susceptible iron oxide nanoparticles. With magnetic heating at 20 °C in the bulk solution, the half-life of CO release from Dextran500k@CORM@IONP particles decreased to 155 ± 18 min without a noticeable temperature increase in the dispersion. At 37 and 50 °C, the half-life for the CO release triggered by local magnetic heating was 65 ± 5 min and 30 ± 3 min, respectively. Thus, at a physiological temperature of 37 °C, magnetic heating accelerates the CO release of the IONP-bound CORM by a factor of ∼ 2.6. The activation energy for CO release from a CORM-3 analogue was determined to be EA = 78 kJ/mol.

The gold(I) bis-NHC (NHC = imidazol-2-ylidene) parent compound was synthesised in high yield by a three step reaction starting from imidazole. The compound is highly water soluble and stable in concentrated hydrochloric acid.