Synthesis and immobilization of modified Ruthenium(II)-pyrithione complexes on mesoporous nanostructured silica

Abstract

Since the discovery of first anticancer drug, cisplatin, in the late 1960´s the importance of chemotherapeutics is rising constantly. However, problems of commonly used platinum-based drugs like low bioavailability, severe side-effects and drug resistance towards several cancers limit the application of established anticancer agents, thus requiring further research for more efficient and safe alternatives. Organoruthenium(II) complexes have proven to provide high bioactivity towards malignant cells, making them prominent candidates for alternative anticancer drugs. Especially when bound to arene ligands like p-cymene they provide enhanced stability in aqueous solutions as well as less toxicity towards normal cells compared to platinum-based drugs. Their cytotoxicity could further be enhanced if pyrithione ligands are bonded to ruthenium(II). To overcome still present drawbacks of these complexes (e.g., complex hydrolysis), the usage of drug delivery systems could lead to improved bioavailability and selectivity. Mesoporous silica nanostructures (MSNs) provide high surface area and good biocompatibility, thus being prominent candidates for the use as carrier systems. Regarding the enhanced accumulation of MSNs in tumour tissues due to the EPR-effect, loading of transition-metal drugs into mesoporous nanostructured silica is likely to increase the bioavailability and selectivity of anticancer drugs, leading to lower doses required. Within this work the three (p-cymene)ruthenium(II) pyrithione compounds 1–3 were successfully synthesized and characterized by IR and multinuclear NMR spectroscopy and purity was also confirmed by elemental analysis. Evaluation of the prepared complexes revealed a novel coordination mode of the carboxylate pyrithione derivative HL2– when bonded to the ruthenium(II) central ion, assuming that coordination in compound 2 takes place via thione sulphur and the carboxylate oxygen atoms. However, this presumption has to be further verified by X-ray structural analysis. Mesoporous nanostructured silica particles MCM-41 and SBA-15 were synthesized and further characterized using SEM, DLS and BET-analysis, showing size, shape and surface area sufficient for drug loading. Subsequently complexes 1–3 were successfully loaded into prepared MSNs, revealing ruthenium contents of 21.0–27.0 w% with EDX-analysis. Loading efficiencies of used compounds vary between 57.0–90.4 %, showing highest values for complex 1 due to less bulky ligand substitutes. Furthermore, a tendency of increased adsorption of all compounds into MCM-41 was observed. Nanomaterials remained without alterations in shape and morphology upon immobilization. Obtained results reveal successful preparation of loaded nanostructures with organoruthenium(II) complexes MCM-41|1–3 and SBA-15|1–3 thus highlighting their potential use for subsequent biological studies towards tumour cells.