Antitumor Activities Of Polypyridyl Ruthenium(?) Complexes And Magnectic Composite Nanoparticles

The success of platinum as anticancer angent has greatly stimulated the researches on the transition metal complexes as antitumor drugs. However, the drug resistance, high toxicity, and side effects of platinum prompted people to develop new antitumor drugs. The ruthenium(II) complexes were thought as potential antitumor drugs due to their low cytotoxicity, broad spectra and anticancer activities. On the other hand, the ruthenium(II) complexes could act as luminescence probes for cell imaging because of their rich photochamical properties. Studying the cellular uptake, the distribution amd transportation of ruthenium complexes can provide important information for the development of new desired antitumor drug. Herein, we studied the antitumor activities of several ruthenium complexes with different substituents and explored the antitumor mechanisms. Besides these, the magnetic composite nanoparticles have also attracted much attention due to their potential applications in magnetic-heat therapy, which can overcome the drug resistance in traditional chemotherapy. Based on the above reasons, we chose the ruthenium(II) complexes and magnetic nickel composite nanoparticles as the research objects, the antitumor activities of the rutheniums complexes and the composite nanoparticles were studied and the mechanisms were explored. The main contents are as follows:1. The cytotoxicity of two ruthenium(II) complexes [Ru(phen)2-2,4MDHIP]2+([Ru-pMH]2+) and [Ru(phen)2-2,3ODHIP]2+([Ru-pOH]2+) with two hydroxyl substituent in the different positions of ligands were studied by MTT method. The results exbited that both complexes show significant growth inhibition and dose-dependent to human liver cancer cell bel-7402 and human laryngeal cancer cells hep-2, the IC50 values were calculated, too. The flow cytometer analysis indicated that [Ru-p OH]2+ induced much more cell apoptosis than [Ru-pMH]2+. However, the apoptosis rate decreases as increasing the incubation time, which indicating the trait of metastasis-easier of [Ru-pOH]2+. The cell uptake and localization in cytoplasm and nucleus were observed by confocal laser scan microscope. Both complexes could induce the bel-7402 cell apoptosis at the high concentration, and the changed morphology of cell, neucleus shrunk, membrane blebbling with apoptotic bodies were observed. Western blot studies indicated that complexes effected cells through decreasing the expression of bax protein and increasing the expression of bcl-2 protein on the mitochondria surface eara. Based on the above all, the two ruthenium comlex with hydroxyl substitutes may induce bel-7402 and hep-2 cells apoptosis via triggering mitochondria mediate pathway.2. The interaction of two complexes [Ru(bpy)2-2,3ODCIP]2+([Ru-bOC]2+) and [Ru(phen)2-2,3ODCIP]2+([Ru-pOC]2+) with two chloride substitues with telomerase G4 DNA were investigated by UV-vis spectra and circular dichroism spectra. Complex with large planar hydrophobic ancillary ligand([Ru-pOC]2+) preferred to stabilized or transformed G4 sequences. Both of them shown significant inhibition and dose-dependent to bel-7402 cells and hep-2 cells, the IC50 values were calculated, too. Both complexes show high cytotoxicity towards hep-2 cells with low IC50 values. [Ru-bOC]2+ induced much more cell apoptosis than [Ru-pOC]2+ according to the flow cytometer analysis. Hoechst 33258 stainning show obvious nucleus shrunk, aggregated of chromatin when cells were treated with ruthenium complexes. Both complexes transported into cell and dispersed mostly in cytoplasm while little in nucleus. Western blot studies indicated that complexes effected down-regulated expression of bcl-2 protein and up-grade expression of bax protein. Based on the above all, the mitochondria mediate pathway plays an important role in the hep-2 apoptosis induced by the ruthenium complexes with chloride subsitutes.3. The antitumor activities of magnetic nickel composits nanoparticles(Ni@C) were also studied. The structures of Ni@C were characterized by TEM and XRD. The particles size was about 500 nm measured by particle size analyzer(DLS). The cytotoxicity of Ni@C were studied by MTT methods, and the results indicated that the inhibition of hep-2 cells is related to concentration-dependent, which presented high apoptotic rate of hep-2 cells detected by flow cytometer.