Nitric oxide photorelease from a trinuclear ruthenium nitrosyl complex and its in vitro cytotoxicity against melanoma cells (original) (raw)
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Journal of Inorganic Biochemistry, 2011
The synthesis, structural aspects, pharmacological assays, and in vitro photoinduced cytotoxic properties of [Ru(NO)(ONO)(pc)] (pc = phthalocyanine) are described. Its biological effect on the B16F10 cell line was studied in the presence and absence of visible light irradiation. At comparable irradiation levels, [Ru(NO) (ONO)(pc)] was more effective than [Ru(pc)] at inhibiting cell growth, suggesting that occurrence of nitric oxide release following singlet oxygen production upon light irradiation may be an important mechanism by which the nitrosyl ruthenium complex exhibits enhanced biological activity in cells. Following visible light activation, the [Ru(NO)(ONO)(pc)] complex displayed increased potency in B16F10 cells upon modifications to the photoinduced dose; indeed, enhanced potency was detected when the nitrosyl ruthenium complex was encapsulated in a drug delivery system. The liposome containing the [Ru(NO)(ONO)(pc)] complex was over 25% more active than the corresponding ruthenium complex in phosphate buffer solution. The activity of the complex was directly proportional to the ruthenium amount present inside the cell, as determined by inductively coupled plasma mass spectroscopy. Flow cytometry analysis revealed that the photocytotoxic activity was mainly due to apoptosis. Furthermore, the vasorelaxation induced by [Ru(NO)(ONO)(pc)], proposed as NO carrier, was studied in rat isolated aorta. The observed vasodilation was concentrationdependent. Taken together, the present findings demonstrate that the [Ru(NO)(ONO)(pc)] complex induces vascular relaxation and could be a potent anti-tumor agent. Nitric oxide release following singlet oxygen production upon visible light irradiation on a nitrosyl ruthenium complex produces two radicals and may elicit phototoxic responses that may find useful applications in photodynamic therapy.
Journal of Molecular Structure
Pentadentate electron rich MePBITA ligand in [Ru II (MePBITA)(NO)] n + (n = 3, 2 and MePBITA = 1-(6-(1-methyl-1H-benzo[d]imidazol-2-yl)pyridin-2-yl)-N,N-bis(pyridin-2-ylmethyl)methanamine) permits the isolation of both the redox states of nitrosyls with Enemark-Feltham notation {RuNO} 6 and {RuNO} 7. The nitrosyl derivative [Ru II (MePBITA)(NO)](ClO 4) 3 : [ 4 ](ClO 4) 3 was synthesized by stepwise synthetic manner from the chloro precursor [Ru II (MePBITA)(Cl)](PF 6): [ 1 ](PF 6), via the acetonitrile derivative [Ru II (MePBITA)(CH 3 CN)](PF 6) 2 : [ 2 ](PF 6) 2 followed by nitro complex [Ru II (MePBITA)(NO 2)](PF 6): [ 3 ](PF 6). All the complexes were fully characterized by different analytical and spectroscopic techniques. Single crystal X-ray structures of the complexes [ 1 ](PF 6), [ 2 ](PF 6) 2 , [ 3 ](PF 6), and [ 4 ](ClO 4) 3 were profitably determined for understanding the molecular integrity. Ru −NO stretching frequency observed at 1931 cm −1 for [ 4 ](ClO 4) 3 suggests a moderately electrophilic character of NO. The huge shift in ν NO frequency, ν (solid) = 325 cm −1 was observed by reducing [ 4 ](ClO 4) 3 to [ 4 ](ClO 4) 2. The conversion of [ 3 ] + from [ 4 ] 3 + was examined both electrochemically and spectrophotometrically with the addition of 0.5 M NaOH solution. Rate constants of the first order photorelease (k NO) have been found to be 8.99 × 10 −3 min −1 ; half-life (t 1/2) = 77 min and 3.84 × 10 −2 min −1 ; half-life (t 1/2) = 18 min for [ 4 ] 3 + and [ 4 ] 2 + , respectively with visible Xenon light (200 W) source. The photo liberated NO has been scavenged by biologically relevant target protein reduced myoglobin as Mb −NO adduct. Photoactivation of [ 4 ] 3 + and [ 4 ] 2 + by visible light induces significant cytotoxicity in prostate cancer cell lines; VCaP (IC 50 29.74 and 4.42 μM) and 22Rv1 (IC 50 29.96 and 6.88 μM), and lung cancer cell line; A549 (IC 50 2.24 and 0.12 μM). Collectively our results pave the way for the development of metallodrugs as potential therapeutics for a variety of cancers. Additionally, our results also demonstrate how ligand modification could enhance the photolability of metal nitrosyl, adding a new dimension for future efficient photoactive metal nitrosyl design.
Inorganic Chemistry, 2005
Ru II L(NH 3 ) 4 (pz)Ru II (bpy) 2 (NO)](PF 6 ) 5 (L is NH 3 , py, or 4-acpy) was prepared with good yields in a straightforward way by mixing an equimolar ratio of cis-[Ru(NO 2 )(bpy) 2 (NO)](PF 6 ) 2 , sodium azide (NaN 3 ), and trans-[RuL(NH 3 ) 4 -(pz)] (PF 6 ) 2 in acetone. These binuclear compounds display ν(NO) at ca. 1945 cm -1 , indicating that the nitrosyl group exhibits a sufficiently high degree of nitrosonium ion (NO + ). The electronic spectrum of the [Ru II L(NH 3 ) 4 -(pz)Ru II (bpy) 2 (NO)] 5+ complex in aqueous solution displays the bands in the ultraviolet and visible regions typical of intraligand and metal-to-ligand charge transfers, respectively. Cyclic voltammograms of the binuclear complexes in acetonitrile give evidence of three one-electron redox processes consisting of one oxidation due to the Ru 2+/3+ redox couple and two reductions concerning the nitrosyl ligand. Flash photolysis of the [Ru II L(NH 3 ) 4 (pz)Ru II (bpy) 2 -(NO)] 5+ complex is capable of releasing nitric oxide (NO) upon irradiation at 355 and 532 nm. NO production was detected and quantified by an amperometric technique with a selective electrode (NOmeter). The irradiation at 532 nm leads to NO release as a consequence of a photoinduced electron transfer. All species exhibit similar photochemical behavior, a feature that makes their study extremely important for their future application in the upgrade of photodynamic therapy in living organisms. Inorg. Chem. 2005, 44, 9946−9951 9946 (34) Zavarine, S.; Kini, A. D.; Morimoto, B. H.; Kubiak, C. P. J. Phys. Chem B 1998, 102, 7287. (35) Carter, T. D.; Bettache, N.; Ogden, D. Brit. J. Pharmacol. 1997, 122, 971.
Polyhedron, 2009
The photochemical, photophysical and photobiological studies of a mixture containing cis-[Ru(Hdcbpy À ) 2 (Cl)(NO)] (H 2 -dcbpy = 4,4 0 -dicarboxy-2,2 0 -bipyridine) and Na 4 [Tb(TsPc)(acac)] (TsPc = tetrasulfonated phthalocyanines; acac = acetylacetone), a system capable of improving photodynamic therapy (PDT), were accomplished. cis-[Ru(H-dcbpy À ) 2 (Cl)(NO)] was obtained from cis-[Ru(H 2 -dcbpy) 2 Cl 2 ]Á2H 2 O, whereas Na 4 [Tb(TsPc)(acac)] was obtained by reacting phthalocyanine with terbium acetylacetonate. The UV-Vis spectrum of cis-[Ru(H-dcbpy À ) 2 (Cl)(NO)] displays a band in the region of 305 nm (k max in 0.1 mol L À1 HCl)(p-p*) and a shoulder at 323 nm (MLCT), while the UV-Vis spectrum of Na 4 [Tb(TsPc)(acac)] presents the typical phthalocyanine bands at 342 nm (Soret k max in H 2 O) and 642, 682 (Q bands). The cis-[Ru(H-dcbpy À ) 2 (Cl)(NO)] FTIR spectrum displays a band at 1932 cm À1 (Ru-NO + ). The cyclic voltammogram of the cis-[Ru(H-dcbpy À ) 2 (Cl)(NO)] complex in aqueous solution presented peaks at E = 0.10 V (NO +/0 ) and E = À0.50 V (NO 0/À ) versus Ag/AgCl. The NO concentration and 1 O 2 quantum yield for light irradiation in the k > 550 nm region were measured as [NO] = 1.21 ± 0.14 lmol L À1 and ø OS = 0.41, respectively. The amount of released NO seems to be dependent on oxygen concentration, once the NO concentration measured in aerated condition was 1.51 ± 0.11 lmol L À1 The photochemical pathway of the cis-[Ru(H-dcbpy À ) 2 (Cl)(NO)]/Na 4 [Tb(TsPc)(acac)] mixture could be attributed to a photoinduced electron transfer process. The cytotoxic assays of cis-[Ru(H-dcbpy -) 2 (Cl)(NO)] and of the mixture carried out with B16F10 cells show a decrease in cell viability to 80% in the dark and to 20% under light irradiation. Our results document that the simultaneous production of NO and 1 O 2 could improve PDT and be useful in cancer treatment.
Inorganic Chemistry Communications, 2008
The photochemical behavior of [Ru(NO)(NO) 2 pc] (pc = phthalocyanine) is reported in this paper. In addition to ligand localized absorption bands (k < 300 nm), the electronic spectrum of this complex in dichloromethane solution was dominated by an intense absorption at 640 nm characterized as Q-bands. Irradiation of [Ru(NO)(NO) 2 pc] at 366 and 660 nm led to the production of nitric oxide (NO) as detected by a NO-sensor. NO production by light irradiation at high energy involved excitation of d p -p à transition, while a photoinduced electron transfer occurred at long wavelength irradiation. The NO quantum yields varied from 1.4  10 À3 to 2.3  10 À2 mol einstein À1 , depending on oxygen concentration.
Photochemical and Electrochemical Study of the Release of Nitric Oxide from Ru(bpy)2L(NO)nComplexes (L = Imidazole, 1-Methylimidazole, Sulfite and Thiourea), Toward the Development of Therapeutic Photodynamic Agents
Journal of the Brazilian Chemical Society, 2015
The development of NO photoreleaser compounds has important potential applications on medicine, particularly on preventing topic infections and controlling cancers. Due to these expectations, the photochemical release of nitric oxide from complexes of [Ru(bpy) 2 LX] n+ , where L = imidazole, 1-methylimidazole, sulphite and thiourea and X = NO + and NO 2 − was investigated employing spectroscopic and electrochemical techniques. The release of NO was confirmed by chronoamperometry using a NO selective electrode, while the other product, mainly [Ru II H 2 O], was detected by UV-Visible spectroscopy and electrochemical techniques for all complexes except for thiourea. The amount of NO released by these complexes upon irradiation was determined using a new developed method using square wave voltammetry.
trans-Ru(NO)(NH3)4(py)3·H2O encapsulated in PLGA microparticles for delivery of nitric oxide to B16-F10 cells: Cytotoxicity and phototoxicity
Journal of Inorganic Biochemistry, 2008
The NO donor trans-[Ru(NO)(NH 3 ) 4 (py)](BF 4 ) 3 ÁH 2 O (py = pyridine) was loaded into poly-lactic-co-glycolic acid (PLGA) microparticles using the double emulsification technique. Scanning electron microscopy (SEM) and dynamic light scattering revealed that the particles are spherical in shape, have a diameter of 1600 nm, and have low tendency to aggregate. The entrapment efficiency was 25%. SEM analysis of the melanoma cell B16-F10 in the presence of the microparticles containing the complex trans-[Ru(NO)(NH 3 ) 4 -(py)](BF 4 ) 3 ÁH 2 O (pyMP) showed that the microparticles were adhered to the cell surface after 2 h of incubation. The complex with concentrations lower than 1 Â 10 À4 M did not show toxicity in B16-F10 murine cells. The complex in solution is toxic at higher concentrations (>1 Â 10 À3 M), with cell death attributed to NO release following the reduction of the complex. pyMP is not cytotoxic due to the lower bioavailability and availability of the entrapped complex to the medium and its reducing agents. However, pyMP is phototoxic upon light irradiation. The phototoxicity strongly suggests that cell death is due to NO release from trans-[Ru(NO)(NH 3 ) 4 (py)] 3+ . This work shows that pyMP can serve as a model for a drug delivery system carrying the NO donor trans-[Ru(NO)(NH 3 ) 4 (py)](BF 4 ) 3 ÁH 2 O, which can release NO locally at the tumor cell by irradiation with light only.
The In Vitro and In Vivo Antitumour Activities of Nitrosyl Ruthenium Amine Complexes
Australian Journal of Chemistry, 2012
Ruthenium compounds of the type trans-[Ru(NO)(NH3)4(L)]X3, L = N-heterocyclic ligands, P(OEt)3, SO32–, X = BF4– or PF6–, or [Ru(NO)Hedta], were tested for antitumour activity in vitro against murine melanoma and human tumour cells. The ruthenium complexes induced DNA fragmentation and morphological alterations suggestive of necrotic tumour cell death. The calculated IC50 values were lower than 100 μM. Complexes for which L = isn or imN were partially effective in vivo in a syngeneic model of murine melanoma B16F10, increasing animal survival. In addition, the same ruthenium complexes effectively inhibited angiogenesis of HUVEC cells in vitro. The results suggest that these nitrosyl complexes are a promising platform to be explored for the development of novel antitumour agents.