Versatile Impact of Serum Proteins on Ruthenium(II) Polypyridyl Complexes Properties - Opportunities and Obstacles

Author(s): Olga Mazuryk*, Przemysław Gajda-Morszewski, Małgorzata Brindell

Journal Name: Current Protein & Peptide Science

Volume 20 , Issue 11 , 2019


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Ruthenium(II) polypyridyl complexes have been extensively studied for the past few decades as promising anticancer agents. Despite the expected intravenous route of administration, the interaction between Ru(II) polypyridyl compounds and serum proteins is not well characterized and vast majority of the available literature data concerns determination of the binding constant. Ru-protein adducts can modify the biological effects of the Ru complexes influencing their cytotoxic and antimicrobial activity as well as introduce significant changes in their photophysical properties. More extensive research on the interaction between serum proteins and Ru(II) polypyridyl complexes is important for further development of Ru(II) polypyridyl compounds towards their application in anticancer therapy and diagnostics and can open new opportunities for already developed complexes.

Keywords: Ruthenium(II) polypyridyl complexes, serum protein, albumin, binding, anticancer activity, RU-protien.

[1]
Alessio, E. Thirty years of the drug candidate NAMI-A and the myths in the field of ruthenium anticancer compounds: A personal perspective. Eur. J. Inorg. Chem., 2017, 2017(12), 1549-1560.
[2]
Trondl, R.; Heffeter, P.; Kowol, C.R.; Jakupec, M.A.; Berger, W.; Keppler, B.K. NKP-1339, the first ruthenium-based anticancer drug on the edge to clinical application. Chem. Sci., 2014, 5(8), 2925-2932.
[3]
Available from. https://clinicaltrials.gov Identifier: NCT01415297.
[4]
McConnell, A.J.; Lim, M.H.; Olmon, E.D.; Song, H.; Dervan, E.; Barton, J.K. Luminescent properties of ruthenium(II) complexes with sterically expansive ligands bound to DNA defects. Inorg. Chem., 2012, 51(22), 12511-12520.
[5]
Zhou, Q.X.; Lei, W.H.; Chen, J.R.; Li, C.; Hou, Y.J.; Wang, X.S.; Zhang, B.W. A new heteroleptic ruthenium(II) polypyridyl complex with long-wavelength absorption and high singlet-oxygen quantum yield. Chem. Eur. J., 2010, 16(10), 3157-3165.
[6]
Gill, M.R.; Derrat, H.; Smythe, C.G.W.; Battaglia, G.; Thomas, J.A. Ruthenium(II) metallo-intercalators: DNA imaging and cytotoxicity. ChemBioChem, 2011, 12(6), 877-880.
[7]
Medici, S.; Peana, M.; Nurchi, V.M.; Lachowicz, J.I.; Crisponi, G.; Zoroddu, M.A. Noble metals in medicine: Latest advances. Coord. Chem. Rev., 2015, 284, 329-350.
[8]
Cardoso, C.R.; Lima, M.V.S.; Cheleski, J.; Peterson, E.J.; Venancio, T.; Farrell, N.P.; Carlos, R.M. Luminescent ruthenium complexes for theranostic applications. J. Med. Chem., 2014, 57(11), 4906-4915.
[9]
Chen, Y.; Qin, M.Y.; Wang, L.; Chao, H.; Ji, L.N.; Xu, A.L. A ruthenium(II) β-carboline complex induced p53-mediated apoptosis in cancer cells. Biochimie, 2013, 95(11), 2050-2059.
[10]
Li, M.J.; Wong, K.M.C.; Yi, C.; Yam, V.W.W. New ruthenium(II) complexes functionalized with coumarin derivatives: synthesis, energy-transfer-based sensing of esterase, cytotoxicity, and imaging studies. Chem.Eur. J., 2012, 18, 8727-8730.
[11]
Yu, H.J.; Chen, Y.; Yu, L.; Hao, Z.F.; Zhou, L.H. Synthesis, visible light photocleavage, antiproliferative and cellular uptake properties of ruthenium complex [Ru(phen)2(mitatp)]2+. Eur. J. Med. Chem., 2012, 55, 146-154.
[12]
Wang, C.; Yu, Q.; Yang, L.; Liu, Y.; Sun, D.; Huang, Y.; Zhou, Y.; Zhang, Q.; Liu, J. Ruthenium (II) polypyridyl complexes stabilize the bcl-2 promoter quadruplex and induce apoptosis of Hela tumor cells. Biometals, 2013, 26(3), 387-402.
[13]
Guo, Q.F.; Liu, S.H.; Liu, Q.H.; Xu, H.H.; Zhao, J.H.; Wu, H.F.; Li, X.Y.; Wang, J.W. Cytotoxicity, apoptosis, cellular uptake, cell cycle distribution, and DNA-binding investigation of ruthenium complexes. DNA Cell Biol., 2012, 31(7), 1205-1213.
[14]
Lo, K.K.W.; Lee, T.K.M.; Lau, J.S.Y.; Poon, W.L.; Cheng, S.H. Luminescent biological probes derived from ruthenium(II) estradiol polypyridine complexes. Inorg. Chem., 2008, 47, 200-208.
[15]
Srishailam, A.; Kumar, Y.R.; Gabra, N.M.D.; Reddy, P.V.; Deepika, N.; Veerababu, N.; Satyanarayanna, S. Synthesis, DNA-binding, cytotoxicity, photo cleavage, antimicrobal and docking studies of Ru(II) polypyridyl complexes. J. Fluoresc., 2013, 23(5), 897-908.
[16]
Zhang, J.X.; Zhou, J.W.; Chan, C.F.; Kwong, D.W.J.; Tam, H.L.; Mak, N.K.; Wong, K.L.; Wong, W.K. Comparative studies of the cellular uptake, subcellular localization, and cytotoxic and phototoxic antitumor properties of ruthenium(II)−porphyrin conjugates with different linkers. BioConjugate Chem., 2012, 23, 1623-1638.
[17]
Xie, Y.Y.; Huang, H.L.; Yao, J.H.; Lin, G.J.; Jiang, G.B.; Liu, Y.J. DNA-binding, photocleavage, cytotoxicity in vitro, apoptosis and cell cycle arrest studies of symmetric ruthenium(II) complexes. Eur. J. Med. Chem., 2013, 63, 603-610.
[18]
Dobrucki, J.W. Interaction of oxygen-sensitive luminescent probes [Ru(phen)3]2+ and [Ru(bipy)3]2+ with animal and plant cells in vitro - Mechanism of phototoxicity and conditions for non-invasive oxygen measurements. J. Photochem. Photobiol. B-Biol, 2001, 65(2-3), 136-144.
[19]
Komatsu, H.; Yoshihara, K.; Yamada, H.; Kimura, Y.; Son, A.; Nishimoto, S.; Tanabe, K. Ruthenium complexes with hydrophobic ligands that are key factors for the optical imaging of physiological hypoxia. Chem. Eur. J., 2013, 19(6), 1971-1977.
[20]
Mazuryk, O.; Maciuszek, M.; Stochel, G.; Suzenet, F.; Brindell, M. 2-Nitroimidazole-ruthenium polypyridyl complex as a new conjugate for cancer treatment and visualization. J. Inorg. Biochem., 2014, 134, 83-91.
[21]
Mazuryk, O.; Magiera, K.; Rys, B.; Suzenet, F.; Kieda, C.; Brindell, M. Multifaceted interplay between lipophilicity, protein interaction and luminescence parameters of non-intercalative ruthenium(II) polypyridyl complexes controlling cellular imaging and cytotoxic properties. J. Biol. Inorg. Chem., 2014, 19(8), 1305-1316.
[22]
Liu, X.W.; Chen, Z.G.; Li, L.; Chen, Y.D.; Lu, J.L.; Zhang, D.S. DNA-binding, photocleavage studies of ruthenium(II) complexes with 2-(2-quinolinyl) imidazo 4,5-f 1,10 phenanthroline. Spectroc. Acta Pt. A-Mol. Biomol. Spectr., 2013, 102, 142-149.
[23]
Liu, X.W.; Zhang, S.B.; Li, L.; Chen, Y.D.; Lu, J.L. Ruthenium (II) complexes containing a new asymmetric ligand: DNA interaction, photocleavage and topoisomerase I inhibition. J. Organomet. Chem., 2013, 729, 1-8.
[24]
Available from. https://clinicaltrials.gov Identifier: NCT03053635.
[25]
Poynton, F.E.; Bright, S.A.; Blasco, S.; Williams, D.C.; Kelly, J.M.; Gunnlaugsson, T. The development of ruthenium(II) polypyridyl complexes and conjugates for: In vitro cellular and in vivo applications. Chem. Soc. Rev., 2017, 46(24), 7706-7756.
[26]
Mazuryk, O.; Suzenet, F.; Kieda, C.; Brindell, M. The biological effect of the nitroimidazole derivative of a polypyridyl ruthenium complex on cancer and endothelial cells. Metallomics, 2015, 7(3), 553-566.
[27]
Łomzik, M.; Mazuryk, O.; Rutkowska-Zbik, D.; Stochel, G.; Gros, P.C.; Brindell, M. New ruthenium compounds bearing semicarbazone 2-formylopyridine moiety: Playing with auxiliary ligands for tuning the mechanism of biological activity. J. Inorg. Biochem., 2017, 175, 80-91.
[28]
Gao, F.; Chao, H.; Zhou, F.; Yuan, Y.X.; Peng, B.; Ji, L.N. DNA interactions of a functionalized ruthenium(II) mixed-polypyridyl complex [Ru(bpy)2ppd]2+. J. Inorg. Biochem., 2006, 100(9), 1487-1494.
[29]
Puckett, C.A.; Barton, J.K. Targeting a ruthenium complex to the nucleus with short peptides. Bioorg. Med. Chem., 2010, 18, 3564-3569.
[30]
Puckett, C.A.; Barton, J.K. Fluorescein redirects a ruthenium-octaarginine conjugate to the nucleus. J. Am. Chem. Soc., 2009, 131(25), 8738-8739.
[31]
Blackmore, L.; Moriarty, R.; Dolan, C.; Adamson, K.; Forster, R.J.; Devocelle, M.; Keyes, T.E. Peptide directed transmembrane transport and nuclear localization of Ru(II) polypyridyl complexes in mammalian cells. Chem. Commun., 2013, 49, 2658-2660.
[32]
Kumar, D.; Banerjee, D. Methods of albumin estimation in clinical biochemistry: Past, present, and future. Clin. Chim. Acta, 2017, 469, 150-160.
[33]
Kuscuoglu, D.; Janciauskiene, S.; Hamesch, K.; Haybaeck, J.; Trautwein, C.; Strnad, P. Liver – master and servant of serum proteome. J. Hepatol., 2018, 69(2), 512-524.
[34]
He, X.M.; Carter, D.C. Atomic structure and chemistry of human serum albumin. Nature, 1992, 358(6383), 209-215.
[35]
Soriani, M.; Pietraforte, D.; Minetti, M. Antioxidant potential of anaerobic human plasma: Role of serum albumin and thiols as scavengers of carbon radicals. Arch. Biochem. Biophys., 1994, 312(1), 180-188.
[36]
Petitpas, I.; Bhattacharya, A.A.; Twine, S.; East, M.; Curry, S. Crystal structure analysis of warfarin binding to human serum albumin. Anatomy of drug site I. J. Biol. Chem., 2001, 276(25), 22804-22809.
[37]
Nurdiansyah, R. Rifa’I, M.; Widodo. A comparative analysis of serum albumin from different species to determine a natural source of albumin that might be useful for human therapy. J. Taibah. Univ. Sci., 2016, 11(3), 243-249.
[38]
Bailey, S.; Evans, R.W.; Garratt, R.C.; Gorinskv, B.; Mydin, A.; Horsburg, C.; Jhoti, H.; Lindley, P.F.; Hasnain, S.; Sarra, R.; Watson, J.L. Molecular structure of serum transferrin at 3: 3-A resolution. Biochemistry, 1988, 27(15), 5804-5812.
[39]
Weinberg, E.D. The hazards of iron loading. Metallomics, 2010, 2(11), 732-740.
[40]
Fanali, G.; di Masi, A.; Trezza, V.; Marino, M.; Fasano, M.; Ascenzi, P. Human serum albumin: From bench to bedside. Mol. Asp. Med., 2012, 33(3), 209-290.
[41]
Elsadek, B.; Kratz, F. Impact of albumin on drug delivery - New applications on the horizon. J. Control. Release, 2012, 157(1), 4-28.
[42]
Kratz, F.; Elsadek, B. Clinical impact of serum proteins on drug delivery. J. Control. Release, 2012, 161(2), 429-445.
[43]
Kratz, F. A clinical update of using albumin as a drug vehicle - A commentary. J. Control. Release, 2014, 190, 331-336.
[44]
Szwed, M.; Matusiak, A.; Laroche-Clary, A.; Robert, J.; Marszalek, I.; Jozwiak, Z. Transferrin as a drug carrier: Cytotoxicity, cellular uptake and transport kinetics of doxorubicin transferrin conjugate in the human leukemia cells. Toxicol. In vitro, 2014, 28(2), 187-197.
[45]
Kratz, F. Drug conjugates with albumin and transferrin. Expert Opin. Ther. Pat., 2002, 12(3), 433-439.
[46]
Daniels, T.R.; Bernabeu, E.; Rodríguez, J.A.; Patel, S.; Kozman, M.; Chiappetta, D.A.; Holler, E.; Ljubimova, J.Y.; Helguera, G.; Penichet, M.L. The transferrin receptor and the targeted delivery of therapeutic agents against cancer. Biochim. Biophys. Acta, Gen. Subj., 2012, 1820(3), 291-317.
[47]
Verrijk, R.; Smolders, I.J.H.; McVie, J.G.; Begg, A.C. Polymer-coated albumin microspheres as carriers for intravascular tumour targeting of cisplatin. Cancer Chemother. Pharmacol., 1991, 29(2), 117-121.
[48]
Chen, H.K.; Zhang, S.M.; Chang, J.L.; Chen, H.C.; Lin, Y.C.; Shih, C.P.; Sytwu, H.K.; Fang, M.C.; Lin, Y.Y.; Kuo, C.Y.; Liao, A.H.; Chu, Y.H.; Wang, C.H. Insonation of systemically delivered cisplatin-loaded microbubbles significantly attenuates nephrotoxicity of chemotherapy in experimental models of head and neck cancer. Cancers, 2018, 10(9)E311
[49]
Bergamo, A.; Messori, L.; Piccioli, F.; Cocchietto, M.; Sava, G. Biological role of adduct formation of the ruthenium(III) complex NAMI-A with serum albumin and serum transferrin. Invest. New Drugs, 2003, 21, 401-411.
[50]
Novohradský, V.; Bergamo, A.; Cocchietto, M.; Zajac, J.; Brabec, V.; Mestroni, G.; Sava, G. Influence of the binding of reduced NAMI-A to human serum albumin on the pharmacokinetics and biological activity. Dalton Trans., 2015, 44(4), 1905-1913.
[51]
Frausin, F.; Cocchietto, M.; Bergamo, A.; Scarcia, V.; Furlani, A.; Sava, G. Tumour cell uptake of the metastasis inhibitor ruthenium complex NAMI-A and its in vitro effects on KB cells. Cancer Chemother. Pharmacol., 2002, 50(5), 405-411.
[52]
Mazuryk, O.; Kurpiewska, K.; Lewinski, K.; Stochel, G.; Brindell, M. Interaction of apo-transferrin with anticancer ruthenium complexes NAMI-A and its reduced form. J. Inorg. Biochem., 2012, 116, 11-18.
[53]
Śpiewak, K.; Brindell, M. Impact of low- and high-molecular-mass components of human serum on NAMI-A binding to transferrin. J. Biol. Inorg. Chem., 2015, 20(4), 695-703.
[54]
Liu, Y.; Yu, Q.; Wang, C.; Sun, D.; Huang, Y.; Zhou, Y.; Liu, J. Ruthenium (II) complexes binding to human serum albumin and inducing apoptosis of tumor cells. Inorg. Chem. Comm., 2012, 24, 104-109.
[55]
Lai, S.H.; Li, W.; Wang, X.Z.; Zhang, C.; Zeng, C.C.; Tang, B.; Wan, D.; Liu, Y.J. Apoptosis, autophagy, cell cycle arrest, cell invasion and BSA-binding studies: In vitro of ruthenium(II) polypyridyl complexes. RSC Adv, 2016, 6(68), 63143-63155.
[56]
Beckford, F.A.; Thessing, J.; Shaloski, M. Jr; Mbarushimana, P.C.; Brock, A.; Didion, J.; Woods, J.; Gonzalez-Sarrías, A.; Seeram, N.P. Synthesis and characterization of mixed-ligand diimine-piperonal thiosemicarbazone complexes of ruthenium(II): Biophysical investigations and biological evaluation as anticancer and antibacterial agents. J. Mol. Struct., 2011, 992(1-3), 39-47.
[57]
Morais, T.S.; Santos, F.C.; Jorge, T.F.; Côrte-Real, L.; Madeira, P.J.A.; Marques, F.; Robalo, M.P.; Matos, A.; Santos, I.; Garcia, M.H. New water-soluble ruthenium(II) cytotoxic complex: Biological activity and cellular distribution. J. Inorg. Biochem., 2014, 130(1), 1-14.
[58]
Dias, J.S.M.; Silva, H.V.R.; Ferreira-Silva, G.Á.; Ionta, M.; Corrêa, C.C.; Almeida, F.; Colina-Vegas, L.; Barbosa, M.I.F.; Doriguetto, A.C. Pro-apoptotic activity of ruthenium 1-methylimidazole complex on non-small cell lung cancer. J. Inorg. Biochem., 2018, 187, 1-13.
[59]
de Melo, A.C.C.; Santana, J.M.S.V.P.; da Costa Nunes, K.J.R.; de Amorim Marques, M.; de Oliveira, G.A.P.; Moraes, A.H.; Pereira-Maia, E.C. Interactions of ruthenium(II) compounds with sulfasalazine and N,N′-heterocyclic ligands with proteins. Inorg. Chim. Acta, 2017, 467, 385-390.
[60]
http://www.vcclab.org VCCLAB (Virtual Computational Chemistry Laboratory). (accessed 04.2015).
[61]
http://www.molinspiration.com . Molinspiration Property Calculation Service. (accessed 04.2015).
[62]
Mehrotra, R.; Shukla, S.N.; Gaur, P. Promising trend for amendment of drug molecule against resist pathogens: Synthesis, characterization, and application. Med. Chem. Res., 2012, 21(12), 4455-4462.
[63]
Kaspler, P.; Lazic, S.; Forward, S.; Arenas, Y.; Mandel, A.; Lilge, L. A ruthenium(II) based photosensitizer and transferrin complexes enhance photo-physical properties, cell uptake, and photodynamic therapy safety and efficacy. Photochem. Photobiol. Sci., 2016, 15(4), 481-495.
[64]
Giménez, R.E.; Vargová, V.; Rey, V.; Turbay, M.B.E.; Abatedaga, I.; Morán Vieyra, F.E.; Paz Zanini, V.I.; Mecchia Ortiz, J.H.; Katz, N.E.; Ostatná, V.; Borsarelli, C.D. Interaction of singlet oxygen with bovine serum albumin and the role of the protein nano-compartmentalization. Free Radic. Biol. Med., 2016, 94, 99-109.
[65]
Rajendiran, V.; Palaniandavar, M.; Periasamy, V.S. Akbarsha, M.A. New [Ru(5,6-dmp/3,4,7,8-tmp)2(diimine)]2+ complexes: Non-covalent DNA and protein binding, anticancer activity and fluorescent probes for nuclear and protein components. J. Inorg. Biochem., 2012, 116, 151-162.
[66]
Castellano, F.N.; Dattelbaum, J.D.; Lakowicz, J.R. Long-lifetime Ru(II) complexes as labeling reagents for sulfhydryl groups. Anal. Biochem., 1998, 255(2), 165-170.
[67]
Lasey, R.C.; Banerji, S.S.; Ogawa, M.Y. Synthesis and characterization of a sequence-specific DNA-binding protein that contains ruthenium polypyridyl centers. Inorg. Chim. Acta, 2000, 300-302, 822-828.
[68]
Wragg, A.; Gill, M.R.; McKenzie, L.; Glover, C.; Mowll, R.; Weinstein, J.A.; Su, X.; Smythe, C.; Thomas, J.A. Serum albumin binding inhibits nuclear uptake of luminescent metal-complex-based DNA imaging probes. Chem. Eur. J., 2015, 21(33), 11865-11871.
[69]
Belej, D.; Jurasekova, Z.; Nemergut, M.; Wagnieres, G.; Jancura, D.; Huntosova, V. Negligible interaction of [Ru(Phen)3]2+ with human serum albumin makes it promising for a reliable in vivo assessment of the tissue oxygenation. J. Inorg. Biochem., 2017, 174, 37-44.
[70]
Li, X.; Zhang, Y.; Chen, H.; Sun, J.; Feng, F. Protein nanocages for delivery and release of luminescent ruthenium(II) polypyridyl complexes. ACS Appl. Mater. Interfaces, 2016, 8(35), 22756-22761.
[71]
Li, F.F.; Feterl, M.; Warner, J.M.; Day, A.I.; Keene, F.R.; Collins, J.G. Protein binding by dinuclear polypyridyl ruthenium(II) complexes and the effect of cucurbit[10]uril encapsulation. Dalton Trans., 2013, 42(24), 8868-8877.
[72]
Neugebauer, U.; Cosgrave, L.; Pellegrin, Y.; Devocelle, M.; Forster, R.J.; Keyes, T.E. In Membrane permeable luminescent metal complexes for cellular imaging, SPIE Photonics Europe; SPIE, 2012, p. 13.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 11
Year: 2019
Published on: 23 October, 2019
Page: [1052 - 1059]
Pages: 8
DOI: 10.2174/1389203720666190513090851
Price: $65

Article Metrics

PDF: 23
HTML: 2
EPUB: 1
PRC: 1