Phosphorescent ruthenium complexes with a nitroimidazole unit that image oxygen fluctuation in tumor tissue.

Understanding oxygen fluctuation in a cancerous tumor is important for effective treatment, especially during radiotherapy. In this paper, ruthenium complexes bearing a nitroimidazole group are shown to report the oxygen status in tumor tissue directly. The nitroimidazole group was known to be accumulated in hypoxic tumor tissues. On the other hand, the ruthenium complex showed strong phosphorescence around 600 nm. The emission of ruthenium is quenched instantaneously by molecular oxygen due to energy transfer between triplet states of oxygen and ruthenium complex, but the emission is then recovered by the removal of oxygen. Thus, we could observe oxygen fluctuation in tumor tissue in a real-time manner by monitoring the phosphorescence of the ruthenium complex. The versatility of the probe is demonstrated by monitoring oxygen fluctuation in living cells and tumor tissue planted in mice. The ruthenium complex promptly penetrated plasma membrane and accumulated in cells to emit its oxygen-dependent phosphorescence. In vivo experiments revealed that the oxygen level in tumor tissue seems to fluctuate at the sub-minute timescale.

[1]  Olga Mazuryk,et al.  2-Nitroimidazole-ruthenium polypyridyl complex as a new conjugate for cancer treatment and visualization. , 2014, Journal of inorganic biochemistry.

[2]  K. K. Lo,et al.  Utilization of the photophysical and photochemical properties of phosphorescent transition metal complexes in the development of photofunctional cellular sensors, imaging reagents, and cytotoxic agents , 2014 .

[3]  Robie A. Hennigar,et al.  Exploitation of long-lived 3IL excited states for metal-organic photodynamic therapy: verification in a metastatic melanoma model. , 2013, Journal of the American Chemical Society.

[4]  Dmitri B Papkovsky,et al.  Biological detection by optical oxygen sensing. , 2013, Chemical Society reviews.

[5]  K. Christensen,et al.  Peptide-targeted delivery of a pH sensor for quantitative measurements of intraglycosomal pH in live Trypanosoma brucei. , 2013, Biochemistry.

[6]  S. Nishimoto,et al.  Ruthenium complexes with hydrophobic ligands that are key factors for the optical imaging of physiological hypoxia. , 2013, Chemistry.

[7]  Alex Soltermann,et al.  Dynamics of Tumor Hypoxia in Response to Patupilone and Ionizing Radiation , 2012, PloS one.

[8]  A. Mathur,et al.  On the structural modification of 2-nitroimidazole-(99m)Tc(CO)(3) complex, a hypoxia marker, for improving in vivo pharmacokinetics. , 2012, Nuclear medicine and biology.

[9]  Wen Shi,et al.  Development of hypoxia enhanced 111In-labeled Bombesin conjugates: design, synthesis, and in vitro evaluation in PC-3 human prostate cancer. , 2012, Bioconjugate chemistry.

[10]  Scott S. Verbridge,et al.  Phosphorescent nanoparticles for quantitative measurements of oxygen profiles in vitro and in vivo. , 2012, Biomaterials.

[11]  Dmitri B Papkovsky,et al.  Assessment of cellular oxygen gradients with a panel of phosphorescent oxygen-sensitive probes. , 2012, Analytical chemistry.

[12]  H. Nagasawa,et al.  2-Nitroimidazole-tricarbocyanine conjugate as a near-infrared fluorescent probe for in vivo imaging of tumor hypoxia. , 2012, Bioconjugate chemistry.

[13]  Ingo Klimant,et al.  Intracellular O2 sensing probe based on cell-penetrating phosphorescent nanoparticles. , 2011, ACS nano.

[14]  James B. Mitchell,et al.  Imaging cycling tumor hypoxia. , 2010, Cancer research.

[15]  Koichi Nozaki,et al.  Recent advances in instrumentation for absolute emission quantum yield measurements , 2010 .

[16]  James B. Mitchell,et al.  Low-field magnetic resonance imaging to visualize chronic and cycling hypoxia in tumor-bearing mice. , 2010, Cancer research.

[17]  Shasha Liu,et al.  Tuning the luminescence lifetimes of ruthenium(II) polypyridine complexes and its application in luminescent oxygen sensing , 2010 .

[18]  Kazuya Negishi,et al.  Phosphorescent light-emitting iridium complexes serve as a hypoxia-sensing probe for tumor imaging in living animals , 2010, BiOS.

[19]  Flora L Thorp-Greenwood,et al.  Application of d6 transition metal complexes in fluorescence cell imaging. , 2010, Chemical communications.

[20]  M. Dewhirst.  Relationships between Cycling Hypoxia, HIF-1, Angiogenesis and Oxidative Stress , 2009, Radiation research.

[21]  G. Lukács,et al.  Site-specific ubiquitination exposes a linear motif to promote interferon-α receptor endocytosis , 2007, The Journal of cell biology.

[22]  T. Kamachi,et al.  Development of novel optical oxygen sensing system based on stationary T–T absorption , 2006 .

[23]  Bruce Klitzman,et al.  Direct demonstration of instabilities in oxygen concentrations within the extravascular compartment of an experimental tumor. , 2006, Cancer research.

[24]  Bernard Gallez,et al.  The role of vessel maturation and vessel functionality in spontaneous fluctuations of T2*‐weighted GRE signal within tumors , 2006, NMR in biomedicine.

[25]  Sergei A Vinogradov,et al.  Oxygen distribution in murine tumors: characterization using oxygen-dependent quenching of phosphorescence. , 2005, Journal of applied physiology.

[26]  K. Bennewith,et al.  Quantifying Transient Hypoxia in Human Tumor Xenografts by Flow Cytometry , 2004, Cancer Research.

[27]  Benoit Macq,et al.  Physiological noise in murine solid tumours using T2*-weighted gradient-echo imaging: a marker of tumour acute hypoxia? , 2004, Physics in medicine and biology.

[28]  Sergei A Vinogradov,et al.  Oxyphor R2 and G2: phosphors for measuring oxygen by oxygen-dependent quenching of phosphorescence. , 2002, Analytical biochemistry.

[29]  K. Kohshi,et al.  Preservation of tumour oxygen after hyperbaric oxygenation monitored by magnetic resonance imaging , 1999, British Journal of Cancer.

[30]  M. Dewhirst,et al.  Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. , 1999, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[31]  G S Karczmar,et al.  Correlation of magnetic resonance and oxygen microelectrode measurements of carbogen-induced changes in tumor oxygenation. , 1998, International journal of radiation oncology, biology, physics.

[32]  Rakesh K. Jain,et al.  Interstitial pH and pO2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation , 1997, Nature Medicine.

[33]  M. Dewhirst,et al.  Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. , 1996, Cancer research.

[34]  P Vaupel,et al.  Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. , 1996, Cancer research.

[35]  E. Rofstad,et al.  Fluctuations in pO2 in Irradiated Human Melanoma Xenografts , 2006, Radiation research.