Studies of KP46 and KP1019 and the Hydrolysis Product of KP1019 in Lipiodol Emulsions: Preparation and Initial Characterizations as Potential Theragnostic Agents.

BACKGROUND: Lipiodol (iodized poppy seed oil) accumulates predominately in the tumor rather than in the liver tissue [1, 2]. Therefore, mixing anticancer drugs with Lipiodol may enhance the antitumor effect by increasing the local drug concentration. OBJECTIVE: In this pilot study, we made use of Lipiodol as a potential carrier of three promising antitumor metal complexes (tris(8-quinolato)gallium(III) (KP46), tetrachlorobis(indazole)ruthenate(III) (KP1019) and the hydrolysis product of KP1019, mer,trans-[RuCl3(H2O)(Hind)2]. METHODS: The stability of the drugs in Lipiodol and the release profile into the aqueous phase were examined independently by three different analytical techniques (high pressure liquid chromatography, HPLC; atom absorption spectroscopy, AAS; and electron spray ionization mass spectrometry, ESI-MS). RESULTS: The complexes were stable and remained in the Lipiodol emulsion over 3 days. In contrast to KP1019 and KP46, evaluation of Lipiodol emulsions of mer,trans-[RuCl3 (H2O) (Hind) 2] was not possible due to the insolubility of the compound in Lipiodol. KP1019 released rapidly into the aqueous phase in the first week and after 1 month it was not possible to detect the complex in the emulsion. KP46 showed a gradual release with the time resulting in the release of about 6.4 % of KP46 into the aqueous phase after 1 month of incubation. CONCLUSION: The initial results show that Lipiodol can be successfully employed as a carrier of anticancer Ru- or Ga-complexes. Furthermore, advantages can overcome the poor water solubility of the metal complexes, opening new perspectives for the use of Lipiodol emulsions in molecular imaging and cancer therapy as theragnostic agents.

Iodine isotopes (127I and 129I) in aerosols at high altitude Alp stations.

Concentrations of gases and particulate matter have been proven to be affected by meteorological and geographical variables from urban locations to high mountain clean air sites. Following our previous research in Vienna, we summarize here new findings about concentration levels of iodine isotopes in aerosols collected at two Alpine meteorological stations, Sonnblick (Austria) and Zugspitze (Germany) during 2001. The present study mainly focuses on the effect of altitude on the anthropogenic concentration of (129)I and on the isotopic ratio (129)I/(127)I. Iodine was separated from matrix elements by using either an anion exchange method or solvent extraction, and was analyzed by ICP-MS and AMS. Over the altitude change from Vienna to Zugspitze and Sonnblick (202 m to 2962 m and 3106 m above sea level), stable iodine level decreased from an average of 0.94 ng m(-3) to 0.52 ng m(-3) and 0.62 ng m(-3), respectively. Similarly, (129)I concentrations at both Alpine stations were about 1 order of magnitude lower (10(4) atoms m(-3)) than values obtained for Vienna (10(5) atoms m(-3)) and reveal a strong vertical concentration gradient of (129)I. A high degree of variability is observed, which is due to wide variation in the origin of air masses. Furthermore, air trajectory analysis demonstrates the importance of large scale air transport mostly from southeast Europe for influencing Sonnblick whereas influence from northwest Europe is strong at Zugspitze. In contrast to (129)I, a higher concentration of (7)Be was found at higher altitude stations compared to Vienna which probably results from its production in the upper atmosphere.

Retrospective measurements of airborne 129iodine in Austria.

The knowledge about the distribution of anthropogenic (129)I is crucial for a successful establishment of transport mechanisms, fate and behaviour in the environment. In present study, the historical record of dry deposition of (129)I in Austria over four decades back to the 1960s is reconstructed. The (129)I/(127)I isotopic ratio of the order of 10(-9)-10(-7) in airborne particles revealed a prominent anthropogenic (129)I signature. The time profile of airborne (129)I follows directly the pattern of the gaseous emissions from European reprocessing plants. Furthermore, temporal variations of (129)I were traced monthly over two years. The potential risks of internal exposure to (129)I are associated with both inhalation and ingestion. Since dose via inhalation was found insignificant, the thyroid equivalent dose from the internal exposure of (129)I using a value of 10(-8) for the isotopic ratio (129)I/(127)I in the thyroid and ICRP reference man was calculated. The corresponding thyroid cancer risk factor of 10(-11) for an adult from life-time exposure is one order of magnitude higher than for a 1-year old child. Due to low radiation toxicity of (129)I the annual dose is 8 × 10(4) times lower than the dose limit of the National Research Council, USA which is 0.04 mSv y(-1) to whole body or any organ for a combined beta and photon emitting radionuclide.

Monitoring of radionuclides in soil and bone samples from Austria.

The activity concentrations of anthropogenic (9°Sr, ¹³7Cs) and natural (²³8U, ²³²Th, 4°K, ²¹°Pb) radionuclides were determined in eight soil profiles from three different regions in Austria (Styria, Carinthia and Salzburg). A direct correlation between the activity concentration of 9°Sr and ¹³7Cs in soil samples and site altitude was found. 9°Sr and ²¹°Pb activity concentrations were also determined in bone ash of deer hunted in these regions. Additional bone samples were collected all over Austria. Totally 39 deer bones were investigated for this work, and some values were adopted from our earlier publications to give an overview of samples collected from sites covering a broad range of altitudes. The bone and soil samples were collected in the time period of 2001-2009. The 9°Sr values in deer bones are directly proportional to the values in the respective soil samples and also to the age of the animals. For the 9°Sr and ²¹°Pb determinations in bone samples first Pb was separated on a Dowex column, then Sr was purified using Sr·Spec® resin. In soil samples an additional hydroxide precipitation was employed to eliminate interfering iron. For the first time also the 3M Empore® Sr Rad disk method was successfully applied to bone samples. With this method the chemical procedure can be shortened by more than a factor of 2. The 9°Sr and ²¹°Pb fractions were measured by liquid scintillation counting, while the chemical yields were determined by ICP-MS. The activity concentrations of 4°K, ²³8U, ²³²Th and ¹³7Cs in soil samples were evaluated using gamma-ray spectrometry. The investigation was part of the PhD work of the first author.

The first metal-based paullone derivative with high antiproliferative activity in vitro.

9-Bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one, kenpaullone, which displays similarities in the activity profile to flavopiridol, was modified by chemical transformations at the lactam unit to provide a peripheral binding site able to accommodate metal ions. The first metal-based paullone has been prepared and characterized by single-crystal X-ray diffraction methods, solid-state cross-polarization magic angle spinning 13C NMR spectroscopy, electrospray ionization mass spectra, and electronic spectra. The gallium complex [GaL2]Cl.2.5H2O, the metal-free ligand (HL), and the starting compound used for the preparation of HL were assessed in vitro for their cytotoxicity in a panel of human tumor cell lines. The gallium complex was found to be 1.5-18-fold more cytotoxic than HL, with an average IC50 value of 2.0 microM.

Tuning of redox properties for the design of ruthenium anticancer drugs: part 2. Syntheses, crystal structures, and electrochemistry of potentially antitumor [Ru III/II Cl6-n(Azole)n]z(n = 3, 4, 6) complexes.

A series of mixed chloro-azole ruthenium complexes with potential antitumor activity, viz., mer-[RuIIICl3(azole)3] (B), trans-[RuIIICl2(azole)4]Cl (C), trans-[RuIICl2(azole)4] (D), and [RuII(azole)6](SO3CF3)2 (E), where azole = 1-butylimidazole (1), imidazole (2), benzimidazole (3), 1-methyl-1,2,4-triazole (4), 4-methylpyrazole (5), 1,2,4-triazole (6), pyrazole (7), and indazole (8), have been prepared as a further development of anticancer drugs with the general formula [RuCl4(azole)2]- (A). These compounds were characterized by elemental analysis, IR spectroscopy, electronic spectra, electrospray mass spectrometry, and X-ray crystallography. The electrochemical behavior has been studied in detail in DMF, DMSO, and aqueous media using cyclic voltammetry, square wave voltammetry, and controlled potential electrolysis. Compounds B and a number of C complexes exhibit one RuIII/RuII reduction, followed, at a sufficiently long time scale, by metal dechlorination on solvolysis. The redox potential values in organic media agree with those predicted by Lever's parametrization method, and the yet unknown EL parameters were estimated for 1 (EL = 0.06 V), 3 (EL = 0.10 V), 4 (EL = 0.17 V), and 5 (EL = 0.18 V). The EL values for the azole ligands 1-8 correlate linearly with their basicity (pK(a) value of the corresponding azolium acid H2L+). In addition, a logarithmic dependence between the homogeneous rate constants for the reductively induced stepwise replacement of chloro ligands by solvent molecules and the RuIII/RuII redox potentials was observed. Lower E(1/2) values (higher net electron donor character of the ligands) result in enhanced kinetic rate constants of solvolysis upon reduction. The effect of the net charge on the RuIII/RuII redox potentials in water is tentatively explained by the application of the Born equation. In addition, the pH-dependent electrochemical behavior of trans-[RuCl2(1,2,4-triazole)4]Cl is discussed.