Radioactive decay of some radionuclides produces a shower of Auger electrons, potent ionizing radiation within a very short range in living tissue (typically ca. 100 nm). Therefore, they must be brought to DNA-containing cell compartments and preferentially directly to DNA to be fully biologically effective. They may be used for a triple-targeting approach (first targeting, polymer-based system targeting into tumor tissue due to EPR effect; second targeting, pH-controlled release of intercalator-bound Auger electron emitter in slightly acidic tumor tissue or endosome; third targeting, into DNA in cell nucleus by the intercalator) minimizing radiation burden of healthy tissues. We describe a first system of this type, an ellipticine derivative-bound iodine-125 attached to hydrazide moieties containing poly[N-(2-hydroxypropyl)methacrylamide]. The system is stable at pH 7.4 (0% intercalator released after 24 h incubation), while iodine-containing biologically active intercalator is released upon decrease of pH (25% intercalator released after 24 h incubation at pH 5.0-model of late endosomes). Both 2-N-(2-oxobutyl)-9-iodoellipticinium bromide and the noniodinated 2-N-(2-oxobutyl)ellipticinium bromide are potent intercalators, as proven by direct titration with DNA and ethidium displacement assay, and readily penetrate into cell nuclei, as proven by confocal microscopy. They retain chemotherapeutical antiproliferative properties of ellipticine against Raji, EL-4, and 4T1cells with IC(50) in the range 0.27-8.8 μmol/L. Polymer conjugate of 2-N-(2-oxobutyl)-9-iodoellipticinium bromide is internalized into endosomes, releases active drug, possesses cytotoxic activity, and the drug accumulates in cell nuclei.

• MeSH
• buněčné jádro účinky léků   metabolismus   MeSH
• DNA chemie   MeSH
• elektrony MeSH
• elipticiny chemie   farmakologie   MeSH
• hydraziny chemie   MeSH
• koncentrace vodíkových iontů MeSH
• kyseliny polymethakrylové chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• organely chemie   účinky léků   MeSH
• radioizotopy jodu MeSH
• stereoizomerie MeSH
• tkáňová distribuce MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Auger electrons-emitting radioisotopes (such as iodine-125) are a potentially effective cancer treatment. They are extremely biologically effective, but only within a short range (nanometers). Their use as an effective cancer therapy requires that they will be transported within close proximity of DNA by an intercalator, where they induce double-strand breaks leading to cell death. This type of therapy may be even more beneficial when associated with drug delivery systems. In this report, we describe an optimized triple-targeted polymer delivery system for the intercalator ellipticine, which contains radioisotope iodine-125 with high specific radioactivity (63.2 GBq/mg). This compound is linked to an N-(2-hydroxypropyl)methacrylamide copolymer via an optimized acid-sensitive hydrazone linker. The system is stable at pH 7.4 (representing the pH of blood plasma), and the radioiodine-containing biologically active intercalator is released upon a decrease in pH (44% of the intercalator is released after 24h of incubation in pH 5.0 buffer, which mimics the pH in late endosomes). The active compound is a potent intercalator, as shown with direct titration with a DNA solution, and readily penetrates into cell nuclei, as observed by confocal microscopy. Its polymer conjugate is internalized into endosomes and releases the radioactive intercalator, which accumulates in the cell nuclei. In vivo experiments on mice with 4T1 murine breast cancer resulted in a statistically significant increase in the survival of mice treated with the polymer radioconjugate. The free radiolabeled intercalator was also shown to be effective, but it was less potent than the polymer conjugate.

• MeSH
• antitumorózní látky chemie   farmakologie   MeSH
• elektrony * MeSH
• elipticiny chemie   farmakologie   MeSH
• koncentrace vodíkových iontů MeSH
• léky antitumorózní - screeningové testy MeSH
• molekulární struktura MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádory prsu farmakoterapie   patologie   MeSH
• polymery chemická syntéza   chemie   MeSH
• radioizotopy jodu MeSH
• systémy cílené aplikace léků MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

PURPOSE: Geant4-DNA is used to calculate S-values for different subcellular distributions of low-energy electron sources in various cell geometries. METHOD: Calculations of cellular S-values for monoenergetic electron sources with energy from 1 to 100 keV and the Auger-electron emitting radionuclides Tc-99m, In-111, and I-125 have been made using the Geant4 Monte Carlo toolkit. The Geant4-DNA low-energy extension is employed for simulating collision-by-collision the complete slowing-down of electron tracks (down to 8 eV) in liquid water, used as a surrogate of human cells. The effect of cell geometry on S-values is examined by simulating electron tracks within different cell geometries, namely, a spherical, two ellipsoidal, and an irregular shape, all having equal cellular and nuclear volumes. Algorithms for randomly sampling the volume of the nucleus, cytoplasm, surface, and whole cell for each cell phantom are presented. RESULTS: Differences between Geant4-DNA and MIRD database up to 50% were found, although, for the present radionuclides, they mostly remain below 10%. For most source-target combinations the S-values for the spherical cell geometry were found to be within 20% of those for the ellipsoidal cell geometries, with a maximum deviation of 32%. Differences between the spherical and irregular geometries are generally larger reaching 100-300%. Most sensitive to the cell geometry is the absorbed dose to the nucleus when the source is localized on the cell surface. Interestingly, two published AAPM spectra for I-125 yield noticeable differences (up to 19%) in cellular S-values. CONCLUSION: Monte Carlo simulations of cellular S-values with Geant4-DNA reveal that, for the examined radionuclides, the widely used approximation of spherical cells is reasonably accurate (within 20-30%) even for ellipsoidal geometries. For irregular cell geometries the spherical approximation should be used with caution because, as in the present example, it may lead to erroneous results for the nuclear dose for the commonly encountered situation where the source is localized to the cell surface.

• MeSH
• absorpce radiace * MeSH
• biologické modely * MeSH
• dávka záření MeSH
• elektrony MeSH
• lidé MeSH
• metoda Monte Carlo MeSH
• počítačová simulace MeSH
• radiometrie metody   MeSH
• statistické modely * MeSH
• velikost buňky * MeSH
• viabilita buněk účinky léků   fyziologie   MeSH
• vztah dávky záření a odpovědi MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The ultrafast dynamic processes initiated by ioni¬zing radiation in water are discussed. At low photon energies, the primary processes are photoexcitation and photoionization. Both reaction channels ultimately lead to the formation of reactive species such as OH•radical or solvated electron. Ejection of low-lying electrons initiate further electron processes such as the Auger decay or the recently identified intermolecular Coulomb decay. All these processes contribute to radiation damage of biomolecules. Novel experimental and theoretical methods used for the study of primary events in radiation chemistry of water are described.

• Klíčová slova
• radiační chemie, Augerův rozpad, intermolekulární coulombovský rozpad, solvatovaný elektron, neadiabatická dynamika,
• MeSH
• voda MeSH

The aim of this work is to draw attention to possible injuries of the eye and the facial skeleton caused by firefighting sport. There was a group of 9 patients presented who were treated from 2006 to 2015 in the Department of Ophthalmology at the University Hospital in Pilsen and diagnosed with severe eyeball contusion after being hit by a jet of water and/or a water pipe. Three cases are presented in detail.

• MeSH
• fraktury lebky diagnostické zobrazování   etiologie   chirurgie   MeSH
• hasiči * MeSH
• hydrostatický tlak MeSH
• konjunktiva zranění   chirurgie   MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mydriáza diagnostické zobrazování   etiologie   chirurgie   MeSH
• následné studie MeSH
• obličejové kosti diagnostické zobrazování   zranění   MeSH
• odchlípení sítnice diagnostické zobrazování   etiologie   chirurgie   MeSH
• počítačová rentgenová tomografie MeSH
• pooperační komplikace etiologie   MeSH
• poranění obličeje diagnostické zobrazování   etiologie   chirurgie   MeSH
• poranění oka diagnostické zobrazování   etiologie   chirurgie   MeSH
• rizikové faktory MeSH
• sportovní úrazy diagnostické zobrazování   etiologie   chirurgie   MeSH
• zhmoždění diagnostické zobrazování   etiologie   chirurgie   MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH