title: Effect of gallium-porphyrin analogue ATX-70 on nitroxide formation from a cyclic secondary amine by ultrasound: on the mechanism of sonodynamic activation.
abstract: Sonodynamic therapy is a promising new modality for cancer treatment based on the synergistic effect on tumor cell killing by combination of a drug (typically a photosensitizer) and ultrasound. The mechanism of sonodynamic action was suggested to involve photoexcitation of the sensitizer by sonoluminescent light, with subsequent formation of singlet oxygen. In this work we studied the aqueous sonochemical reactions of the gallium-porphyrin derivative ATX-70, one of the most active sonodynamic agents found, using 50 kHz ultrasound. The experiments were carried out in the presence of 2,2,6,6-tetramethyl-4-piperidone hydrochloride (TMP), which reacts with singlet oxygen or .OH radicals to give the EPR-detectable nitroxide 2,2,6,6-tetramethyl-4-piperidone-N-oxyl (TMP-NO). Recently it has been suggested that the enhancement of TMP-NO yields in the presence of aqueous solutions of ATX-70 exposed to ultrasound was evidence for the formation of singlet oxygen in the system. Our results show that the surfactant cetyltrimethylammonium bromide (CTAB) can mimic the ATX-70-induced increase in the TMP-NO signal, but it fails to reproduce the behavior of ATX-70 in D2O: while the yields of TMP-NO in the presence of ATX-70 increase in D2O, the opposite effect was found with the surfactant CTAB. However, our data show that the increased TMP-NO yields in D2O are paralleled by an increased concentration of ATX-70 dimer, a form that is inactive in the photochemical generation of singlet oxygen. Our finding that the ATX-70-dependent enhancement of the TMP-NO signal was highest at approximately 20% O2, in both N2/O2 and argon/O2 mixtures, and decreased with increasing oxygen concentration is not compatible with the singlet oxygen mechanism. Finally, our results on the temperature dependence of the ATX-70-induced formation of TMP-NO are not consistent with the photochemical excitation of ATX-70 by sonoluminescent light: the ATX-70-dependent enhancement of TMP-NO signal increased with temperature in the range 10-25 degrees C, while the intensity of sonoluminescence of aqueous solutions both in multiple-bubble fields and in single-bubble experiments is known to decrease with increasing temperature.
authors.affiliation: Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: N
authors.initials: N
authors.lastname: Miyoshi
authors.forename: V
authors.initials: V
authors.lastname: Misík
authors.forename: M
authors.initials: M
authors.lastname: Fukuda
authors.forename: P
authors.initials: P
authors.lastname: Riesz
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D003903:Deuterium; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D009589:Nitrogen Oxides / Q000378:metabolism*; D010100:Oxygen / Q000737:chemistry; D010881:Piperidones / Q000737:chemistry; D011166:Porphyrins / Q000737:chemistry / Q000494:pharmacology*; D014216:Triacetoneamine-N-Oxyl / Q000031:analogs & derivatives / Q000737:chemistry; D014465:Ultrasonics; D014867:Water
chemical_list: D000970:Antineoplastic Agents; D005609:Free Radicals; D009589:Nitrogen Oxides; D010881:Piperidones; D011166:Porphyrins; D014867:Water; C081908:ATX 70; D014216:Triacetoneamine-N-Oxyl; C002273:tempidon; D003903:Deuterium; C039900:nitroxyl; D010100:Oxygen