Nitroxide radical containing nanoparticles with controlled radical release

Abstract:  Nitroxide radicals are known as scavengers of reactive oxygen species that cause oxidative stress and cell damage. It has also been found that nitroxide radicals induce apoptosis in cancer cells and suppress tumor growth. However, in "in vivo" conditions, these radicals cannot be efficiently used because of their non-specific accumulation in normal tissue and rapid excretion from the body. To overcome these difficulties we developed nanoparticles based on the poly[N-(2-hydroxypropyl)methacrylamide] and cholesterol containing 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) nitroxide radical bound to the polymer carrier by a pH-sensitive hydrazone bond. These nanoparticles showed almost no interaction with blood proteins such as low- and high-density lipoproteins, immunoglobulin G, human serum albumin, and human plasma and no hard corona was detected around the nanoparticles. It was found that the nitroxide radicals are quickly released from nanoparticles at pH 5 which corresponds to the pH of endosomal/lysosomal compartments of cancer cells while there was no significant release of radicals at physiological pH. These results indicate that HPMA based nanoparticles could be used as potential carriers of nitroxide radicals to prolong their circulation in the blood and increase the accumulation of radicals in tumor tissue.