Selective radioprotection of normal lung by cerium oxide nanoparticles: a novel approach for the prevention of radiation pneumonitis

4814

Background: At the onset of radiation exposure, free radicals are formed through ionizing reactions that are then capable of destroying normal tissues. During thoracic radiation, injury to normal lung can result in radiation pneumonitis and pulmonary fibrosis in patients. The most effective free radical scavenger currently in clinical use is amifostine, however, this drug suffers from a very short half-life in serum and has serious side effects which make it difficult and costly to administer. In previous studies, we have identified a novel approach to free radical scavenging and radiation protection using cerium oxide nanoparticles (nanoceria). We determined whether nanoceria rendered protection against radiological insults on human normal lung or lung cancer cells in vitro cultures and in a murine model of radiation pneumonitis. Results: We show that in the presence of 10 nM nanoceria (pre-determined optimal dose) human normal lung CCL135 cells were protected from radiation-induced cell death. In sharp contrast, human lung cancer A549 cells exposed to the same dose of radiation combined with nanoceria were not protected from radiation-induced cell death. In an attempt to apply nanoceria in live animals, we measured the toxicity of nanoceria and amifostine on non-tumor bearing (NTB) athymic nude mice. Mice (n=10) were randomized into the following groups: 1) control mice injected intraperitoneal (i.p.) with saline solution; 2) weekly administration of 5 Gy radiation for a total of 30 Gy; 3) twice weekly i.p. injections of 15 nM cerium oxide nanoceria; 4) weekly administration of radiation combined with twice weekly i.p. injections of nanoceria; 5) weekly i.p.150 mg/kg amifostine; 6) weekly administration of radiation combined with i.p. injections of amifostine 30 minutes prior to radiation. The weight and mortality of each mouse was measured throughout the experiment. The percent survival for saline, radiation alone, nanoceria alone, amifostine alone, radiation plus nanoceria, or radiation plus amifostine, was 100%, 20%, 100%, 80%, 100% and 40%, respectively. In order to induce radiation pneumonitis, non-tumor bearing mice were irradiated with 5 Gy radiation/6 doses in a total of 12 days. Mice received saline (control), twice weekly i.p. injections of 15 nM nanoceria, i.p. injections of 150 mg/kg of amifostine 30 minutes prior to radiation or nanoceria combined with amifostine. The percent survival 80 days post last radiation administration for control, nanoceria, amifostine and nanoceria combined with amifostine, was 70%, 90%, 40%, 80%, respectively. Conclusions: These data suggest that cerium oxide nanoparticles are well tolerated by mice and could effectively prevent radiation pneumonitis. The observed radiation protection against normal cells and not cancer cells warrant further investigation in an orthotopic murine lung cancer model.