Lung cancer chemo-interception by sulfasalazine and disulfiram codelivered using a nano self-emulsifying drug delivery system in mice.

Abstract

Although preclinical studies consistently indicate that sulfasalazine (SAS) and disulfiram (DSF) are promising agents for the prevention and treatment of lung cancer, their clinical efficacy is limited. This discrepancy is attributed to the poor bioavailability of the drugs. Therefore, in the present study, we explored whether delivery of lower doses of SAS and DSF in nano self-emulsifying drug delivery systems (Nano-SEDDS) improves their potency and efficacy in suppressing malignant progression of lung tumors. Mice were treated with the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and once lung adenoma developed, high doses of free SAS (250 mg/kg) + DSF (100 mg/kg) or SEDDS formulations containing lower doses of SAS + DSF (40 mg/kg SAS + 8, 16 or 40 mg/kg DSF) were administered by oral gavage, every other day, for 10 weeks. Although the doses of SAS and DSF contained in SAS + DSF-SEDDS were about 6-fold and 3-15-fold lower, respectively, than the doses of the respective free drugs, SAS + DSF-SEDDS was more effective than free SAS + DSF in reducing the multiplicity of bigger lung tumors (≥1 mm). These effects were paralleled by significant reductions in the multiplicity of adenoma with progression and adenocarcinoma histopathological lesions. Also, lung tumors from mice treated with SAS + DSF-SEDDS exhibited an increase in the level of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), lipid peroxidation products. Overall, our results show that the Nano-SEDDS formulation of SAS + DSF is a promising approach to enhance the potency and efficacy of the drugs for lung cancer chemo-interception and treatment.