Nanoemulsion system for intravenous administration of bioactive nitroaromatic compound reduces genotoxicity and increases tumor uptake in murine experimental model

Abstract

The 4-(chloromethyl)-3-nitro-N-(2-hydroxyethyl)benzamide (CNB) showed a potential antitumor activity in solid tumors. In this study CNB-loaded nanoemulsions (NE-CNB) composed of medium chain triglycerides, Tween™ 80 and soybean lecithin were developed by the hot melt homogenization method to allow its intravenous administration. NE without CNB had a diameter of 93 ± 4 nm, polydispersity index of 0.25 ± 0.03 and zeta potential of −38 ± 3 mV. The incorporation of CNB significantly increased the globule diameter, as the concentration was increased from 2.0 to 4.0 mg/mL. The concentration of NE-CNB was about 1.66 and 2.50 mg/mL, for 2.0 and 4.0 mg/mL, respectively. There was no significant variation in the physicochemical parameters of the formulations over time of evaluation. However, a significant reduction in CNB concentration was observed after 14 days of storage. Studies to investigate the mutagenic and genotoxic potential of NE-CNB, as well as the in vivo behavior were also performed. NE-CNB showed no mutagenicity and lower genotoxicity than in free form. Biodistribution data and scintigraphic images showed pronounced uptake in the liver, kidneys and intestine and significant accumulation in the tumor region. Tumor-to-muscle ratio was significantly higher for NE-CNB than free CNB. Therefore, NE formulation might be a good strategy to allow intravenous administration of CNB, reducing its toxicity and leading to higher tumor accumulation.