Safety profile of thiazole derivative and its complex with PEG-based polymeric nanoparticles on liver and blood cells in tumor-bearing mice

Abstract

Background. Drug delivery systems (DDS) have demonstrated a significant ability to overcome many of the challenges associated with the delivery of hydrophobic chemotherapeutic compounds to tumor tissues. However, hepatotoxicity and suppression of the hematopoietic system are the key problems in the clinical treatment of cancer by nanoparticle-based DDS that can limit their medical exposure. The aim of this work was to investigate the effect of thiazole derivative N-(5-benzyl-1,3-thiazol-2-yl)-3,5-dimethyl-1-benzofuran-2-carboxamide (BF1) conjugated with PEG-based polymeric nanoparticles (PEG-PN – Th1) on the hepatocytes and blood hematological parameters of mice with grafted NK/Ly. Materials and Methods. The experiments were conducted on white wild-type male mice with grafted NK/Ly lymphoma. Investigated compounds BF1, PEG-PN Th1, and combination of PEG-PN + BF1 (Th2) at a final concentration of 10 μM were added to the liver samples and incubated for 10 minutes. The level of lipid peroxidation products and the level of antioxidant defense system (AOS) enzymes were determined according to the techniques described below. The cytological parameters of blood were investigated after the treatment of mice with BF1 in concentrations of 10 and 20 mg/kg, PEG-PN (20 mg/kg) and Th2 complex (10 mg/kg). On the 14th day of the experiment, blood was taken from all groups and the number of erythrocytes, leukocytes and leukocyte formula were counted. Results. It was reported that neither BF1, PEG-PN, nor their complex Th2 changed the content of lipid peroxidation products or the level of AOS enzymes in hepatocytes from mice with NK/Ly. BF1 (in concentration 10 mg/kg) and PEG-PN + BF1 complex did not change the level of murine erythrocytes compared to Doxorubicin. All investigated compounds, except free PEG-PN, significantly decreased the NK/Ly-triggered leukocytosis and increased the level of small lymphocytes. The NK/Ly lymphoma development led to an increase in the number of neutrophils, while BF1 and its complex with PEG-PN reduced it significantly. Conclusions. BF1 and PEG-PN + BF1 complex had limited negative side effects in the mice with NK/Ly. The investigated compounds were not hepatotoxic toward murine liver cells. Both BF1 and its complex with PEG-PN did not cause any major side effects on the murine blood cells.