Introduction. Synthetic heterocyclic 4-thiazolidinone derivatives demonstrated high cytotoxic potential in vitro and low toxic effect in vivo as compared with doxorubicin’s action. However, poor solubility in water is a serious obstacle in further application of these compounds as anticancer drugs for chemotherapy. In recent years, nanomaterials have been proposed for the encapsulation of anticancer drugs and their delivery to target tumor cells. Most often, the biocompatible hydrophilic polymers decorated with polyethylene glycol decoration are used for the drug delivery. The oxidative stress is considered to be one of the main mechanisms of damaging tissues and organs by nanoparticles.
Purpose. The study was to determine the biochemical criteria of balance in the system of lipid peroxidation and antioxidant activity under the influence of experimental antitumor compounds Les-3288, Les-3833 and Les-3882 in the liver, heart and kidney tissues of rats.
Materials and methods. The 4-thiazolidinones derivatives used in this study (Les-3288, Les-3833 and Les-3882) were synthesized at the Department of Pharmaceutical, Organic and Bioorganic Chemistry of Danylo Halytsky Lviv National Medical University. The nanocarrier was synthesized at the Department of Organic Chemistry of Lviv National Polytechnic University. It is a surface-active polymer of a comb-like structure that contains the hydrophilic polyethylene glycol chains grafted to the main hydrophobic chain. It was found that in aqueous solutions the amphiphilic polymer forms the nanocomplexes with the micelle-shaped structure providing an ability to solubilize water-insoluble 4-thiazolidinones derivatives. Laboratory rats had been given daily the compounds Les-3882, Les-3288 and Les-3833 for 20 days, as well as their complexes with polymeric nanocarrier. Doses for antitumor compounds were 10 % of LD50: doxorubicin 5.5 mg/kg, Les-3882 and Les-3833 - 10.7 mg/kg, Les-3288 - 24.3 mg/kg.
Results. The obtained results showed that the experimental antitumor drugs Les-3288, Les-3833 and Les-3882 which had been given during 20 days to rats have led to the balance disturbance in the system of lipid peroxidation and antioxidant activity. These changes have been manifested as the enhancement of lipid peroxidation reactions and the exhaustion of the antioxidant system in liver, heart and kidney tissues of the experimental rats. In general, the Les-3288, Les-3833 and Les-3882 compounds showed less destructive actions, comparing with a doxorubicin’s effect towards a disturbance of equilibrium in the lipid peroxidation and antioxidant activity systems, although the mechanism of such influence for each compound looks to be different. According to the results of activation of the lipid peroxidation and the decrease of the antioxidant activity in tissues, the studied compounds can be placed in the following sequence: doxorubicin >> Les-3833> Les-3288 >> Les-3882. It can be concluded that all studied antitumor compounds in complexes with the polymeric nanocarrier have caused less destructive and toxic effects on the lipid peroxidation and the activity of antioxidant enzymes.
Conclusions. Thus, the correspondence of the protection of antioxidant systems in the investigated organs to the level of lipid peroxidation processes is the most informative indicator for estimating the mechanisms of tissue damage by toxic antitumor agents. The balance in the system of the lipid peroxidation and the antioxidant activity can be used as a criteria of toxic effects of anticancer compounds in vivo, and the indicators of the oxidative metabolism are crucial for the development of metabolic disorders, toxicological damage in tissues under the influence of antitumor drugs.
Article recieved: 03.08.2018
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