Lukianova N. Experimental basis for use of ferromagnetic nanocomposite in overcoming of tumor cells resistance to cisplatin

Thesis is devoted to the actual question in oncology - increase of cisplatin selectivity due to use of nanocomposite for correction of endogenous iron metabolism in tumor cells with drug resistance phenotype. In vitro and in vivo we showed that changes in endogenous iron metabolism in tumor cells play important role in development of drug resistance to cisplatin. All of the found changes have the same direction and prove the increase in iron demands on resistant cells. We developed technology for synthesis of nanocomposite, which consists of ferromagnetic nanoparticles and cisplatin. In experiments in vitro and in vivo we proved that nanocomposite has higher cytotoxic effect compared to cisplatin both on sensitive and resistant tumor cells. We found that nanocomposite was able to inhibit growth of cisplatin-resistant Guerin carcinoma by 40% (p<0,05), while effect of officinal form of cytostatic was only 2%. We showed that nanocomposite side effects on organisms of studied animals (nephro-, hepato- and genotoxicity) were not higher than those of cisplatin. Nanocomposite toxicity on reticulo-endothelial system cells, liver and blood is more tolerant compared to cisplatin. In vitro we found that changes of endogenous iron metabolism play important role in realisation of nanocomposite-induced apoptosis programme. Oxidative stress, initiated by nanocomposite in resistant cells, caused apoptosis initiation, activation of lipids peroxidation, resulting in structural and functional rearrangements of biological membranes and in decrease of their invasion potential. For the first time we experimentally proved basis for new strategy for overcoming of tumor drug resistance to cisplatin by pharmacocorrection of iron endogenous metabolism with nanocomposite, which consists of ferromagnetic and cisplatin.