Development and properties of a new doxorubicin carrier based on surface-modified iron zero-valent microparticles with high encapsulation efficiency and the possibility of its controlled release

Abstract

Currently, chemotherapy combined with surgery and radiation therapy is the most effective treatment for cancer. At the same time, the use of this method is accompanied by serious side effects caused by the lack of specificity of most chemotherapeutic agents. In this regard, the development of drug delivery systems (DDS) capable of addressing a chemotherapeutic agent to cancer cells, as well as its controlled release, is a promising approach for the effective treatment of cancer. The aim of the study is to synthesize a new DDS based on surface-modified microparticles of zero-valent iron, to study its properties as a carrier of a chemotherapeutic agent (encapsulation efficiency, loading capacity, possibility of controlled release of a chemotherapeutic agent) and safety. Materials and methods. The microparticles were synthesised by reduction of iron (III) chloride with sodium borohydride followed by in situ surface modification by 4-carboxybenzyldiazonium tosylate. To confirm the occurrence of the reaction, FTIR spectroscopy (Nicolet iS5 Infrared Spectrometer (Thermo Scientific, USA)) was used. Hydrodynamic diameter and surface charge of the microparticles in solution were investigated by dynamic light scattering (DLS) and z-potential. DOX release studies were performed in simulated physiological conditions (pH 3.3; 5.5; 7.4) to evaluate the effect of the external pH on the release rate. Release studies under ultrasound irradiation were performed simultaneously in the same conditions. The effect of surface modification on encapsulation efficiency was evaluated at various pH values (3.3; 5.5; 7.4) and doxorubicin concentrations (0.2; 0.35; 0.5; 0.75; 1.0 mg/ml). To demonstrate the safety of the developed system, cytotoxicity studies were performed on HeLa cell lines (ATCC® CCL-2™). Results. An original method of preparation of the drug carrier, based on iron zero-valent microparticleswith covalently attached chitosan (Fe-CS) on their surface was proposed. Prepared microparticles demonstrated high encapsulation efficiency, drug loading capacity of DOX (0.9 mg per 1 mg of FeCS microparticles), low cytotoxicity and also a possibility to modulate the release rate by ultrasound irradiation and by changing pH of the external environment. Conclusion. A carrier based on microparticles of zero-valent iron with covalently attached to the surface chitosan (Fe-CS) was obtained. The efficiency of encapsulation, the loading capacity of doxorubicin was determined and the possibility of its controlled release under the influence of an ultrasonic field at different pH values was confirmed. In an in vitro experiment on the HeLa cell line (ATCC® CCL-2™), no toxicity was established for all samples (Fe0, Fe-COOH и Fe-CS), regardless of their concentration.