Electrochemical Study of the Antitumor Antibiotic Doxorubicin in Its Free Form and Encapsulated in a Biocompatible Copolymer of N-Vinylpyrrolidone and (di)Methacrylates

Abstract

A comparative study of the electrochemical behavior of various forms of the antitumor antibiotic doxorubicin (DOX), both free and encapsulated in micelle-like nanoparticles of the biocompatible amphiphilic copolymer of N-vinylpyrrolidone (VP) and methacrylic acid, viz., triethylene glycol dimethacrylate (TEGDM), is carried out in aqueous neutral buffers on a glassy carbon electrode. The hydrodynamic radii R_h of the copolymer and the DOX polymeric nanostructures are determined using dynamic light scattering. Using cyclic and square wave voltammetry, for both forms of DOX at pH 7.24, the two main redox transitions are revealed namely, the irreversible oxidation/rereduction in the potential interval from 0.2 to 0.6 V and the reversible reduction/reoxidation in the interval from –0.4 to –0.7 V (vs. saturated Ag/AgCl), and their redox potentials are determined. For both redox transitions, the potential difference between the corresponding peaks does not exceed several tens (20–30) mV; and, moreover, the oxidation of the encapsulated form proceeds easier as compared with the free form, whereas its reduction is somewhat more difficult. The analysis of the dependence of the reduction current of both DOX forms on the potential scan rate shows that the electron transfer to a free DOX molecule is largely determined by the rate of reagent accumulation in the adsorption layer, whereas the electron transfer to the encapsulated form is characterized by the mixed adsorption-diffusion control. Based on voltammetric data and the results of quantum chemical modeling, it is concluded that a hydrogen bond is formed between the oxygen-containing groups of copolymer’s monomeric units and the H atoms in OH and NH₂ groups of DOX. The bond energy in these structures is calculated and shown to be close to the classical values, assuming that the carbonyl group in the VP lactam ring in the encapsulating polymer is the electron donor, and the hydrogen atoms in OH and NH₂ groups of DOX are the electron acceptors. At the same time, the bonds involving oxygen of the ester group in the TEGDM unit are extremely weak.