Drug delivery systems containing a nitrosyl ruthenium complex releasing NO for topical photodynamic therapy

Abstract

The Photodynamic Therapy (PDT) is a relatively new modality of cancer treatment, that involves the use of a photosensitizing agent and its subsequent activation for the light, to produce reactive species of oxygen, that destroys tumor cells selectively. As the neoplasia hypoxia is a great barrier for the success of the PDT based in singlet oxygen as reactive specie, new photosensitizing agents that produce radicalar species independent of the oxygen are constantly in search. Then, the use of compounds capable of releasing NO, as the nitro ruthenium complexes, has recently become a very active area of research. NO delivery agents administration is limited, however, due to the instability of some of these substances in physiological conditions and the lack of specificity, resulting in numerous unwanted effects. The development of drug delivery systems for NO-donors, as well as the correct site of administration of them, are strategies that can reduce or prevent the problems previously described. The topical administration of these systems is an alternative for skin cancer treatment. The purpose of this project is, therefore, to study the influence of iontophoresis and the use of microparticles in the cutaneous penetration of the nitro ruthenium complex [RuII (NO2)(bpy)(terpy)]+ and of the NO, in comparison with metotrexate (MTX) as a drug model, both released from similar formulations. The cutaneous absorption of the drugs from microparticles and from hydrophilic gels by iontophoresis will be verified in vitro. The cytotoxic activity of the best passive and iontophoretic formulations will be also analyzed in culture of tumoral cells, and in vivo, in mice inoculated with these same cells.