Desenvolvimento de sistemas de liberação biodegradáveis contendo cidofovir como alternativa para o tratamento da papilomatose laríngea recorrente

Abstract

Recurrent respiratory papillomatosis (RRP) is a chronic disease caused by Human Papilloma Virus (HPV) and affects mainly children and teenagers. Besides there is no definitive treatment, several surgical interventions are necessary for the maintenance of the disease, which causes considerable discomfort. The use of antivirals as adjuvants on the treatment of RRP has been shown to be more effective in the control of laryngeal lesions, with cidofovir (CDV) being the most used off-label drug currently used. Intralesional injection of CDV, however, shows limitations on the bioavailability of the drug, since there is loss of the solution injected into the laryngeal cavity. Thus, the search for therapeutic innovations, as well as the development of new formulations, have been the subject of studies concerning the treatment of RRP. The development of controlled drug delivery systems emerges as an alternative to modulate the release kinetics of the active substance and prolong its permanence at the site of action, which allows a reduction in the frequency of administration of the dose and, in this case, a reduction in the number of injections during the treatment. In this context, the aim of this project was the development of biodegradable release systems composed of injectable suspensions of microspheres based on PLGA 75:25 and based on a blend of HPMC K100 and carbopol 940 containing CDV. MEs were produced by the simple emulsification method followed by solvent evaporation, and were characterized by pH, zeta potential, size distribution, drug encapsulation content, scanning electron microscopy and thermal analysis. In vitro studies showed absence of incompatibilities between the drug and the polymers and adequate morphological characteristics. The in vivo studies were performed to verify the biocompatibility and absence of toxicity of the developed systems, through histological analysis and the chorioallantoic membrane assay. CDV radiolabeling was performed with technetium-99m in order to develop a radiotracer to elucidate the drug's behavior in the body. Through the radiolabelling of the CDV and the developed MEs, it was also possible to compare and confirm the adhesion of the particles after local injection in the vocal folds for a longer time in relation to the CDV solution, which is currently used in the clinic.