Síntese, caracterização e funcionalização de nanopartículas de RuO2 conjugadas com dasatinibe visando o tratamento da leucemia mielóide crônica

Abstract

Nanoparticles have shown promise in several areas, especially in the pharmaceutical context, where their physicochemical properties have been investigated as an alternative to overcome limitations associated with conventional chemotherapy. This work is dedicated to the study of ruthenium-based nanoparticles, as it brings together the intrinsic benefits of the metal as a therapeutic agent — including its multiple oxidation states, low toxicity, high selectivity to cancer cells, ligand exchange capacity, and ability to mimic interactions between iron and biomolecules — and the structural advantages of nanoparticles. In this context, properties such as size, morphology, surface charge, and porosity can be modulated, directly influencing biodistribution, cell internalization, and behavior in biological systems. Ruthenium(IV) oxide nanoparticles (RuO2NPs) were synthesized, and a nanodrug proposal was developed through the conjugation of these nanoparticles to dasatinib (das), which is a tyrosine kinase Abl inhibitor, used in the treatment of chronic myeloid leukemia. The formation of RuO2NPs and RuO2NPs-das by coating them with the drug dasatinib were confirmed by X-ray excited photoelectron spectroscopy (XPS), vibrational spectroscopy, transmission electron microscopy (TEM), Energy Dispersive Spectroscopy (EDS) and powder X-ray diffraction. The TEM analyses allowed the determination of the average size of the spherical nanoparticles, obtaining values of 1.83 nm for the RuO2NPs and 1.76 nm for the RuO2NPs-das. The elemental composition of the samples was mapped by EDS. The XPS results showed that the nanoparticles are made of ruthenium(IV) oxide and that dasatinib was incorporated into the RuO2NPs-das. In solution, dynamic light scattering measurements indicated average hydrodynamic sizes of 290 nm for RuO2NPs and 209 nm for RuO2NPs-das, evidencing the presence of hydrated layers. The Zeta potential analysis revealed greater stability for the functionalized nanoparticles (39.8 mV) compared to the non-functionalized RuO2NPs (18.8 mV), demonstrating that the incorporation of dasatinib contributes significantly to the physical stabilization of the system. In the UV-Vis region, both samples showed a maximum absorption at 305 nm. In the spectrum of nanoparticles functionalized with dasatinib, the appearance of a shoulder around 355 nm, absent in RuO2NPs, confirms the presence of the ligand in RuO2NPs das.The nanoparticles containing dasatinib inhibited 50% of the growth of chronic myeloid leukemia cells at a concentration of 7.14×10-7 g L-1, a concentration at which RuO2Nps did not reach IC50. Thus, the results obtained show the potential of the nanosystem developed for future investigations involving pharmaceutical applications.