Desenvolvimento de nanocomplexos eletrolíticos de quitosana e metotrexato com potencial aplicação antirreumática e anticancerígena

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovial inflammation. It is associated with progressive disability, systemic complications, premature death, and socioeconomic costs. One of the challenges related to treatment is the occurrence of undesirable side effects. Methotrexate (MTX) is an antirheumatic and anticancer drug used in the treatment of RA, as well as breast cancer, leukemia, lymphoma, lung cancer, among others. It presents some systemic side effects, even at low concentrations, mainly due to the nonspecific accumulation of the drug in certain organs. To minimize the effects of traditional drug administration, this study aims to develop chitosan – methotrexate polyelectrolyte nanocomplexes with potential antirheumatic and anticancer applications. The polyelectrolyte nanocomplexes (PNCs) QTS/MTX were characterized by Fourier Transform Infrared Spectroscopy (FTIR) and Thermogravimetric Analysis (TGA), with the resulting signals confirming the presence of the formulation components within the nanostructures. Nanoparticle formation was observed through the unimodal size distribution obtained by Dynamic Light Scattering (DLS). Samples with QTS/MTX molar ratios of 0.75 and 1 presented a polydispersity index (PDI) below 0.3, indicating better homogeneity of particle sizes in solutions. The particles exhibited diameters below 300 nm, making these systems suitable for use as nanocarriers. Scanning Electron Microscopy (SEM) confirmed that the nanostructures are spherical. Encapsulation efficiency was determined by Ultraviolet-Visible Absorption Spectroscopy (UV-Vis), with the QTS/MTX 0.75 sample showing the highest drug encapsulation efficiency and loading, at 79% and 62%, respectively. Stability in solutions were analyzed over six months in the absence of the stabilizer Pluronic® F-127. Nanoparticles with a QTS/MTX ratio of 1 demonstrated better stability. Tests using HL-60 leukemia cells and nontumoral MRC-5 cells showed differentiated selectivity in the presence of F-127. Zebrafish tests showed that the PNC was non-toxic at concentrations of 40, 200, and 400 µg kg⁻¹, reversed the inflammatory phase at all three concentrations, and reversed the neurogenic phase only at the 400 µg kg⁻¹ concentration. In rat models, the PNC reduced edema and leukocyte migration induced by the arthritis model and showed, through biochemical analysis, that it causes less hepatic damage compared to free MTX. Histopathology of the organs showed that the use of NCE resulted in the preservation of renal and hepatic morphology. The PNCs show promising results for antirheumatic and anticancer applications.