Lipossomas termossensíveis contendo complexos de gadolínio como potencial estratégia para o tratamento seletivo do câncer de mama.

Abstract

Currently, cancer is identified as one of the main causes of morbidity and mortality. Therefore, the development of more selective therapeutic options is of fundamental importance. Gadodiamide (Gd-DTPA-BMA) is a gadolinium complex traditionally used in magnetic resonance imaging. Our research group has demonstrated the potential of this drug, encapsulated in liposomes, for cancer treatment. In the present study, analytical method, by hydrophilic interaction chromatography, was developed and validated for determining Gd- DTPA-BMA in thermosensitive liposomes. In addition, two thermosensitive liposomal formulations containing Gd-DTPA-BMA were developed and characterized. The developed liposomes presented adequate physicochemical characteristics in terms of mean diameter (114 to 118 nm), zeta potential (2.1 to 2.8 mV), and Gd-DTPA-BMA entrapment (23.8 to 25.7 mol/mL). These formulations remained stable during the 4-month storage period. Photomicrographs obtained from these liposomes showed spherical, unilamellar vesicles and evidenced, by contrast, the encapsulation of the drug. The thermosensitivity of the formulations was demonstrated by dynamic light scattering, microcalorimetry, and small-angle X-ray scattering. The results obtained by the three techniques were consistent and showed thermosensitivity at temperatures compatible with the cancer treatment by moderate hyperthermia (41 °C to 45 °C). The results of release studies, performed in fetal bovine serum, suggest that the formulations present release kinetics according to the Higuchi model, by diffusion based on Fick's Law. These analyses also showed that the composition of the formulation directly influences the release profile obtained. Cytotoxicity studies were performed on healthy fibroblast cells and murine and human breast adenocarcinoma cells. In tumor cells, blank liposomes and Gd-DTPA-BMA in free form did not show significant cytotoxicity. On the other hand, Gd-DTPA-BMA-containing liposomes showed 100-fold higher cytotoxicity compared to the free drug. Analyses in the healthy cell line revealed the selectivity of the proposed treatment. Therefore, the results presented suggest that thermosensitive liposomes containing Gd-DTPA-BMA are a promising alternative for the selective treatment of breast cancer.