This article presents the preparation and biological activities of new 5'-arylchalcogeno-3-aminothymidine derivatives as antioxidants (inhibition of lipid peroxidation, scavenging of the free radical 2,2-diphenylpicrylhydrazyl and demonstration of a thiol peroxidase-like activity) as well as antitumoral agents against bladder carcinoma 5637. The chalcogeno-aminothymidines presented prominent activity in the tests for both biological properties, showing a direct relation with the chalcogenium atom.

In this study, we developed PLGA nanoparticles (NPs) as an effective carrier for 5′-Se-(phenyl)-3-(amino)-thymidine (ACAT-Se), an organoselenium compound, nucleoside analogue that showed promising antitumor activity in vitro. The PLGA NPs were prepared by the nanoprecipitation method and modified with a pH-responsive lysine-based surfactant (77KL). The ACAT-Se-PLGA-77KL-NPs presented nanometric size (around 120 nm), polydispersity index values <0.20 and negative zeta potential values. The nanoencapsulation of ACAT-Se increased its antioxidant (DPPH and ABTS assays) and antitumor activity in MCF-7 tumor cells. Hemolysis study indicated that ACAT-Se-PLGA-77KL-NPs are hemocompatible and that 77KL provided a pH-sensitive membranolytic behavior to the NPs. The NPs did not induce cytotoxic effects on the nontumor cell line 3T3, suggesting its selectivity for the tumor cells. Moreover, the in vitro antiproliferative activity of NPs was evaluated in association with the antitumor drug doxorubicin. This combination result in synergistic effect in sensitive (MCF-7) and resistant (NCI/ADR-RES) tumor cells, being especially able to successfully sensitize the MDR cells. The obtained results suggested that the proposed ACAT-Se-loaded NPs are a promising delivery system for cancer therapy, especially associated with doxorubicin.

Multidrug resistance (MDR) is the main challenge in cancer treatment. In this sense, we designed transferrin (Tf)-conjugated PLGA nanoparticles (NPs) containing an organoselenium compound as an alternative to enhance the efficacy of cancer therapy and sensitize MDR tumor cells. Cytotoxicity studies were performed on different sensitive tumor cell lines and on an MDR tumor cell line, and the Tf-conjugated NPs presented significantly higher antiproliferative activity than the nontargeted counterparts in all tested cell lines. Due to the promising antitumor activity of the Tf-decorated NPs, further studies were performed using the MDR cells (NCI/ADR-RES cell line) comparatively to one sensitive cell line (HeLa). The cytotoxicity of NPs was evaluated in 3D tumor spheroids and, similarly to the results achieved in the 2D assays, the Tf-conjugated NPs were more effective at reducing the spheroid’s growth. The targeted Tf-NPs were also able to inhibit tumor cell migration, presented a higher cell internalization and induced a greater number of apoptotic events in both cell lines. Therefore, these findings evidenced the advantages of Tf-decorated NPs over the nontargeted counterparts, with the Tf-conjugated NPs containing an organoselenium compound representing a promising drug delivery system to overcome MDR and enhance the efficacy of cancer therapy.