Combination of Organoselenium-Loaded Nanoparticles and Conventional Chemotherapeutics Synergistically Enhances Antitumor Efficacy and Modulates Multidrug Resistance: An In Vitro Study

Background/Objectives: Cancer causes high premature death worldwide, with 35 million new cases expected by 2050. Multidrug resistance (MDR), driven by genetic and epigenetic changes, hampers chemotherapy. In this study, polymeric nanoparticles (NPs) were formulated with an organoselenium nucleoside analogue (AFAT-Se) to investigate their potential antitumor activity against MDR tumor cells, especially when co-administered with conventional chemotherapeutic agents. Methods: Various in vitro methods were used to assess antitumor activity, effects on non-tumor cells (L929 fibroblasts), and synergy with drugs like doxorubicin, docetaxel, paclitaxel, and methotrexate. Results: The NPs measured below 200 nm, exhibited a low polydispersity index, a negative zeta potential, and high drug content and encapsulation efficiency. AFAT-Se-NPs induced a time- and concentration-dependent reduction in L929 cell viability, with lower effects observed after 24 h and a concentration-dependent toxicity after 72 h. They exhibited limited efficacy against a resistant/MDR cell line (NCI/ADR-RES) even at high doses, but enhanced efficacy when combined with conventional antitumor agents, thereby reducing tumor cell viability more efficiently. In the 3D spheroid model, the combination of AFAT-Se-NPs + doxorubicin showed marked growth inhibition, reducing spheroid size to just 53.2% of its initial area. Likewise, the same combination treatment significantly enhanced the antimigratory effect, yielding a migration rate of only 10.30% versus 55.24% in the untreated control. Finally, the internalization of the NPs was confirmed by fluorescence microscopy. Conclusions: AFAT-Se-NPs have good physicochemical properties, time- and concentration-dependent effects on non-tumor cells, limited cytotoxic activity as a single agent against MDR cells and boost chemotherapy when combined with standard antitumor drugs. Co-administering NPs with doxorubicin slowed cell migration and tumor growth in a 3D model, suggesting that this approach could enhance treatment activity in an MDR cell model and improve cancer therapy. Overall, these findings provide a preliminary basis for further investigation of AFAT-Se-NPs.