Avaliação biológica in sílico e in vitro de um organoseleneto inovador e sua associação sinérgica em nanopartículas de PCL ao antitumoral paclitaxel vislumbrando a reversão do fenômeno MDR

Abstract

Cancer is characterized by uncontrolled cell proliferation, often resulting from genetic mutations compromising cell cycle regulation. Conventional treatments, such as chemotherapy, while widely utilized, face challenges including lack of specificity and resistance. Nucleoside analogs stand out for their ability to disrupt metabolic and regulatory pathways. However, despite being an intriguing class, they have limitations such as inadequate conversion to the active metabolite and cellular resistance. Concurrently, antimitotic drugs of the taxane class, such as paclitaxel, also have various uses as antineoplastics, known for stabilizing microtubules; however, they encounter significant challenges, including severe side effects and resistance issues. Thus, this study focused on exploring the therapeutic potential of the innovative organoselenium compound AFAT-Se, its synergistic association with paclitaxel, and the incorporation of the combination into pH-sensitive polymeric nanoparticles. Therefore, using in silico and in vitro approaches, the physicochemical properties and biological activity of this compound were investigated. Initial promising results were observed, especially against the sensitive HT-29 tumor cell line (human colorectal adenocarcinoma). Furthermore, the synergistic association with paclitaxel was explored both in free form and after coencapsulation in polymeric nanoparticles. Formulation strategies were employed, including the addition of the amphiphilic copolymer poloxamer and the lysine-derived surfactant with sodium counter-ion (77KS), to add tumor sensitization effect and pH-dependent behavior. The nanoparticles exhibited suitable physicochemical characteristics and encapsulation efficiency. Hemocompatibility and pH-dependent behavior were evidenced by the hemolysis assay. ABTS and DPPH antioxidant assays determined a good free radical scavenging capacity. Evaluation of cytotoxicity profiles in non-tumor cells, 3T3 and PBMCs, provided interesting insights into the probable biological safety of the proposed therapeutic approach. The AFAT-Se + PTX association, especially after co-encapsulation in pH-sensitive nanoparticles, was able to sensitize resistant tumor cells, NCI-ADR/RES (ovarian tumor cell line), in both 2D and 3D cell models, and thus, it can be considered an interesting approach for reversing the multidrug resistence phenomenon (MDR). This study emphasizes the importance of computational tools, in vitro cell culture, and nanotechnology in the pursuit of more specific and safe antitumor therapies. Promising findings from this work suggest a new direction for cancer therapy development, aiming to minimize adverse effects and overcome tumor cell resistance mechanisms.