Reposicionamento da lamivudina: potencial anticâncer de nanopartículas poliméricas carregadas de lamivudina

Abstract

Lamivudine is a synthetic nucleoside analog to the cytosine. Recently, studies have shown that lamivudine (3TC) can induce apoptosis in cancer cells and inhibit their proliferation, including breast cancer. This study was developed polymeric nanoparticles (PCL) loaded with lamivudine. The nanoparticles were characterized by atomic force microscopy and dynamic light scattering. Then, a full set of in vitro and in vivo analyses were performed, including cytotoxicity, radiolabeling, biodistribution, and biochemistry. The results showed the formation of a 273 nm spherical nanoparticle with a monodisperse behavior (PDI=0.052). The radiolabeling with 99mTc demonstrated the feasibility of the direct radiolabeling process. The cytotoxicity corroborated the potential against breast cancer (MDA-MB-231). The biodistribution assay showed a high uptake in the liver, small and large intestines, and bladder. Also showed the presence of nanoparticles in the urine. The biochemistry analysis in vivo showed alterations in some enzyme levels, including alanine aminotransferase (ALT) and lactate dehydrogenase pyruvate (LDH-P). Finally, in this same work, theoretical studies of molecular docking and molecular dynamics explored interactions between lamivudine and key proteins regulating necroptosis, including Epidermal Growth Factor Receptor (EGFR), Receptor-Interacting Protein Kinase 1 (RIPK1), and Receptor-Interacting Protein Kinase 3 (RIPK3). Theoretical results showed lamivudine's adaptability to the binding sites of these proteins, with potential for optimization to enhance hydrophobic interactions and binding affinity. The data displayed in this study demonstrated the efficacy of the lamivudine against breast cancer cells, and the necessity to better understand the interplay of the nanosystem with biochemical parameters.