Work

Copper-coordinated nanomedicine for the concurrent treatment of lung cancer through the induction of cuproptosis and apoptosis

Year: 2024

Type: article

Abstract: • In comparison to other copper complexes, CLS-modified copper complexes exhibit significant water solubility and excellent in vivo biocompatibility. • The higher content of copper in LCD composite is more conducive to inducing cuproptosis of tumor cells. • LCD can overcome resistance to apoptosis by inducing both cuproptosis and apoptosis. The resistance of tumor cells to apoptosis often leads to chemoresistance and treatment failure in clinic. In this study, we have developed a Cu 2+ -coordinated lignosulfonate (CLS) /doxorubicin (DOX) biological complex (referred to as LCD) with the aim of overcoming cellular resistance to apoptosis for combined lung cancer therapy. The copper complexes modified by CLS exhibit significant water solubility and excellent in vivo biocompatibility. The proportion of copper in the composite is simultaneously increased. Due to the coordination and π-π stacking effects, the self-assembled LCD exhibits nanometer-scale particle size, a narrow and homogeneous grain distribution, as well as excellent dispersion stability. Furthermore, LCD has the potential to disassemble in the presence of high levels of glutathione (GSH) and low pH, leading to effective drug release. Cu 2+ -mediated cuproptosis can lead to the down-regulation of FDX1 and DLAT protein expression by reducing mitochondrial membrane potential, resulting in non-apoptotic programmed cell death (PCD) regardless of cellular resistance to apoptosis. Moreover, the released DOX not only exhibits a preference for localizing in the cell nucleus to induce apoptosis for combined chemotherapy, but also generates a substantial amount of H 2 O 2 . This H 2 O 2 further produces ROS to induce apoptosis through Fenton reaction with Cu 2+ . LCD demonstrates significant superiority over monotherapy in inhibiting tumor growth while minimizing systemic toxicity through the combined action of cuproptosis and apoptosis. This study may provide a potential avenue for the advancement of self-delivery nanomedicine to overcome resistance to apoptosis in tumor therapy. The preparation of LCD and the proposed mechanism for synergistic tumor therapy through concurrent induction of cuproptosis and apoptosis. In the presence of Cu 2+ , DOX and CLS can undergo self-assembly to form LCD through coordination and π-π stacking effects. LCD could effectively accumulate in tumor tissue and then be internalized by tumor cells via endocytosis. The internalized LCD could be disassembled by high GSH and low pH to release DOX and Cu 2+ . The released Cu 2+ could reduce mitochondrial membrane potential, leading to the induction of cell cuproptosis by down-regulating the expression of FDK1 and DLAT. Doxorubicin not only shows a tendency to accumulate in the cell nucleus, leading to apoptosis, but also generates reactive oxygen species (ROS) that induce apoptosis by engaging in Fenton reaction with Cu 2+ , ultimately resulting in cell apoptosis as part of combined tumor therapy.

Source: European Journal of Pharmaceutical Sciences

DOI: 10.1016/j.ejps.2024.106942