Multifunctional system for combined chemodynamic–photodynamic therapy employing the endothelin axis based on conjugated polymer nanoparticles

Most nanomedicines that attack tumors by Reactive Oxygen Species (ROS) based on lipid peroxidation mechanisms require external activation to work. The leading example is Photodynamic Therapy (PDT), for which an external light source stimulates ROS production. PDT has been utilized in the treatment of melanoma patients as part of palliative care, and it has shown promise in clinical trials. However, it has several limitations in terms of practical applications, such as inadequate photosensitizer (PS) dispersion, tumor-oxygenation dependency, and therapeutic escape in aggressive tumors. To overcome these obstacles, our targeted dual-modal PDT/Chemodynamic therapy (CDT) has produced promising results, with a stronger therapeutic impact than CDT or PDT alone. We herein report polymer nanoparticles functionalized with endothelin ligands (EDN3-CP nanocomposite) that are specifically designed to target melanoma tumors. The nanoparticles are intrinsically active against melanoma tumor cells even without the use of external light. The Iron in the EDN3-CP nanocomposite catalyzes the Fenton reaction in tumor cells, allowing for CDT. CDT produces ROS by converting endogenous hydrogen peroxide (H₂O₂), which is elevated in most tumor microenvironments (TME), to hydroxyl radicals (˙OH). The ˙OH that result can quickly oxidize bio-macromolecules, destroy DNA and kill tumor cells. The EDN3-CP nanocomposite is therefore not reliant on oxygen availability, making it a promising therapeutic option for hypoxic malignancies. Herein, the melanoma-targeted EDN3-CP nanocomposite demonstrated substantial PDT and CDT together with respect to Malme-3M and A375 melanoma cells. Our findings suggest that tumor cells that overexpress EDNRB, particularly melanoma cells, can be effectively targeted. Our data indicate that the EDN3-CP nanocomposite allows for ferroptosis-assisted CDT, paving the way to combine with PDT for maximized therapeutic efficacy as a new therapeutic approach to tumor treatment.