PEG-GE11-modified nanoplatform for co-delivery of cisplatin and plumbagin in targeted therapy of oral squamous cell carcinoma

Abstract

This study tackles key challenges in oral squamous cell carcinoma (OSCC) chemotherapy, such as poor targeting, systemic toxicity, and drug resistance. We developed a pH-responsive, targeted nanoplatform (CP@Cu-Z@P-G) based on copper-doped zeolitic imidazolate framework-8 (Cu-ZIF-8). The nanoplatform was functionalized with an Epidermal Growth Factor Receptor (EGFR)-specific ligand (PEG-GE11) for active tumor targeting and designed to degrade in the acidic tumor microenvironment, enabling the synchronous release of cisplatin (CDDP) and plumbagin (PLB). The released copper ions (Cu2+) disrupt intracellular redox homeostasis via glutathione (GSH) depletion and catalyze Fenton-like reactions to generate hydroxyl radicals (˙OH). These radicals act synergistically with PLB-induced reactive oxygen species (ROS) to augment oxidative stress, thereby sensitizing tumor cells to CDDP. In vitro experiments confirmed the pH-responsive drug release profile of the nanoplatform under simulated tumor microenvironment conditions. In vivo imaging studies demonstrated that EGFR-targeted modification significantly enhanced nanoparticle accumulation in tumor sites. Treatment with CP@Cu-Z@P-G exhibited potent antitumor efficacy with minimal systemic toxicity. Thus, this innovative nanoplatform combines active targeting, stimuli-responsive drug release, and chemo-chemodynamic therapy (CCDT), presenting a promising approach to overcome drug resistance and improve the treatment of OSCC.