Abstract
Cisplatin is a commonly used chemotherapy drug that improves survival in many cancer patients but often causes severe neurotoxicity. Quercetin, a flavonoid antioxidant, has neuroprotective properties that can reduce cisplatin-induced neurotoxicity, but its clinical application is limited by poor bioavailability. This study aimed to combine nanomedicine and network pharmacology to develop Tween 80-functionalized chitosan-selenium nanoparticles containing quercetin (Q-Tw-Cs@Se NPs) and evaluate their protective effects against cisplatin-induced neurotoxicity in PC12 cells. Q-Tw-Cs@Se NPs were synthesized in a core-shell structure and characterized for size, morphology, optical properties, and chemical composition. Hemocompatibility, scavenging activity, and reducing power were assessed. The protective effects of the nanoparticles against cisplatin-induced toxicity in PC12 cells, used as a neuronal cell model, were evaluated using MTT assays and flow cytometry. Furthermore, network pharmacology was employed to predict hub targets and probable cellular mechanisms responsible for the protective effects of the nanoparticles. Q-Tw-Cs@Se NPs had an average size of 110 nm, a zeta potential of + 11.5 mV, and a quercetin encapsulation efficiency of ~ 50%. Pre-exposure to Q-Tw-Cs@Se NPs (1.25 µg/mL) for 24 h increased cell viability from 50% to nearly 80% in PC12 cells treated with cisplatin at its IC50 concentration. The nanoparticles also inhibited cisplatin-induced apoptosis and necrosis. Network pharmacology analysis identified BCL2, CASP3, AKT1, EGFR, STAT3, TNF, HSP90AA1, CTNNB1, IL-1β, and BCL2L1 as main targets enriched in apoptotic regulation. Altogether, Q-Tw-Cs@Se NPs show potential as neuroprotective adjuvants to reduce cisplatin-induced neurotoxicity. However, further in vitro and in vivo studies are required to confirm their therapeutic value.