P07.01.A ENHANCED NEUROBLASTOMA ANTITUMOR EFFECTS BY NANOFORMULATED FENRETINIDE AND BERBERINE COMBINATION

Abstract BACKGROUND Neuroblastoma is an aggressive pediatric tumor arising from neural crest cells and frequently linked with recurrent multidrug-resistant disease, needing the development of new antitumor treatments to improve survival rates. Fenretinide is a synthetic derivative of all-trans retinoic acid that exhibits a broad spectrum of biological activities, including antitumor properties, and a low toxicity profile. However, its low aqueous solubility poses a significant challenge to its bioavailability and, consequently, its therapeutic efficacy. To overcome this limitation, innovative nanoformulations were developed to deliver fenretinide, showing activity in a wide range of tumor models. Berberine is a plant alkaloid with potential for neuronal differentiation and inhibition of cancer stemness in neuroblastoma. In this study, we aimed to explore in vitro antitumoral effects of an innovative nanoformulation, based on phospholipid nanomicelles that co-deliver fenretinide and berberine in neuroblastoma cells, with the primary objective of enhancing their bioavailability and efficacy. MATERIAL AND METHODS To evaluate the efficacy of the nanoformulated fenretinide and berberine combination, in vitro experiments were conducted on neuroblastoma cell lines and normal cell lines. The analyses were performed using the MTT cell viability assay, flow cytometry, confocal microscopy, and Quantum Phase Imaging (QPI). RESULTS The obtained nanoformulation exhibited an average size below 200 nm and dimensional stability upon physiological dilution. These characteristics make them potentially suitable for applications in anticancer nanotherapies, where the maintenance of physicochemical properties in a biological environment is crucial. Confocal microscopy analysis revealed an increased uptake of both fenretinide and berberine in neuroblastoma cells due to nanoencapsulation. Measurements by Quantum Phase Imaging allowed for quantifying kinetic and morphological changes in neuroblastoma cells treated with the nanoformulated combination, highlighting a reduction in cell proliferation and the induction of apoptosis in all conditions. The results obtained indicate that the nanoformulated combination exhibits marked cytotoxic activity against neuroblastoma tumor cells, without significant cytotoxic effects on normal cells. A comparison with nanoformulated fenretinide indicates that the co-presence of berberine, while not significantly enhancing the cytotoxic activity of fenretinide, promotes a transition towards a differentiated cell phenotype in the tumor cell lines. CONCLUSION These data suggest that the co-delivery of fenretinide and berberine via phospholipid nanomicelles enhances antitumor efficacy and supports neuroblastoma cell differentiation, offering a promising strategy for innovative therapeutic approaches in pediatric oncology.