4‑Oxo-fenretinide-Loaded Human Serum Albumin Nanoparticles for the Inhibition of Epithelial–Mesenchymal Transition in Neuroblastoma Xenografts

Neuroblastoma (NB) is a highly invasive and clinically challenging form of tumor to treat; despite multiple treatment strategies, a concrete treatment plan has not been developed so far. Here, for the first time, we have fabricated 4-oxo-fenretinide-loaded human serum albumin nanoparticles with acetyl group modification on their surface (4OFnANP) using acetic anhydride as an acetylation agent. 4OFnANP are evaluated for their therapeutic potential for inducing apoptosis and modulating the histone epigenetic modifiers in NB. 4OFnANP show multi-phase cell cycle arrest with >75% inhibition in cancer cell proliferation after 72 h of treatment, which is 25–30% higher than the bare 4OFn drug response for a similar treatment time. 4OFnANP show an impressive reduction in the volume and size of NB xenografts with significant decrease in the expression of mesenchymal marker fibronectin and increased expression of epithelial marker E-cadherin, showing inhibition of epithelial mesenchymal transition (EMT). The nanoformulation marked the efficacy in NB by targeting the slug and E-cadherin axis and downregulating the expression of histone methyltransferase EZH2 and histone demethylase JMJD3 [histone H3 lysine 27 (H3K27) demethylase]; aberrant expression of JMJD3 and EZH2 is linked to carcinogenesis and EMT. Histopathological evaluation of major body organs of mice treated with the nanoformulation shows no systemic toxicities of the treatment. This study confers a novel, biocompatible, and effective way for targeting the EMT in NB.