Construction of a cancer-targeted nanosystem as a payload of iron complexes to reverse cancer multidrug resistance

Multidrug resistance has been identified as a major cause of failure of cancer treatment. Due to their relative non-toxicity, selenium nanoparticles (SeNPs) have been reported as excellent cancer therapeutic nanodrugs. In this study, we designed and prepared a novel nanosystem with borneol surface-functionalized and liver targeting to overcome the multidrug resistance. Borneol (Bor)-modified SeNPs can significantly improve the stability of SeNPs and their anticancer activity. Fe(PiP)₃ (PiP = 2-phenylimidazo [4,5-f][1,10] phenanthroline) is a novel anticancer agent with low solubility and stability. In this study, we have constructed a functionalized SeNPs (GAL/Bor@SeNPs) by the surface decoration of galactosamine (GAL), which is a liver targeting ligand that significantly enhanced the cellular uptake of Fe(PiP)₃-loaded nanosystem via dynamin-mediated lipid raft endocytosis and clathrin-mediated endocytosis in liver cancer cells overexpressing asialoglycoprotein receptor, thus achieving amplified anticancer efficacy. This multifunctional nanosystem exhibited excellent hemocompatibility and anticancer activity comparing with Fe(PiP)₃ or SeNPs alone. Remarkably, GAL/Bor@SeNPs antagonized the multidrug resistance in R-HepG2 cells by inhibiting the expression of ABC family proteins, resulting in enhanced drug accumulation and retention. Internalized nanoparticles released free iron complexes into the cytoplasm, which triggered ROS down-regulation and induced apoptosis through activating AKT and MAPKs pathways. Moreover, this nanosystem effectively prolonged the circulation time of encapsulated drugs. Taken together, this study suggests that GAL and Bor functionalization could be an effective strategy to design cancer-targeted nanomaterials to antagonize multidrug resistance in cancers.