Novel nanostructured lipid-dextran sulfate hybrid carriers overcome tumor multidrug resistance of mitoxantrone hydrochloride

Abstract 

Novel nanostructured lipid-dextran sulfate hybrid carriers (NLDCs) were successfully developed for sustained delivery of water-soluble cationic mitoxantrone hydrochloride (MTO) and overcoming multidrug resistance. The introduction of negative polymer of dextran sulfate sodium significantly improved the encapsulation efficiency (97.4%) and sustained the release of MTO (86.9% at 72 hours). In vivo pharmacokinetics in rats after intravenous administration demonstrated that MTO-loaded NLDCs (MTO-NLDCs) had higher area under the curve and longer half-life than MTO solution (MTO-Sol). In the biodistribution study, NLDCs significantly improved the MTO levels in plasma, spleen, and brain, and decreased the distribution of MTO in heart and kidney. In comparison with MTO-Sol, MTO-NLDCs efficiently enhanced cytotoxicity through the higher accumulation of MTO in breast cancer resistance protein (BCRP)-overexpressing MCF-7/MX cells. MTO-NLDCs entered into the resistant cancer cells by the clathrin-mediated endocytosis pathway, which escaped the efflux induced by BCRP transporter and thereby overcame the multidrug resistance of MCF-7/MX cells.

From the Clinical Editor

In this study, novel nanostructured lipid-dextran sulfate hybrid carriers were synthesized and utilized for sustained delivery of mitoxantrone hydrochloride. The utilized methods successfully addressed multidrug resistance to this chemotherapy agent.

Graphical Abstract 

Key words: Mitoxantrone hydrochloride, Nanostructured lipid-dextran sulfate hybrid carriers, Pharmacokinetics, Cellular uptake, Multidrug resistance