Hypoxia responsive fucoidan-based micelles for oxidative stress-augmented chemotherapy

Abstract

Enhancing tumor reactive oxygen species (ROS) is a promising strategy for improved cancer chemotherapy. However, the high level of glutathione (GSH) in hypoxic tumor cells can neutralize ROS, restricting the application of ROS boosted therapy. Herein, hypoxia-responsive polymer micelles (FAL@DOX) were constructed to amplify intra-tumor oxidative stress to enhance the chemotherapeutic efficacy of doxorubicin (DOX). The amphiphilic polymer consists of hydrophilic fucoidan (Fuc) linked by azobenzene with hydrophobic linolenic acid (LA), and can self-assemble into micelles to encapsulate DOX. Under hypoxia, FAL@DOX decreased intratumoral GSH by consuming nicotinamide adenine dinucleotide phosphate (NADPH), and caused accumulation of lethal ROS and lipid peroxides, resulting in mitochondrial damage and enhanced anti-tumor performance of DOX. FAL@DOX (IC50 1.685 μg/mL) improved the effect of DOX (IC50 7.847 μg/mL) on hypoxic tumor cells by nearly 4.6-fold. The current work provides a novel strategy for enhancing the antitumor efficacy via oxidative stress augmented chemotherapy.