Rationally designed multifunctional nanoparticles as GSH-responsive anticancer drug delivery systems based on host-guest polymers derived from dextran and β-cyclodextrin

Tumor proliferation and metastasis rely on energy provided by mitochondria. The hexokinase inhibitor lonidamine (LND) could suppress the activities in mitochondria, being a potential antitumor drug. However, limited water-solubility of LND may hinder its biomedical applications. Besides, the cancer-killing effect of LND is compromised by the high level of glutathione (GSH) in cancer cells. Therefore, it is urgent to find a proper method to simultaneously deliver LND and deplete GSH as well as monitor GSH level in cancer cells. Herein, a host polymer β-cyclodextrin-polyethylenimine (β-CD-PEI) and a guest polymer dextran-5-dithio-(2-nitrobenzoic acid) (Dextran-SS-TNB) were synthesized and allowed to form LND-loaded GSH-responsive nanoparticles through host-guest inclusion complexation between β-CD and TNB as host and guest molecular moieties, respectively, which functioned as a system for simultaneous delivery of LND and -SS-TNB species into cancer cells. As a result, the delivery system could deplete GSH and elevate reactive oxygen species (ROS) level in cancer cells, further induce LND-based mitochondrial dysfunction and ROS-based immunogenic cell death (ICD), leading to a synergistic and efficient anticancer effect. In addition, -SS-TNB reacted with GSH to release TNB2-, which could be a probe with visible light absorption at 410 nm for monitoring the GSH level in the cells.