Stimuli-responsive cancer nanomedicines inhibit glycolysis and impair redox homeostasis

Abstract

The solid tumors are characterized with oxidative stress and metabolic reprogramming, which has been independently used for targeted tumor monotherapy. However, the potential of targeting metabolism-redox circuit in tumor therapy has long been neglected. Herein, we report a hybrid nanocarrier for concurrent targeting of glycolysis and redox balance in the current work. The nanocarriers are made of pH- and ATP-responsive zeolitic imidazolate framework (ZIF-8) as the porous core that was further coated with poloxamer 407 as the steric stabilizer. Two active cargos, glucose oxidase (GOx) and 3-bromopyruvate (3-BrPA) were co-loaded in the core of nanocarrier. GOx is well-known for its ability of producing hydrogen peroxide at the expense of glucose and oxygen. 3-BrPA can reduce oxygen and glucose consumption through glycolysis, which sensitized cancer cells to GOx-induced apoptosis. At the cellular level, the hybrid nanocarrier significantly impaired the redox balance in the liver hepatocellular carcinoma cell line (HepG2), as evidenced by the depletion of glutathione and boost of reactive oxygen species. The potency of hybrid nanocarrier in terms of suppressing HepG2 cell energy metabolism was proven by the exhaustion of ATP. As a consequence, cell viability was greatly reduced. The in vivo efficacy of hybrid nanocarriers was demonstrated in HepG2 tumor-bearing mice. The current work presents an approach of targeting metabolism-redox circuit for tumor treatment, which may enrich the available anti-tumor strategies. STATEMENT OF SIGNIFICANCE: Metabolic alterations and elevated reactive oxygen species (ROS) are two characteristics of cancer. The metabolic patterns of cancer cells are elaborately reprogrammed to enable the rapid propagation of cancer cells. However, the potential of targeting the metabolism-redox circuit in anti-tumor therapy has long been neglected. As a proof-of-concept, we report an engineered stimuli-responsive nanomedicine that can eradicate cancer cells via cooperative glycolysis inhibition and redox impairment. The current work presents an approach of targeting the metabolism-redox circuit for tumor treatment, which may enrich the available anti-tumor strategies.

Keywords: Drug delivery; Glycolysis; Nanocarrier; Redox homeostasis; Tumor therapy.