Dual-Depletion of Intratumoral Lactate and ATP with Radicals Generation for Cascade Metabolic-Chemodynamic Therapy

Increasing evidence has demonstrated that lactate and adenosine triphosphate (ATP) both play important roles in regulating abnormal metabolism in the tumor microenvironment. Herein, an O-2 self-supplying catalytic nanoagent, based on tannic acid (TA)-Fe(III) coordination complexes-coated perfluorooctyl bromide (PFOB) nanodroplets with lactate oxidases (LOX) loading (PFOB@TA-Fe(III)-LOX, PTFL), is designed for cascade metabolic-chemodynamic therapy (CDT) by dual-depletion of lactate and ATP with hydroxyl (OH)-O-center dot radicals generation. Benefiting from the catalytic property of loaded LOX and O-2 self-supplying of PFOB nanodroplets, PTFL nanoparticles (NPs) efficiently deplete tumoral lactate for down-regulation of vascular endothelial growth factor expression and supplement the insufficient endogenous H2O2 . Simultaneously, TA-Fe(III) complexes release Fe(III) ions and TA in response to intracellular up-regulated ATP in tumor cells followed by TA-mediated Fe(III)/Fe(II) conversion, leading to the depletion of energy source ATP and the generation of cytotoxic (OH)-O-center dot radicals from H2O2. Moreover, TA-Fe(III) complexes provide photoacoustic contrast as imaging guidance to enhance therapeutic accuracy. As a result, PTFL NPs efficiently accumulate in tumors for suppression of tumor growth and show evidence of anti-angiogenesis and anti-metastasis effects. This multifunctional nanoagent may provide new insight for targeting abnormal tumor metabolism with the combination of CDT to achieve a synergistic therapeutic effect.

Automated summary

A multifunctional nanoagent designed for cascade metabolic-chemodynamic therapy efficiently depletes lactate and ATP in the tumor microenvironment, generating hydroxyl radicals for therapy. The nanoagent efficiently accumulates in tumors, showing evidence of anti-angiogenesis and anti-metastasis effects.