Reactive Glycolysis Metabolite-Activatable Nanotheranostics for NIR-II Fluorescence Imaging-Guided Phototherapy of Cancer

Second near-infrared (NIR-II) fluorescence imaging with deep tissue-penetration ability holds remarkable potential for cancer diagnosis. However, clinical translation of NIR-II fluorescence imaging-based cancer treatment is severely restricted by the low signal-to-background ratio due to insufficient tumor specificity of fluorophores. In this study, it is hypothesized that methylglyoxal (MGO), an intermediate metabolite of tumor glycolysis could be used as a potent biomarker for triggering NIR-II fluorescence imaging-guided cancer theranostic. For proof-of-concept, first a MGO-activatable NIR-II fluorescence probe is developed, and then MGO-responsive “dual lock-and-key” nanotheranostics by integrating the NIR-II fluorophore and a photodynamic prodrug (i.e., hexyl 5-aminolevulinic acid hydrochloride (HAL)) into one nanoparticle is engineered. The nanotheranostic can be specifically activated with tumorous MGO for NIR-II fluorescence imaging-guided combinatory cancer therapy. Upon 808 nm laser irradiation, the activated NIR-II fluorophore can generate tunable photothermal effect to trigger HAL release. Subsequently, HAL is converted to protoporphyrin IX inside the tumor cells for 655 nm laser irradiation-induced photodynamic therapy. It is demonstrated that the NIR-II fluorescence nanotheranostics is highly specifically activated in the tumor and efficiently suppressed 4T1 breast tumor growth in mouse model. The NIR-II fluorescence imaging-based nanotheranostic might imply novel insight into reactive metabolite-activatable precise therapy of tumor.