Tumor-specific nitric oxide generator to amplify peroxynitrite based on highly penetrable nanoparticles for metastasis inhibition and enhanced cancer therapy

Abstract

Multiple biological barriers and tumor metastasis severely impede the tumor therapy. To address these adversities, an acid-activated poly (ethylene glycol)-poly-l-lysine-2,3-dimethylmaleic anhydride/poly (ε-caprolactone)-poly(l-arginine)/β-lapachone nanoparticles (mPEG-PLL-DMA/PCL-P(L-arg)/β-Lap, PLM/PPA/β-Lap NPs) were constructed with charge-reversal and size-reduction for β-Lap delivery with a cascade reaction of reactive oxygen species (ROS) and nitric oxide (NO) production. The nanosystem exhibited highly penetrable, superior cellular uptake and desirable endo-lysosomal escape thanks to size-reduction, charge-reversal and proton sponge, respectively. The vast bulk of ROS, which rapidly generated from β-Lap under high concentration quinone oxidoreductase 1 (NQO1), catalyzed guanidine groups to produce NO and generated highly toxic peroxynitrite (ONOO−). ONOO− would activate pro-matrix metalloproteinases (pro-MMPs) to generate MMPs, degrade the dense extracellular matrix (ECM) to augment the penetration capability, and aggravate DNA damage. NO and ONOO− influenced mitochondrial function by decreasing mitochondrial membrane potential and prevented the production of adenosine triphosphate (ATP), which inhibited the ATP-dependent tumor-derived microvesicles (TMVs) and restrained tumor metastasis. NO was defined as an epithelial mesenchymal transition (EMT) inhibitor to restrain tumor metastasis. All consequences demonstrated that PLM/PPA/β-lap NPs exhibited efficient penetration capability, outstanding anti-metastasis activity and favorable antitumor efficacy. Those novel acid-activated NPs are intended to provide further inspiration for multifunctional NO gas therapy.