Acidity-Triggered Tumor-Targeted Nanosystem for Synergistic Therapy via a Cascade of ROS Generation and NO Release

Nitric oxide (NO) gas therapy has aroused intense interest in recent years. l-Arginine (l-Arg) reacts with reactive oxygen species (ROS) in tumor cells to generate NO. This phenomenon represents an effective method for tumor therapy. However, endogenous ROS levels in most types of tumor cells cannot enable an effective reaction. β-Lapachone is generally used to increase H₂O₂, which can oxidize guanidine derivatives to form nitric oxide in tumor cells. In addition, based on the ferrocene (Fc)-catalyzed Fenton reaction, ·OH is generated from H₂O₂, and the ONOO^- could be generated from an interaction between ·O₂^- (generated through the Haber-Weiss reaction) and NO. Arg-rich poly(ε-caprolactone) (PCL)-b-PArg, a macromolecular NO donor, was accurately synthesized to avoid premature l-Arg leakage during in vivo transport. In this design, the self-assembled PCL-b-PArg nanoparticles were dressed with the tumor-shreddable masking (PEG-b-PDMA, a negatively charged pH-sensitive hydrophilic diblock polymer), to prepare P-lapa-Fc nanoparticles and hide penetrative capability in the circulation. The experimental results confirmed that this synergistic therapy based on ROS and NO had a significant inhibitory effect on cancer cells, thereby providing new inspiration for NO gas treatment.