Tailoring Supramolecular Prodrug Nanoassemblies for Reactive Nitrogen Species-Potentiated Chemotherapy of Liver Cancer

The development of a controllable reactive nitrogen species (RNS) generation system for cancer treatment has remained elusive. Herein, a supramolecular prodrug nanoassemblies (SPNA) strategy that co-delivers a nitric oxide (NO) donor and a superoxide anion (O2•–) inducing chemotherapeutic agent was reported for RNS-potentiated chemotherapy. The mole ratio of platinum(IV) prodrug and NO donor could be precisely tailored in SPNAPt/NO. Platinum(II) and NO would be released intracellularly to produce a highly toxic RNS, peroxynitrite anion (ONOO–). The levels of glutathione reductase (GR) and xeroderma pigmentosum group A (XPA) were down-regulated by ONOO–, thus synergistically decreasing detoxification and blocking DNA damage repair of Pt-based chemotherapy. The RNS-potentiated efficacy of SPNAPt/NO was validated on subcutaneous hepatoma xenograft models and an orthotopic cisplatin-resistant hepatoma model. This co-delivery strategy of NO donor and O2•– inducing chemotherapeutic agents for RNS-mediated therapy provides an insightful direction for cancer treatment.