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 (O-2(center dot-)) inducing chemotherapeutic agent was reported for RNS-potentiated chemotherapy. The mole ratio of platinum(IV) prodrug and NO donor could be precisely tailored in SPNA(Pt/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 SPNA(Pt/NO) was validated on subcutaneous hepatoma xenograft models and an orthotopic cisplatin-resistant hepatoma model. This co-delivery strategy of NO donor and O-2(center dot-) inducing chemotherapeutic agents for RNS-mediated therapy provides an insightful direction for cancer treatment.

Automated summary

This study reports a novel supramolecular prodrug nanoassemblies strategy that co-delivers nitric oxide and superoxide anion inducing chemotherapeutic agents for enhanced reactive nitrogen species effects in chemotherapy. The efficacy of this strategy was validated in hepatoma models, providing a new direction for cancer treatment.