Radiofrequency-responsive dual-valent gold nanoclusters for enhancing synergistic therapy of tumor ablation and artery embolization

Abstract

(a) Schematic illustration of the preparation of dv GC@PNAs. Afer the reduction of hydrogen tetrechloroaurate to dv GCs with the well-defined structure of Au(I)-GSH complex shell and in-situ -formed Au(0) core, temperature sensitive PNA polymers were further modified onto dv GCs by Au-S coordinating bond. (b) Schematics showing how dv GC@PNAs effectively improved the synergistic antitumor efficacy of TAE and RFA by RF-induced heating effect. • We successfully synthesized RF-responsive dual-valent gold nanoclusters ( dv GC@PNAs) as multifunctional blood-vessel-embolic agents for comprehensive interventional theranostics of solid tumors. • dv GC@PNAs with the core-shell nanostructure of Au(0) atoms surrounding with high content of Au(I) ions exhibited distinct RF-induced heating effect. • dv GC@PNAs greatly improved tumor hypoxic microenvironment post TAE procedure, inducing a favorable immune response, and thereby enhancing the synergistic antitumor effect of RFA and TAE. Interventional cancer therapy, till date, experiences a major challenge to improve the synergistic effect of radiofrequency ablation (RFA) and trans-artery embolization (TAE). Here, RF-responsive dual-valent gold nanoclusters ( dv GC@PNAs), as multifunctional blood-vessel-embolic agents, have been successfully manufactured for comprehensive interventional theranostics of solid tumors. Distinct RF-induced heating effect was obtained by reducing Au(I)-thiolate complex using l -glutathione under the template polymer of temperature-sensitive poly( N -isopropylamide- co -acrylic acid) (PNAs), the well-defined dv GC@PNAs with the core-shell nanostructure of Au(0) atoms surrounded by a high content of Au(I) ions, thereby triggering cell apoptosis, necrosis, and metastasis inhibition. Efficient TAE cancer therapy can also be achieved by rapid diffusion of dv GC@PNAs into tumor peripheral arteries that impede tumor blood supply by their favorable temperature-sensitive sol-gel transition. The immunofluorescent analyses substantiated the greatly improved tumor microenvironment post TAE procedure, owing to the radiofrequency-responsive dv GC@PNAs, induced a favorable immune response, thereby augmenting the synergistic antitumor effect of RFA and TAE. The present study provides a valuable paradigm for ameliorating the synergistic interventional therapies by the rational design of RF-responsive metal nanoclusters.