An effective NIR laser/tumor-microenvironment co-responsive cancer theranostic nanoplatform with multi-modal imaging and therapies

Abstract

Cancer is still a major threat to human health at present. Developing new types of integrated nanoplatforms for the accurate diagnosis and effective treatment of cancer is very significant. Herein, an intelligent dual-stage core–shell cancer theranostic nanoplatform (Fe³⁺@Au1Ag24@PbP) with NIR laser/tumor-microenvironment (TME) co-responsiveness and multi-modal imaging-therapy was successfully prepared, which was composed of the precisely structured oil-soluble Au1Ag24 nanoclusters (NCs) and Fe³⁺ ions easily assembled within the oil and aqueous phases of the polyethylene glycol (PEG) block grafted polyketal (PK) copolymer (PK-b-PEG, PbP) vesicles, respectively. In this system, we were delighted to find that the prepared Au1Ag24 NCs possess multi-photoresponsive properties, endowing the nanoplatform with photoacoustic (PA)/photothermal (PT) imaging and synergetic photothermal therapy (PTT)/photodynamic therapy (PDT) for cancer under near-infrared (NIR) laser irradiation. On the other hand, Fe³⁺ ions exhibit multi-TME response and regulation behaviors, including as catalysts for the decomposition of endogenous hydrogen peroxide (H₂O₂) in the solid tumor to produce O₂ and as the oxidizing agent for the consumption of the intracellular GSH to avoid the reduction of the generated ¹O₂; therefore, the synchronously formed Fe²⁺ ions from the redox of Fe³⁺ with GSH could further react with H₂O₂ to produce hydroxyl radical (˙OH), which induced ferroptosis-based cancer treatment. The PbP shell possesses TME/pH sensitivity for controlled drug release and passive targeting, causing a large increase in Au1Ag24/Fe³⁺ accumulation within the weakly acidic tumor region and reducing the side effects on normal tissues. Both in vitro and in vivo experiments demonstrate that the Fe³⁺@Au1Ag24@PbP nanoplatform presented excellent PA/PT imaging-guided synergetic PTT/PDT/ferroptosis effects toward tumor cells and tumors. This integrating multi-responsive and multi-modal theranostic nanoplatform paves a new way for effective cancer therapy.