Enzyme-like copper-encapsulating magnetic nanoassemblies for switchable T1-weighted MRI and potentiating chemo-/photo-dynamic therapy

Abstract

Photodynamic therapy (PDT) has become a promising cancer treatment due to in situ generation of cytotoxic reactive oxygen (ROS); however, it remains limited by the hypoxia of tumor microenvironment (TME) and penetration depth of laser. Herein, we developed a kind of GSH-/H₂O₂-responsive copper-encapsulating magnetic nanoassemblies (MNSs) for switchable T1-weighted magnetic resonance imaging (MRI) and enzyme-like activity potentiating PDT of cancer. MNSs were rationally constructed using the chelation effect of copper ions (Cu²⁺) with polyacrylic acid-coated ultrasmall iron oxide nanoparticles (UIONPs). After uptake by tumor cells, the incorporated Cu²⁺ of MNSs was reduced to Cu⁺ through the intracellular GSH, which resulted in the disassembly of MNSs accompanied by the "silenced" MR signal shifting to a positive state. Sequentially, the generated Cu⁺ manifested peroxidase-like activity, catalyzing local H₂O₂ in TME to cytotoxic ·OH for chemodynamic therapy. Furthermore, Cu²⁺ and UIONPs could decompose H₂O₂ to O_2, thus providing extra oxygen necessary for enhancing the PDT effect of photosensitizer IR-780. Finally, IR-780-loading MNSs (MNSs@IR-780) under laser irradiation significantly inhibited tumor growth and prolonged the survival of gastric MGC-803 tumor-bearing mice. Therefore, this study provides a versatile nanoplatform as a tumor-responsive theragnostic agent. STATEMENT OF SIGNIFICANCE: Tumor hypoxia and penetration depth of laser severely hindered the PDT of cancer. Valence-convertible metal ions (VCMI, e.g., Cu²⁺/Cu⁺, Fe³⁺/Fe²⁺) have been reported as Fenton-like agents disintegrating H₂O₂ to O₂ to enhance PDT. Tumor-delivery of VCMI is of essential importance for in situ triggering of a Fenton-like reaction. We thereby developed magnetic nanoassemblies (MNSs) to encapsulate Cu²⁺ and load photosensitizer (IR-780). Stimulated by GSH and H₂O₂, MNSs performed catalase/peroxidase-like activity that provided extra O₂ for PDT and catalyzed H₂O₂ to ·OH for CDT. Consequently, IR-780-loading MNSs under laser irradiation significantly inhibit the tumor growth due to effective tumor delivery of Cu²⁺ and IR-780. This study might offer a feasible nanoplatform for tumor-delivery of metal ions and drugs.

Keywords: Chemo-/photodynamic therapy; Copper-encapsulating magnetic nanoassemblies; Enzyme-like activity; Reactive oxygen; Switchable magnetic resonance imaging.