Open-Shell Nanosensitizers for Glutathione Responsive Cancer Sonodynamic Therapy

Deleterious effects to normal tissues and short biological half-life of sonosensitizers limit the applications of sonodynamic therapy (SDT). Herein, a new sonosensitizer (Cu(II)NS) is synthesized that consists of porphyrins, chelated Cu²⁺ , and poly(ethylene glycol) (PEG) to overcome the challenges of SDT. As Cu²⁺ contains 27 electrons, Cu(II)NS has an unpaired electron (open shell), resulting in a doublet ground state and little sonosensitivity. Overexpressed glutathione in the tumor can reduce Cu²⁺ to generate Cu(I)NS, leading to a singlet ground state and recuperative sonosensitivity. Additionally, PEG endows Cu(II)NS with increased blood biological half-life and enhanced tumor accumulation, further increasing the effect of SDT. Through regulating the valence state of Cu, cancer SDT with enhanced therapeutic index is achieved.