Dual-path modulation of hydrogen peroxide to ameliorate hypoxia for enhancing photodynamic/starvation synergistic therapy

Abstract

The common existence of hypoxia within the tumor microenvironment severely restricts the efficacy of photodynamic therapy (PDT), which is attributed to the fact that the PDT process is strongly oxygen (O₂) dependent. Here, a multifunctional composite (named CPCG), which combines polyethylene glycol (PEG) functionalized cerium oxide nanoparticles (CeO₂) with photosensitizer chlorin e6 (Ce6) and glucose oxidase (GOx), is reported for generating O₂ within the tumor microenvironment by the dual-path hydrogen peroxide (H₂O₂)-modulated ways to ameliorate hypoxia, thereby enhancing the PDT efficiency. This process is realized based on the dual enzyme-like activity of CeO₂. The first modulated way is to transform the superoxide anion (O₂˙⁻) into H₂O₂ by the superoxide dismutase-like activity of CeO₂. The second modulated way is to decompose glucose into H₂O₂ through the catalysis of GOx. Subsequently, H₂O₂ generated from the above dual modulated ways can further produce O₂via the catalase-like activity of CeO₂. Additionally, the depletion of glucose could impede the nutrient supply to obtain starvation therapy. Both in vitro and in vivo experiments indicate that the CPCG composite could enhance the efficacy of photodynamic/starvation synergistic therapy. Therefore, this strategy offers great potential to modulate the O₂ level in the tumor microenvironment for better therapeutic outcomes, and can act as a promising candidate in photodynamic/starvation synergistic therapy.