Oxygen-producing proenzyme hydrogels for photodynamic-mediated metastasis-inhibiting combinational therapy

Abstract

Photodynamic therapy (PDT) has provided a promising approach for the treatment of solid tumors, while the therapeutic efficacy is often limited due to the hypoxic tumor microenvironment, resulting in tumor metastasis. Herein, we report an oxygen-producing proenzyme hydrogel (OPeH) with photoactivatable enzymatic activity for PDT enabled metastasis-inhibiting combinational therapy of breast cancer. This OPeH based on alginate is composed of protoporphyrin IX (PpIX) conjugated manganese oxide (MnO₂) nanoparticles, which act as both the photosensitizer and oxygen-producing agent, and singlet oxygen (¹O₂)-responsive proenzyme nanoparticles. In the hypoxic and acidic tumor microenvironment, MnO₂ can generate ¹O₂ to promote PpIX-mediated PDT with an amplified ¹O₂ generation efficiency, which also triggers the cleavage of ¹O₂-responsive linkers and cascade activation of proenzymes for cancer cell death. This combinational therapy upon photoactivation not only greatly inhibited the tumor growth, but also suppressed lung metastasis in a mouse xenograft breast tumor model, which is impossible in the case of PDT alone. This study thus provides a proenzyme hydrogel platform with photoactivatable activity for metastasis-inhibiting cancer therapy with high efficacy and safety.