Oxygen Self-Production Red Blood Cell Carrier System for MRI Mediated Cancer Therapy: Ferryl-Hb, Sonodynamic, and Chemical Therapy

Abstract

Hypoxia in tumors can lead to insufficient oxygen supply during sonodynamic therapy (SDT), which in turn strengthens tumor resistance to sonodynamic efficacy. To conquer hypoxia in tumors and improve the treatment effectiveness, we developed oxygen self-production red blood cell (RBC) carrier system to decompose tumor endogenic H₂O₂ into O₂ and combine triplex cancer therapy: ferryl-hemoglobin (ferryl-Hb), sonodynamic, and chemical therapy. Both hydrophilic sonosensitizer and doxorubicin (DOX) were encapsulated inside RBCs (DOX/Mn-TPPS@RBCs). The drug release can be improved by combining the effects of H₂O₂ and ultrasonic irradiation. Here, we introduced a contrast agent, <i>meso</i>-tetra (4-sulfonatephenyl) porphyrinate manganese(III) complex (Mn-TPPS), which could be used to enhance the signal intensity of magnetic resonance imaging (MRI) of the tumor site. The feasibility of Mn-TPPS as a sonosensitizer was investigated during SDT. Importantly, DOX/Mn-TPPS@RBCs overcame hypoxia in the tumor and improved the efficacy of SDT owing to the O₂ generation by the catalase-catalyzed decomposition of tumor endogenic H₂O₂. Hemoglobin was simultaneously oxidized into highly oxidative ferryl-Hb species by H₂O₂ and reactive oxygen species, resulting in cytotoxicity. Overall, this drug delivery system is a promising therapeutic agent involving in situ production of oxygen inside the tumor, triplex therapy, and MRI.