An Oxygen Supply Strategy for Sonodynamic Therapy in Tuberculous Granuloma Lesions Using a Catalase-Loaded Nanoplatform

Can Hu,1,2,* Yan Qiu,1,2,* Jiajun Guo,1,2 Yuchao Cao,1,2 Dairong Li,3 Yonghong Du1,2 1State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dairong Li, Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, No. 1, Youyi Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel +86-23-89012745, Fax +86-23-68485021, Email lidairong@hospital.cqmu.edu.cn Yonghong Du, State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Tel/Fax +86-23-68485021, Email duyonghong@cqmu.edu.cnPurpose: Tuberculosis (TB) is a chronic disease caused by Mycobacterium tuberculosis (MTB) that remains a major global health challenge. One of the main obstacles to effective treatment is the heterogeneous microenvironment of TB granulomas. This study aimed to investigate the potential of a hypoxic remission-based strategy to enhance the outcome of tuberculosis treatment when implemented in combination with ultrasound.Methods: A PLGA nanoparticle (LEV@CAT-NPs) loaded with levofloxacin (LEV) and catalase (CAT) was fabricated by a double emulsification method, and its physical characteristics, oxygen production capacity, drug release capacity, and biosafety were thoroughly investigated. The synergistic therapeutic effects of ultrasound (US)-mediated LEV@CAT-NPs were evaluated using an experimental mouse model of subcutaneous tuberculosis granuloma induced by Bacille Calmette-Guérin (BCG) as a substitute for MTB.Results: LEV@CAT-NPs exhibited excellent oxygen production capacity, biosafety, and biocompatibility. Histological analysis revealed that ultrasound-mediated LEV@CAT-NPs could effectively remove bacteria from tuberculous granulomas, significantly alleviate the hypoxia state, reduce the necrotic area and inflammatory cells within the granuloma, and increase the penetration of dyes in granuloma tissues. The combined treatment also reduced the serum levels of inflammatory cytokines (eg, TNF-α, IL-6, and IL-8), and significantly downregulated the expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF). These results suggested that the synergistic treatment of ultrasound-mediated LEV@CAT-NPs effectively eradicated the bacterial infection and reversed the hypoxic microenvironment of tuberculous granulomas, further promoting tissue repair.Conclusion: This study provides a non-invasive and new avenue for treating refractory tuberculosis infections. The potential role of regulating hypoxia within infected lesions as a therapeutic target for infection deserves further exploration in future studies.Keywords: tuberculosis granulomatous, hypoxia, catalase, sonodynamic therapy, Bacille Calmette-Guérin