pH-Responsive Nanoparticles for Enhanced Antitumor Activity by High-Intensity Focused Ultrasound Therapy Combined with Sonodynamic Therapy

Hui Gao,1,2,* Zhaoxia Wang,1,2,* Mixiao Tan,1 Weiwei Liu,1 Liang Zhang,1 Ju Huang,1 Yang Cao,1 Pan Li,1 Zhigang Wang,1 Jiexin Wen,2 Tingting Shang,1 Haitao Ran1 1Chongqing Key Laboratory of Ultrasound Molecular Imaging & Institute of Ultrasound Imaging, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of Ultrasound, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haitao RanChongqing Key Laboratory of Ultrasound Molecular Imaging & Institute of Ultrasound Imaging, The Second Affiliated Hospital of Chongqing Medical University, No. 76 Linjiang Road, Yuzhong District, Chongqing, 400010, People’s Republic of ChinaTel +86-13-512373563Email ranhaitao@cqmu.edu.cnBackground: Therapeutic ultrasound (US) has been extensively explored for its inherent high tissue-penetrating capability and on-demand irradiation without radioactive damage. Although high-intensity focused ultrasound (HIFU) is evolved as such an outstanding US-based approach, its insufficient therapeutic effect and the high-intensity induced potential damage to surrounding normal tissues hindered its development towards practical application. As opposed to high intensity ultrasound, sonodynamic therapy (SDT) is a low intensity US-based method which exhibits certain therapeutic effects against cancer via sonosensitizers-generated reactive oxygen species (ROS) overproduction.Methods: Hematoporphyrin monomethyl ether (HMME) loaded CaCO3 nanoparticles (designated as Ca@H) were synthesized by a gas diffusion method. The pH-responsive performance, in vitro SDT, ex vivo HIFU therapy (HIFUT), photoacoustic (PA) imaging and in vivo HIFUT combined with SDT were investigated thoroughly.Results: Ca@H NPs gradually decomposed in acid tumor microenvironment, produced CO2 and released HMME. Both CO2 and HMME enhanced pho