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

Background: 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 photoacoustic (PA) imaging. The generated CO2 bubbles also enhanced HIFUT by inducing an enlarged ablation area. The tumor ablation efficiency (61.04%) was significantly improved with a combination of HIFU therapy and SDT. Conclusion: pH-responsive Ca@H NPs have been successfully constructed for PA imagingguided/monitored HIFUT combined with SDT. With the assistance of pH-responsive Ca@H NPs, the combination of these two US-based therapies is expected to play a role in the treatment of non-invasive tumor in the future.