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 imaging-guided/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.