Collagenase-Loaded H-TiO2 Nanoparticles Enhance Ultrasound Imaging-Guided Sonodynamic Therapy in a Pancreatic Carcinoma Xenograft Model via Digesting Stromal Barriers

Sonodynamic therapy (SDT), a noninvasive therapy that relies on sonosensitizers and generates reactive oxygen species (ROS), has attracted considerable attention in the treatment of pancreatic cancer. However, being surrounded by dense stromal barriers, pancreatic cancer exhibits high interstitial fluid pressure (IFP) and hypoxia in the tumor microenvironment (TME), resulting in poor SDT efficacy. Collagenase-loaded hollow TiO₂ (Col-H-TiO₂) nanoparticles (NPs) capable of degrading stromal barriers and producing sufficient ROS production were synthesized in this study. After administration of NPs in the patient-derived xenograft (PDX) model, ultrasonic irradiation-released collagenase degraded tumor matrix fibers, decreased intratumoral IFP, and enhanced the penetration and retention of NPs within tumor tissues. Moreover, the NPs accumulated within the tumor not only generate abundant ROS under the influence of ultrasound irradiation but also improve intratumoral ultrasound signal, providing ultrasonic imaging-guided highly effective SDT for pancreatic cancer. In conclusion, this research improves the SDT technique and enhances the visualization of pancreatic cancer by remodeling the TME and is a promising strategy for further clinical applications.