Investigation of a GPC1-targeted and LIFU-responsive nanoplatform with ADV effect for visualized chemo-sonodynamic therapy against pancreatic ductal adenocarcinoma

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies. Regardless of surgical resection, chemotherapy acts as the first-line treatment for PDAC. However, the clinical outcomes are severely compromised by insufficient tumour-specific targeting, chemoresistance, and systemic toxicity. Thus, new synergistic therapeutic strategies are urgently needed to improve therapeutic efficacy of PDAC. PURPOSE: This study developed a glypican-1 (GPC1)-targeted and low-intensity focused ultrasound (LIFU)-responsive nanoplatform for visualized treatment against PDAC. METHODS: This nanoplatform, termed GCPIP, integrated glypican-1-antibody (GPC1-Ab)-guided tumour-specific targeting, perfluoropentane (PFP)-driven acoustic imaging, ultrasound targeted nanobubble destruction (UTND)-triggered drug release, paclitaxel (PTX)-mediated chemotherapy and sonosensitizer-assisted sonodynamic therapy (SDT). RESULTS: GCPIP exhibited favourable physicochemical properties as a delivery system, showing excellent stability, responsive drug release behaviour, and robust ROS-generating capacity. In vitro studies revealed that GCPIP exhibited outstading tumour-targeting capability and potent inhibitory activity against PDAC tumour cells. Near-infrared fluorescence (NIRF) imaging in vivo demonstrated that GCPIP displayed a biodistribution profile broadly consistent with typical metabolic fate of nanoparticles, enabling preferential intratumoural accumulation. Leveraging acoustic droplet vaporization (ADV) effect of PFP, ultrasound (US) imaging further allowed real-time visualization of the uptake and spatial distribution of GCPIP within the tumour. Importantly, GCPIP elicited a pronounced synergistic antitumour effect upon LIFU, as evidenced by substantial inhibition in both tumour volume and tumour weight. Additionally, GCPIP exhibited favourable biosafety in vivo. CONCLUSION: GCPIP successfully achieved US imaging, tumour-specific drug delivery, spatiotemporally controlled drug release, and amplified chemo-sonodynamic therapy, providing a promising strategy to overcome chemoresistance of PDAC and reduce systemic toxicity.