A GPC1-Targeting multifunctional nanoplatform combining paclitaxel-mediated chemotherapy and chlorin e6-assisted sonodynamic therapy for Pancreatic Ductal Adenocarcinoma (PDAC) treatment.

Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most malignant tumours with limited treatment options and poor prognosis. This study designed a targeting nanoplatform, GCP@NBs, combining paclitaxel (PTX)-mediated chemotherapy and chlorin e6 (Ce6)-assisted sonodynamic therapy (SDT) for PDAC. In vitro targeting ability was validated via glypican-1 antibodies (GPC1-Abs) on the surface. Phase transition of perfluoropentane (PFP) facilitated the ultrasound (US) imaging and the controlled drug release. Live/Dead Cell Dual-fluorescence Staining and flow cytometry were performed to corroborate cell apoptosis. Meanwhile, the generation of reactive oxygen species (ROS) was confirmed by ROS Content Detection Kit. Mitochondrial Membrane Potential (MMP) Assay Kit was leveraged to verify the depolarization of MMP, and western blot was performed to reveal the expression of proteins involved in apoptosis. Additionally, biosafety of GCP@NBs in the absence of US irradiation was validated. Consequently, GCP@NBs exhibited optimal particle size of 378.4 ± 10.54 nm and surface charge of -22.63 ± 0.32 mV, showing excellent stability and drug loading capacity (47.35 ± 0.21% for Ce6 and 64.80 ± 0.19% for PTX). GCP@NBs showed good biosafety and US imaging capability, exhibited specific targeting ability and cellular uptake, demonstrated efficient drug release and US-responsive ROS generation, and achieved excellent anti-cancer effects at low concentration. JC-1 staining showed the obvious MMP depolarization, and Western blot illustrated the increased expression of caspase-3 and Bax/Bcl-2 ratio during the cell apoptosis process. This study highlights the potential of GCP@NBs as novel and highly effective nanoplatforms for treatment of PDAC.