Phenylboronic acid modified nanoparticles simultaneously target pancreatic cancer and its metastasis and alleviate...

Pancreatic ductal adenocarcinoma is one of the most lethal malignant tumors, its drug resistance, immunosuppression and metastasis makes the traditional chemotherapy and immunotherapy inefficient. Here we confirmed a 3-aminophenylboronic acid-modified low molecular weight heparin-D-α-tocopheryl succinate micellar nanoparticle (PBA-LMWH-TOS NP, PLT NP) could inhibit orthotopic pancreatic tumor and its spontaneous metastases. The small particle size and high affinity of PBA to sialic acid residue (SA) made PLT/PTX NPs significantly targeted and accumulated in both pancreatic tumor tissues and metastases. The immunosuppressive microenvironment of pancreatic tumor was most caused by the infiltration of immunosuppressive cells, mainly myeloid-derived suppressor cells (MDSCs). We first reported that P-selectin glycoprotein ligand-1 (PSGL-1) was expressed on the surfaces of MDSCs in pancreatic tumor tissues. Meanwhile, we found that LMWH could inhibit the early stage of adhesion cascade between vascular endothelial cells (VECs) and MDSCs by interfering with P-selectin/PSGL-1 binding, thus inhibiting MDSC recruitment to pancreatic tumor tissues. The therapeutic results indicated that PLT/PTX NPs could significantly improve the immune microenvironment of pancreatic tumor and inhibit spontaneous metastases. This nanosystem provides a new immune microenvironment regulation mechanism based on carrier materials in pancreatic tumor, and has high clinical application potential.