Preparation of CPD12C15 hyaluronic acid nanoparticles, a novel glycolytic inhibitor and preliminary pharmacologic study on anti-pancreatic cancer.

Pancreatic cancer (PC) is one of the most insidious malignant tumors with aggressive metastasis and ineffective treatments. Although gemcitabine (GEM) is the gold standard for PC, the acquired resistance and severe myelosuppression limit clinical utility. It has been found that abnormal aerobic glycolysis may be responsible for drug resistance in PC. Disulfiram (DSF), a commonly used anti-alcoholic drug, possesses potent anti-tumor activity combined with copper. Nevertheless, poor water solubility and neurotoxicity restrict clinical applications. Therefore, our group modified the structure of DSF and synthesized a novel compound CPD12C15, which exhibited stronger anti-tumor activity and lower neurotoxicity than DSF. Nanoparticles with excellent release properties, modified with hyaluronic acid (HA) targeting CD44, which is highly expressed on pancreatic cells, can evade the removal of natural defense system and enhance tumor-targeting ability. Herein, CPD12C15 was loaded into HA-modified PLGA nanoparticles (HPC-NP) in order to improve the sustained release properties and active targeting ability. Our research revealed that CPD12C15 combined with Cu (HPC-NP/Cu) could inhibit tumor proliferation, migration, invasion and induce apoptosis by suppressing the aerobic glycolysis pathway, which further inhibited cell stemness and drug resistance in vivo and in vitro, suggesting that it may be a potential strategy for PC treatment.