Nanoparticles for Delivery of Encapsulated Drugs to Hypoxic Pancreatic Ductal Adenocarcinoma Cell Spheroids

Tumor hypoxia promotes angiogenesis, dysfunctional vascular formation, and the epithelial-to-mesenchymal transition phenotype. We propose that a CXCR4 inhibitor (AMD3100) could decrease cancer stemness and improve the efficacy of the anticancer drug gemcitabine (GEM) in targeting hypoxic pancreatic ductal adenocarcinoma (PDAC) cells. In this study, we synthesized a hypoxia-responsive polymer containing poly(lactic acid)-diazobenzene-poly(ethylene glycol) to produce hypoxia-responsive polymersomes. Cell viability experiments showed that AMD3100 enhanced the cytotoxicity of GEM-encapsulated polymersomes under hypoxic conditions compared to normoxia. The combined treatment significantly elevated pro-apoptotic BAX mRNA levels and reduced antiapoptotic BCL2 mRNA levels. Additionally, the combination therapy decreased the size of cancer cell spheroids from PANC1 and patient-derived cells.