Local delivery of interleukin 12 to the tumor microenvironment via pH-responsive ITGA5 targeting nanoparticles

Pancreatic ductal adenocarcinoma is one of the most severe types of solid tumors and has a 5-year survival rate of 10%. This is mostly due to the dense tumor microenvironment (TME) with an abundance of cancer associated fibroblast (CAFs). In this TME there is a low amount of immune cells, which limits the effect of immunotherapies. Therefore, current research focuses on the conversion from a "cold" immunological state to a "hot" state. A promising molecule for this is interleukin-12 (IL-12). However, systemic administration of IL-12 has showed severe side effects and low anti-tumor effects. This has steered the research field into new techniques for the delivery of IL-12. The goal of this research is to develop a novel method for the delivery of IL-12 to the TME. We hypothesize that delivery of IL-12 to CAFs using nanoparticles increases the local concentration of IL-12, thereby activating immune cells. We encapsulated IL-12 in nanoparticles consisting of PDPA, a pH sensitive polymer, and DSPE-PEG. As the pH is low in the TME, the incorporation of PDPA helps in the local release of IL-12. To a fraction of the DSPE-PEG the CAF targeting ligand AV3 is conjugated, enabling targeting to the TME.