A road map to exploit the tumor microenvironment for the advancement of “smart” nanomedicines in treating pancreatic cancer

Abstract

Pancreatic cancer is one of the deadliest with a 5-year survival of 6 to 9%. Nanotechnology offers paradigm-changing opportunity to treat such cancers. Successful integration of nanotechnology into the current paradigm of cancer therapy requires proper understanding of the interface between nanoparticles (NPs) and cancer cells, as well as other key components within the tumor microenvironment (TME), such as normal fibroblasts (FBs) and cancer-associated FBs (CAFs). So far, much focus has been on cancer cells, but FBs and CAFs also play a critical role: FBs suppress the tumor growth while CAFs promote it. It is not yet known how NPs interact with FBs and CAFs compared to cancer cells. Hence, our goal was to elucidate the extent of NP uptake and retention in cancer cells, FBs, and CAFs of pancreatic origin to further understand the fate of NPs in a real tumor-like environment. We used gold nanoparticles as our model NP system due to their numerous applications in cancer therapy, including radiotherapy and chemotherapy. Our NP uptake studies revealed that both cancer cells and CAFs take up 50% more NPs compared to NFs. We also looked at the potential of NP retention. Cancer cells and CAFs were still managed retain between 70 to 80% of NPs over a 24 hour time period. Higher uptake and retention of NPs in cancer cells and CAFs vs FBs is very important in promoting NP-based applications in cancer therapy. Our results show potential in modulating uptake and retention of GNPs among key components of TME, in an effort to develop NP-based strategies to suppress the tumor growth. An ideal NP-based platform would eradicate tumor cells, protect FBs, and deactivate CAFs. Therefore, this study lays a road map to exploit the TME for the advancement of “smart” nanomedicines that would constitute the next generation of cancer therapeutics to treat pancreatic cancer.