Gemcitabine-loaded ICOS-Fc decorated nanosponges: A new chemo immunotherapy combination against pancreatic cancer.

Pancreatic cancer incidence is rising in both Europe and the USA. The late diagnosis, due to the absence of symptoms during early stages, as well as the intrinsic or acquired chemoresistance, contributed to the observed lowest 5-year relative survival rate among all cancer types. The resistance mechanisms to Gemcitabine hydrochloride (GEM), historically used as monotherapy for unresectable and metastatic pancreatic ductal adenocarcinoma (PDAC), have been widely elucidated. Recently, nanosized drug delivery systems can represent an effective strategy in overcoming poor efficacy and resistance issues, allowing site-specific delivery and improvement of drug bioavailability of encapsulated nanomedicines. Pancreatic cancer is resistant not only to chemotherapy but also to immunotherapy; therefore, identifying strategic alternatives is still necessary. Recently, the inducible T-cell co-stimulator (ICOS)/ICOS ligand (ICOSL) signaling has emerged as an interesting immunomodulatory pathway with anti-invasion activity. Interestingly, nanoparticle-based drug delivery platforms are a very promising tool since it is possible to combine chemotherapy and immunotherapy. Here, we evaluated β-cyclodextrin-based nanosponges (NS) loaded with GEM and functionalized with ICOS-Fc (ICOS-Fc-NS-GEM) as an innovative combination therapy, potentially suitable to overcome drug resistance in pancreatic cancer. NS-GEM affected viability, proliferation, and invasion in the 2D and 3D cultures of pancreatic cancer cells. Moreover, the combined formulation ICOS-Fc-NS-GEM showed an enhancement of anti-invasion properties. The MULTI-ORGAN single flow device (MIVO®) technology was exploited to confirm the anti-invasion effect, raising the system's complexity and achieving evidence closer to the in vivo scenario.