Gemcitabine-loaded ICOS-Fc decorated nanosponges: A new chemo immunotherapy combination againstpancreatic cancer

Pancreatic cancer incidence is rising in both Europe and the USA. The late diagnosis, due to the absence ofsymptoms during early stages, as well as the intrinsic or acquired chemoresistance, contributed to the observedlowest 5-year relative survival rate among all cancer types. The resistance mechanisms to Gemcitabinehydrochloride (GEM), historically used as monotherapy for unresectable and metastatic pancreatic ductaladenocarcinoma (PDAC), have been widely elucidated. Recently, nanosized drug delivery systems can representan effective strategy in overcoming poor efficacy and resistance issues, allowing site-specific delivery andimprovement of drug bioavailability of encapsulated nanomedicines. Pancreatic cancer is resistant not only tochemotherapy 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 interestingimmunomodulatory pathway with anti-invasion activity. Interestingly, nanoparticle-based drug deliveryplatforms are a very promising tool since it is possible to combine chemotherapy and immunotherapy. Here, weevaluated 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 pancreaticcancer. NS-GEM affected viability, proliferation, and invasion in the 2D and 3D cultures of pancreatic cancercells. Moreover, the combined formulation ICOS-Fc-NS-GEM showed an enhancement of anti-invasionproperties. 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.