Pancreatic cancer incidence is rising in both Europe and the USA.
Gemcitabine has been historically used as monotherapy for unresectable and metastatic pancreatic ductal adenocarcinoma (PDAC), however the acquired resistance to it has 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 plat forms 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 proper ties.

The MIVO® multi-organ platform was employed to evaluate the anti-invasive and antimetastatic potential of ICOS-Fc-NS-GEM by simulating both primary and secondary tumor sites, as well as circulating tumor cells. The results confirmed that ICOS-Fc-NS-GEM effectively reduces pancreatic tumor proliferation and invasion, highlighting the potential of combining advanced nanocarriers with organ-on-chip technology for preclinical assessment of novel therapeutics.