Argenziano Monica, Monge Chiara, Scomparin Anna, Trotta Francesco, Boscaro Valentina, Stoppa Ian, Dianzani Umberto, Pizzimenti Stefania, Cavalli Roberta, Dianzani Chiara
Department of Scienza e Tecnologia del Farmaco, University of Turin, Via Pietro Giuria 9, 10125 Turin, Italy.
Department of Chemistry, University of Turin, Via Pietro Giuria 7, 10125 Turin, Italy.
Int J Pharm. 2025 Jun 19;682:125869. doi: 10.1016/j.ijpharm.2025.125869.
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.
欧洲和美国的胰腺癌发病率都在上升。由于早期无症状以及内在或获得性化疗耐药性导致的晚期诊断，使得胰腺癌成为所有癌症类型中5年相对生存率最低的疾病。盐酸吉西他滨（GEM）曾被用作不可切除和转移性胰腺导管腺癌（PDAC）的单一疗法，其耐药机制已得到广泛阐明。最近，纳米级药物递送系统可以成为克服疗效不佳和耐药问题的有效策略，实现药物的靶向递送并提高包封纳米药物的生物利用度。胰腺癌不仅对化疗耐药，对免疫疗法也耐药；因此，仍有必要寻找其他策略。最近，诱导性T细胞共刺激分子（ICOS）/ICOS配体（ICOSL）信号通路已成为一条具有抗侵袭活性的有趣免疫调节途径。有趣的是，基于纳米颗粒的药物递送平台是一种非常有前景的工具，因为它可以将化疗和免疫疗法结合起来。在这里，我们评估了负载GEM并经ICOS-Fc功能化的β-环糊精基纳米海绵（NS）（ICOS-Fc-NS-GEM）作为一种创新的联合疗法，其可能适合克服胰腺癌的耐药性。NS-GEM影响了胰腺癌细胞二维和三维培养中的活力、增殖和侵袭。此外，联合制剂ICOS-Fc-NS-GEM显示出抗侵袭特性增强。利用多器官单流装置（MIVO®）技术证实了抗侵袭效果，提高了系统的复杂性，并获得了更接近体内情况的证据。
