Engineered a Gemcitabine Nano-Prodrug Targeting Desmoplastic Pancreatic Tumor with Dual Enhancement of Penetration Dynamics

The desmoplastic nature characterized by dense tissue and poor vascular conditions in pancreatic cancer (PDAC) poses a significant barrier to effective chemotherapy. Targeting the extracellular matrix and reducing desmoplasia in the tumor microenvironment is a rational approach to improve the penetration and efficacy of gemcitabine (GEM) in PDAC. Herein, a small molecular self-assembly nano-prodrug is developed for the “three-in-one” co-delivery of GEM chemotherapeutics, all-trans retinoic acid (ATRA), and nitric oxide (NO) donors, decorated with PDAC-homing targeting peptide. Stimulated by the PDAC microenvironment, the nano-prodrug releases ATRA that quiesces activated pancreatic stellate cells to alleviate stromal desmoplasia. Simultaneously, it generates abundant NO to induce a vasodilatory effect as well as a “nanomotor” effect. This combinational nano-prodrug delivery strategy, with a dual enhancement of drug penetration dynamics, effectively improves the distribution and bioavailability of the co-delivered GEM into the deep and dense pancreatic tumor tissue, which leads to significant amplification of tumor growth inhibition in different PDAC mouse models.