Abstract
AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most malignant gastrointestinal cancers with an extremely complex tumor microenvironment and a poor prognosis. The upregulation of Hedgehog (Hh) signaling pathway contributes to the abundance of stroma and barren blood vessels in the PDAC tumor microenvironment, creating a physical and biological barrier leading to strong inherent resistance to drugs. Therefore, inhibition of the Hh signaling pathway combined with chemotherapy has been explored in anti‐PDAC chemotherapy. In this study, the paclitaxel (PTX) and itraconazole (ITA) co‐encapsulated poly (ethylene glycol)‐b‐poly (d, l‐lactide) (PEG‐PLA) micelle (PIM) shows superior therapeutic outcome in PDAC. Pharmaceutically, PIM demonstrates optimized systemic pharmacokinetics and increases tumor drug accumulation due to its serum stability. Pharmacologically, through Hh inhibition and blood vessel normalization contributed by ITA and cytotoxicity contributed by PTX, PIM not only significantly inhibits the tumor growth of the human MIA PaCa‐2 cell‐derived orthotopic pancreatic cancer model but also significantly prolongs the survival of LSL‐KrasG12D/+; LSL‐Trp53R172H/+; Pdx‐1‐Cre (KPC) genetic engineered, spontaneous PDAC mice, a clinically relevant PDAC model with high similarity as human PDAC in terms of cancer histology and biology.
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