Enhancing nanomedicine efficacy in KPC pancreatic tumors through ketotifen-mediated tumor microenvironment remodeling

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) poses major barriers to the efficacy of anticancer therapies, particularly through features such as desmoplasia, elevated stiffness, and impaired perfusion that restrict drug delivery. Strategies that modulate these physical abnormalities hold promise for improving therapeutic outcomes, especially for nanomedicines. In this study, we investigated the potential of the antihistamine ketotifen to remodel the TME and enhance intratumoral delivery and efficacy of liposomal therapeutics, PEGylated liposomal doxorubicin (Doxil), and a co-encapsulated alendronate-doxorubicin (PLAD) formulation. We employed the KPC model of PDAC, a tumor type derived from genetically engineered mouse models that mimic key features of human pancreatic tumors, such as a immunosuppresive microenvironment and dense fibrosis. In vitro, ketotifen demonstrated no direct cytotoxic activity on tumor cells, and did not alter cellular drug uptake of Doxil, PLAD or free doxorubicin as assessed by flow cytometry. In vivo, ketotifen pretreatment significantly enhanced intratumoral accumulation of liposomes by reducing stiffness and improving perfusion, as measured by shear wave elastography and contrast-enhanced ultrasound. These microenvironmental changes translated into greater anti-tumor efficacy and prolonged survival in groups that received a combination of ketotifen even at low doses. Cytokine analysis showed reduced IL-10 and an IFN-γ increase in ketotifen combinations, suggesting immune modulation of the TME. Random forest analysis identified tumor stiffness, IL-10, and TNF-α as the strongest predictors of therapeutic outcome. These findings demonstrate that microenvironmental modulation by repurposing ketotifen improves nanomedicine delivery and efficacy in PDAC.