Evaluation of TRAM@PPF Nanoparticles for Efficacy Against Pancreatic Cancer in Mice Model

Introduction: Pancreatic ductal adenocarcinoma (PDAC) poses a major challenge due to the lack of effective treatment options and its extremely poor prognosis. Nanodrug delivery systems can improve drug solubility and enable efficient targeted delivery, offering new possibilities for PDAC therapy. Methods: The oncogenic role of KCa3.1 in PDAC was validated through analyses of The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases combined with functional assays. To overcome the limitations of conventional therapies, we developed a targeted nanodrug delivery system, TRAM@PPF, based on PLGA nanoparticles modified with polyethylene glycol-folate (PEG 2000 -FA). This system was prepared by the emulsion-solvent evaporation method to specifically deliver the KCa3.1 channel inhibitor TRAM-34 to PDAC cells. We characterized the nanosystem’s physical properties and release profile and evaluated its antitumor efficacy in vitro and in vivo. Results: The synthesized TRAM@PPF nanoparticles demonstrated uniform size (~142 nm) and excellent stability, with superior cellular uptake compared to non-folate-modified nanoparticles. In vitro, TRAM@PPF showed potent antitumor activity by markedly inhibiting cell proliferation and enhancing apoptosis. Following intravenous administration in pancreatic cancer mouse models, TRAM@PPF significantly inhibited tumor growth, reduced tumor weight, and prolonged survival. Moreover, TRAM@PPF showed excellent biosafety in animal models, suggesting strong potential for further clinical translation in PDAC therapy. Conclusion: TRAM@PPF preserves folate-mediated tumor-targeting capability while significantly enhancing antitumor activity, offering a promising strategy for targeted therapy of pancreatic cancer. Keywords: nanoparticles, PDAC, KCa3.1 inhibitor