Glycolysis-non-canonical Glutamine Dual-Metabolism Regulation Nanodrug Enhanced the Phototherapy Effect for Pancreatic Ductal Adenocarcinoma Treatment.

Clinical pancreatic ductal adenocarcinoma (PDAC) treatment is severely limited by lack of effective KRAS suppression strategies. To address this dilemma, a reactive oxygen species (ROS)-responsive and PDAC-targeted nanodrug named Z/B-PLS was constructed to confront KRAS through dual-blockade of its downstream PI3K/AKT/mTOR and RAF/MEK/ERK for enhanced PDAC treatment. Specifically, photosensitizer zinc phthalocyanine (ZnPc) and PI3K/mTOR inhibitor BEZ235 (BEZ) were co-loaded into PLS which was constructed by click chemistry conjugating MEK inhibitor selumetinib (SEL) to low molecular weight heparin with ROS-responsive oxalate bond. The BEZ and SEL blocked PI3K/AKT/mTOR and RAF/MEK/ERK respectively to remodel glycolysis and non-canonical glutamine metabolism. ZnPc mediated photodynamic therapy (PDT) could enhance drug release through ROS generation, further facilitating KRAS downstream dual-blockade to create treatment-promoting drug delivery-therapeutic positive feedback. Benefiting from this broad metabolic modulation cascade, the metabolic symbiosis between normoxic and hypoxic tumor cells was also cut off simultaneously and effective tumor vascular normalization effects could be achieved. As a result, PDT was dramatically promoted through glycolysis-non-canonical glutamine dual-metabolism regulation, achieving complete elimination of tumors in vivo. Above all, this study achieved effective multidimensional metabolic modulation based on integrated smart nanodrug delivery, helping overcome the therapeutic challenges posed by KRAS mutations of PDAC.