Nutritional Glutamine-Modified Iron-Delivery System with Enhanced Endocytosis for Ferroptosis Therapy of Pancreatic Tumors

Heterogeneous reprogrammed nutrient metabolic networks formed by oncogenes exhibit the potential for exploring novel druggable targets and developing innovative anticancer therapeutics. Herein, based on the heterogeneous metabolic characteristics of glutamine (Gln) addiction in pancreatic cancer cells, an iron-delivery system (IDS) with enhanced endocytosis is designed for efficient ferroptosis therapy. The IDS is characterized by Gln modification and can be recognized as a source of Gln nutrients for efficient endocytic uptake by pancreatic tumor cells. Because the IDS is flexible to combine with amino acid-like components, the IDS with enhanced endocytosis is further produced by loading the Gln transporter inhibitor of V9302. V9302 is capable of suppressing molecular Gln uptake via transporter ASCT2, which generates Gln deprivation to direct metabolic reprogramming of cancer cells and enhances cellular uptake of Gln-modified IDS via RAS-stimulated macropinocytosis. The enhanced endocytosis and high iron content of IDS facilitate ferroptosis in mice pancreatic tumor models; thus, an amino acid-like ferroptosis inducer of l-buthionine sulfoximine (BSO) is further combined. The enhanced endocytosis resulting from the synergism of Gln and V9302 enables the efficient delivery of iron and BSO for ferroptosis tumor therapy. This work provides an alternative approach for enhancing intracellular drug delivery of the tumors with heterogeneous nutrient metabolism by virtue of combining nutrient-modified nanodrugs with the corresponding nutrient transporter inhibitors.