Dual Enzyme‐Responsive Polymer‐Drug Conjugates Induce Diverse Cells Mutual Transcytosis to Achieve Deep Pancreatic Tumor Penetration

Abstract Enzyme‐responsive active transporting nanomedicines have shown promise in overcoming the tumor‐dense extracellular matrix barrier by inducing cancer cells’ intercellular transcytosis to deliver drugs deep into solid tumors. However, nanomedicine only responsive to the cancer cell‐related enzyme is not very effective in pancreatic tumors because successive transcytosis cannot be established among the cancer cells, which are scattered in a large number of cancer‐associated fibroblasts (CAFs). Here are reported dual‐enzyme‐responsive 7‐ethyl‐10‐hydroxycamptothecin (SN38)‐polymer conjugates capable of inducing transcytosis among cancer cells and CAFs to infiltrate pancreatic tumors efficiently. The conjugates are zwitterionic for long blood circulation. Once in the tumor, the γ‐glutamyl transpeptidase (GGT) overexpressed on the tumor endothelial and cancer cells, or the fibroblast‐activated protease (FAP) on CAFs, can cleave the γ‐glutamylamide or the prolylglycine dipeptide amides, producing primary amines. The cationized conjugate then induces transcytosis among cancer cells and CAFs, establishing successive intercellular transport to infiltrate the tumor. The conjugates' enzyme reactivity and overall hydrophobicity determine their cationization and transcytosis behaviors. The conjugates with high hydrophobicity and fast cationization show potent antitumor activity in pancreatic cancer patient‐derived xenograft and orthotopic tumor models. This study provides an active transportation strategy to overcome the delivery barrier of tumors with rich stroma cells.