Cancer‐Specific and Pro‐Apoptotic PEGylated Liposomes Containing SMAC‐Mimetic Doxorubicin Prodrug for Safe High‐Dose Delivery in Pancreatic Cancer

High-dose chemotherapy exhibits potent therapeutic efficacy in pancreatic cancer. However, its application is often limited because of severe toxicity and drug resistance. Herein, a high-dose therapy of pro-apoptotic doxorubicin (DOX) prodrug-encapsulated PEGylated liposomes (Aposomes) is presented for the treatment of pancreatic cancer. The prodrug is synthesized by conjugating DOX with a second mitochondria-derived activator of caspases mimetic peptide (SMAC-P-FRRL; AVPIAQ-FRRL: antagonist of inhibitor of apoptosis proteins), in which the cathepsin B-cleavable -RR- sequence enables selective release. The resulting SMAC-P-FRRL-DOX is efficiently encapsulated into PEGylated liposomes (87.7 ± 0.48 nm), which induced apoptosis specifically in cathepsin B-overexpressing pancreatic cancer cells. In KPC960 tumor-bearing mice, repeated administration of high-dose Aposomes facilitates preferential tumor accumulation via the enhanced permeability and retention (EPR) effect and exerts potent antitumor activity with minimal toxicity in normal tissues. Moreover, the therapeutic efficacy and safety profile of high-dose Aposomes are validated in humanized NOD scid gamma (NSG) mice. Notably, high-dose Aposomes significantly reduce orthotopic pancreatic tumor size in NSG mice without toxicity in the blood, immune system, and normal tissues. This high-dose therapy of Aposomes can greatly improve the therapeutic index of pancreatic cancer chemotherapy without causing severe toxicity and potential drug resistance.