An\nMMP‑2 Responsive Liposome Integrating Antifibrosis and Chemotherapeutic\nDrugs for Enhanced Drug Perfusion and Efficacy in Pancreatic Cancer

Fibrotic\nstroma, a critical character of pancreatic tumor microenvironment,\nprovides a critical barrier against the penetration and efficacy of\nvarious antitumor drugs. Therefore, new strategies are urgently needed\nto alleviate the fibrotic mass and increase the drug perfusion within\npancreatic cancer tissue. In our current work, we developed a β-cyclodextrin\n(β-CD) modified matrix metalloproteinase-2 (MMP-2) responsive\nliposome, integrating antifibrosis and chemotherapeutic drugs for\nregulation of pancreatic stellate cells (PSCs), a key source of the\nfibrosis, and targeted delivery of cytotoxic drugs for pancreatic\ncancer therapy. These liposomes disassembed into two functional parts\nupon MMP-2 cleavage at the tumor site. One part was constituted by\nthe β-CDs and the antifibrosis drug pirfenidone, which was kept\nin the stroma and inhibited the expression of collagen I and TGF-β\nin PSCs, down-regulating the fibrosis and decreasing the stromal barrier.\nThe other segment, the RGD peptide-modified-liposome loading the chemotherapeutic\ndrug gemcitabine, targeted and killed pancreatic tumor cells. This\nintegrated nanomedicine, showing an increased drug perfusion without\nany overt side effects, may provide a potential strategy for improvement\nof the pancreatic cancer therapy.