PNNL

Abstract

Pancreatic adenocarcinoma is the most lethal of the solid tumors and the fourth leading cause of cancer-related death in North America. Matrix metalloproteinase (MMP) has long been targeted as a potential anti-cancer therapy due to its seminal role in angiogenesis and extracellular matrix (ECM) degradation for the tumor survival and invasion. The inhibition specificity to MMPs and the molecular level understanding of inhibition mechanism, however, remains largely unresolved. Here, we found that endohedral metallofullerenol Gd@C82(OH)22 can successfully inhibit the neoplastic activity with experiments at animal, tissue, and cellular levels. Gd@C82(OH)22 effectively blocks tumor growth in human pancreatic cancer xenografts in nude mice model. Enzyme activity assays also show Gd@C82(OH)22 not only suppresses the expression of MMPs but also significantly reduces their activities. We then further applied large scale molecular dynamics simulations to uncover the molecular mechanism by studying the Gd@C82(OH)22--MMP-9 interactions at atomic detail. Our data demonstrated that Gd@C82(OH)22 inhibits MMP-9 mainly via an exocite interaction while the well-known zinc catalytic site only plays a minimum role. Steered by non-specific electrostatic, hydrophobic and specific hydrogen bonding interactions, Gd@C82(OH)22 exhibits specific binding modes near the ligand specificity loop S1'', thereby inhibiting the MMP-9 activity. Both the suppression of MMPs expression and specific binding mode make Gd@C82(OH)22 a potentially more effective nanomedicine for pancreatic cancer than the traditional medicines which usually target the proteolytic sites directly, but fail in selective inhibition. Our findings based on a combination of in vivo, in vitro and in silico approaches provide new insights for de novo design of nanomedicines for fatal diseases such as pancreatic cancer.