title: Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C82(OH)22 and its implication for de novo design of nanomedicine.
abstract: Pancreatic adenocarcinoma is the most lethal of the solid tumors and the fourth-leading cause of cancer-related death in North America. Matrix metalloproteinases (MMPs) have long been targeted as a potential anticancer therapy because of their seminal role in angiogenesis and extracellular matrix (ECM) degradation of tumor survival and invasion. However, the inhibition specificity to MMPs and the molecular-level understanding of the inhibition mechanism remain largely unresolved. Here, we found that endohedral metallofullerenol Gd@C(82)(OH)(22) can successfully inhibit the neoplastic activity with experiments at animal, tissue, and cellular levels. Gd@C(82)(OH)(22) effectively blocks tumor growth in human pancreatic cancer xenografts in a nude mouse model. Enzyme activity assays also show Gd@C(82)(OH)(22) not only suppresses the expression of MMPs but also significantly reduces their activities. We then applied large-scale molecular-dynamics simulations to illustrate the molecular mechanism by studying the Gd@C(82)(OH)(22)-MMP-9 interactions in atomic detail. Our data demonstrated that Gd@C(82)(OH)(22) inhibits MMP-9 mainly via an exocite interaction, whereas the well-known zinc catalytic site only plays a minimal role. Steered by nonspecific electrostatic, hydrophobic, and specific hydrogen-bonding interactions, Gd@C(82)(OH)(22) exhibits specific binding modes near the ligand-specificity loop S1', thereby inhibiting MMP-9 activity. Both the suppression of MMP expression and specific binding mode make Gd@C(82)(OH)(22) a potentially more effective nanomedicine for pancreatic cancer than traditional medicines, which usually target the proteolytic sites directly but fail in selective inhibition. Our findings provide insights for de novo design of nanomedicines for fatal diseases such as pancreatic cancer.
authors.affiliation: Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA.
authors.forename: Seung-gu
authors.initials: SG
authors.lastname: Kang
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Zhou
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Baoyun
authors.initials: B
authors.lastname: Sun
authors.forename: Tien
authors.initials: T
authors.lastname: Huynh
authors.forename: Huan
authors.initials: H
authors.lastname: Meng
authors.forename: Lina
authors.initials: L
authors.lastname: Zhao
authors.forename: Gengmei
authors.initials: G
authors.lastname: Xing
authors.forename: Chunying
authors.initials: C
authors.lastname: Chen
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ruhong
authors.initials: R
authors.lastname: Zhou
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D015195:Drug Design; D005109:Extracellular Matrix / Q000378:metabolism; D037741:Fullerenes / Q000737:chemistry*; D005682:Gadolinium / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D007477:Ions; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000737:chemistry; D051379:Mice; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D015032:Zinc / Q000737:chemistry
chemical_list: D037741:Fullerenes; D007477:Ions; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D005682:Gadolinium; D020782:Matrix Metalloproteinases; D015032:Zinc