Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C₈₂(OH)₂₂ and its implication for de novo design of nanomedicine

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 38; pp. 15431 - 15436
• Main Authors: Kang, Seung-gu, Zhou, Guoqiang, Yang, Ping, Liu, Ying, Sun, Baoyun, Huynh, Tien, Meng, Huan, Zhao, Lina, Xing, Gengmei, Chen, Chunying, Zhao, Yuliang, Zhou, Ruhong
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 18.09.2012; National Acad Sciences; National Academy of Sciences, Washington, DC (United States)
• Subjects: Active sites; adenocarcinoma; Angiogenesis; animal experimentation; animal models; Animals; Biological Sciences; Blood vessels; Cancer; Catalytic Domain; death; Drug Design; Electrostatics; Environmental Molecular Sciences Laboratory; enzyme activity; extracellular matrix; Extracellular Matrix - metabolism; Fullerenes - chemistry; Gadolinium - chemistry; human growth; Humans; Hydrogen Bonding; hydrophobicity; Ions; Ligands; Matrix Metalloproteinase Inhibitors - chemistry; Matrix Metalloproteinase Inhibitors - pharmacology; Matrix Metalloproteinases - chemistry; metalloproteinases; Metastasis; Mice; molecular dynamics; Nanomedicine; Nanomedicine - methods; Nanoparticles - chemistry; Neoplasm Metastasis; Neoplasm Transplantation; Neovascularization, Pathologic; pancreatic diseases; Pancreatic neoplasms; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Physical Sciences; proteolysis; therapeutics; traditional medicine; Tumors; Zinc; Zinc - chemistry; North America
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1204600109

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.