Optimization of a MT1-MMP-targeting Peptide and Its Application in Near-infrared Fluorescence Tumor Imaging.

Abstract

Membrane type 1 metalloproteinase (MT1-MMP) is an important regulator of cancer invasion, growth and angiogenesis, thus making it an attractive target for cancer imaging and therapy. A non-substrate peptide (MT1-AF7p) that bonded to the "MT-Loop" region of MT1-MMP was identified by using a phage-displayed peptide library and was used to image the MT1-MMP expression in vivo through optical imaging. However, the substrate in the screening did not have a 3D structure, thus resulting in a loose bonding of MT1-AF7p. To simulate the real conformation of the "MT-Loop" and improve the performance of MT1-AF7p, molecular simulations were performed, because this strategy provides multiple methods for predicting the conformation and interaction of proteinase in 3D. In view of the binding site of the receptor-ligand interactions, histidine 4 was selected for mutation to achieve an increased affinity effect. The optimized peptides were further identified and conformed by atomic force microscopy, isothermal titration calorimetry, cell fluorescence imaging in vitro, and near-infrared fluorescence tumor optical imaging in vivo. The results revealed that the optimized peptide with a mutation of histidine 4 to arginine has the highest affinity and specificity, and exhibited an increased fluorescence intensity in the tumor site in optical imaging.

• Authors: Li Ren, Ye Wang, Lei Zhu, Liqiao Shen, Jinrui Zhang, Jingjing Wang, Haolong Li, Qingchuan Zheng, Dahai Yu, Xuexun Fang
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 10334 (07 09 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29985410 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Peptides
• Peptidomimetics
• Recombinant Proteins
• Matrix Metalloproteinase 14

Topics

• Amino Acid Sequence
• Animals
• Binding Sites
• Catalytic Domain (genetics)
• Cell Line, Tumor
• Humans
• Matrix Metalloproteinase 14 (chemistry, genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Microscopy, Confocal
• Molecular Docking Simulation
• Mutagenesis, Site-Directed
• Neoplasms (diagnostic imaging)
• Optical Imaging
• Peptides (chemical synthesis, chemistry, metabolism)
• Peptidomimetics
• Recombinant Proteins (biosynthesis, chemistry, isolation & purification)
• Tissue Distribution
• Transplantation, Heterologous