High-affinity peptide against MT1-MMP for in vivo tumor imaging

• Published in: Journal of controlled release Vol. 150; no. 3; pp. 248 - 255
• Main Authors: Zhu, Lei, Wang, Huiling, Wang, Lin, Wang, Ye, Jiang, Kun, Li, Cheng, Ma, Qingjie, Gao, Shi, Wang, Liping, Li, Wei, Cai, Mingjun, Wang, Hongda, Niu, Gang, Lee, Seulki, Yang, Wei, Fang, Xuexun, Chen, Xiaoyuan
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 30-03-2011; Elsevier
• Subjects: Amino Acid Sequence; angiogenesis; Animals; binding capacity; Biological and medical sciences; Carbocyanines - analysis; Carbocyanines - chemistry; Cattle; Cell Line, Tumor; drugs; extracellular matrix; fluorescence; General pharmacology; Humans; hydrogen bonding; hydrophobic bonding; image analysis; intravenous injection; Matrix metalloproteinase; Matrix Metalloproteinase 14 - metabolism; Medical sciences; metalloproteinases; metastasis; Mice; Models, Molecular; Molecular Sequence Data; monitoring; MT1-MMP (MMP-14); Near-infrared fluorescence optical imaging; neoplasms; Neoplasms - diagnosis; Neoplasms - metabolism; peptide libraries; Peptide Library; Peptides - chemistry; Peptides - metabolism; Phage display peptide library; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; proteolysis; screening; Whole Body Imaging - methods; MT1-MMP (MMP-14); Matrix metalloproteinase; Near-infrared fluorescence optical imaging; Phage display peptide library; Pharmaceutical technology; Peptides; Enzyme; Fluorescence; Metalloendopeptidases; Malignant tumor; Virus; Peptidases; In vivo; Hydrolases; Affinity; Medical imagery; Cancer; Phage
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2011.01.032

Membrane type-1 matrix metalloproteinase (MT1-MMP) is a key member of the matrix metalloproteinase (MMP) family. It participates in pericellular proteolysis of extracellular matrix (ECM) macromolecules and is essential for many biological and pathological processes, such as tumor development, angiogenesis and metastasis. A ligand that specifically binds to MT1-MMP may facilitate the labeling of this molecule, allow imaging at the cellular and organism levels, and provide a means for targeted drug delivery specific to MT1-MMP. A non-substrate MT1-MMP binding peptide was identified by screening a Ph.D.-12™ phage display peptide library and conjugated with near-infrared fluorescent (NIRF) dye Cy5.5 for tumor imaging. Peptide HWKHLHNTKTFL (denoted as MT1-AF7p) showed high MT1-MMP binding affinity. Computer modeling verified that MT1-AF7p binds to the MT-loop region of MT1-MMP and interacts with MT1-MMP through hydrogen bonding and hydrophobic interactions. MDA-MB-435 xenografts with high MT1-MMP expression had significantly higher tumor accumulation and better tumor contrast than the low MT1-MMP expressing A549 xenografts after intravenous injection of Cy5.5-MT1-AF7p. Using NIRF imaging, we have demonstrated specific targeting of MT1-AF7p to MT1-MMP-expressing tumors. Thus, MT1-AF7p is an important tool for noninvasive monitoring of MT1-MMP expression in tumors, and it shows great potential as an imaging agent for MT1-MMP-positive tumors.
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