Investigation Of Matrix Metalloproteinase Targeting Peptide Probes Applications In Tumor Imaging

Nowadays, more and more people die of cancer all over the world. Although we understand the mechanisms of cancer developing better and better, the five-year survive rate of cancer patients is still low. One of these reasons is due to the lacking of early diagnosis and in-time therapy. With the development of different imaging modalities and investigation of tumor targeting drugs, molecular imaging facilitates visualization of tumor early diagnosis and therapy monitoring. Optical imaging technology holds the high resolution, sensitivity, easy-to-use and non-radiation properties. Intensive researches have been putting on designing optical imaging instrument, probes and other related things.Matrix metalloproteinases (MMPs) represent one of the most well-known proteases associated with tumorigenesis. MMPs are a family of zinc-dependent endopeptidases that consist of 24 human MMPs, six of which are membrane bound. Matrix metalloproteinase (MMP) plays an important role in cancer that it involves in tumor invasion, migration and angiogenesis. In numerous studies, expression of MMPs has been shown to be related to invasive phenotype and metastatic potential of tumor cells. Membrane type I matrix metalloproteinase (MT1-MMP) is one of key members in MMPs family. It closely related to other MMPs activation and regulation. MT1-MMP plays an important role in physical (wound healing, bone growth and remodeling) and pathologic (cancer growth, invasion, metastasis and angiogensis) condition. A ligand holding high specific and binding affinity to MT1-MMP may facilitate understanding MT1-MMP functions in vivo. To this aspect, a labeled peptide probe could be used for non-invasively early tumor detection with fast blood clearance, well tissue penetration properties, and almost none immune-reaction. Herein, we using MMPs as target, screened, designed and designed MMPs specific detection peptide probe. Our in vivo imaging experiments showed the possibilities of using peptide as tumor early diagnosis reagent. To start with, we continued on our investigation of MT1-MMP binding peptide originally derived from phage display screening. In the considerate of our in vitro and in vivo data, MT1-MMP binding peptide showed a high specific binding ability of MT1-MMP. It is promising that using this peptide as a carrier for MT1-MMP targeting therapy. However, dye labeled peptide probe (always"on"probe) usually displayed a high background in vivo. To solve this problem, we further developed a MT1-MMP activatable probe based on a reported MT1-MMP specific substrate. The activatable probe kept quenched status until cleaved by MT1-MMP. Our in vitro and in vivo data suggesting MT1-MMP activatable probe has an improved background signal than that of MT1-MMP binding peptide. To combine the advantages of always on probe and activatable probe, we hypothesized a binding peptide conjugated with activatable probe would show an improved binding affinity and low background. Therefore, a dual-targeting probe was designed by conjugating known integrin binding peptide and MMP-2 substrate. As our expectation, in vitro and in vivo results suggesting a dual target probe could be a potential platform for other proteinases imaging.It is well known that peptide probes have great potential in tumor molecular imaging. Developing an ideal peptide imaging reagent is helpful on tumor understanding, prevention diagnosis and therapy. The methods we applied here showed promising results in MMP detection and tumor early diagnosis.