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MMP-2 responsive fluorescent nanoprobes for enhanced selectivity of tumor cell uptake and imaging

Abstract

It is difficult to develop highly selective substrate-based fluorescent nanoprobes for specific matrix metalloproteases (MMPs) due to overlapping substrate specificities among the family of MMP enzymes. To resolve this issue, we have developed novel fluorescent nanoprobes that are highly selective for soluble MMP-2. Herein, MMP-2 responsive nanoprobes were prepared by immobilizing fluorescent fusion proteins on nickel ferrite nanoparticles via the His-tag nickel chelation mechanism. The fusion protein was consisted of a fluorescent mCherry protein with a cell penetrating peptide (CPP) moiety. MMP-2 cleavage site was also introduced within the fusion protein which was directly linked to the nickel ferrite nanoparticles. The selectivity of nanoprobes was modulated by hiding the cleavage site of MMP-2 substrates deeply inside the system, which could result in strong steric hindrance between the nanoprobes and MMPs, especially for membrane-tethered MMPs such as MMP-14. Cell based assay demonstrated that the nanoprobes could only be activated by the tumor cells secreting soluble MMP-2, but not the membrane-tethered MMP-14. To further evaluate the contribution of steric hindrance effect on nanoprobes, a truncated recombinant MMP-14 was employed to confer their cleavage activity as compared to native membrane tethered MMP-14. Further a designed probe with diminished steric hindrance effect was proved to be activated by the membrane-tethered type MMP-14. The results indicated that the design of fluorescent nanoprobes employing steric hindrance effect can greatly enhance the selectivity of MMP responsive nanoprobes realizing the specific detection of soluble MMP-2 in tumor microenvironment. We believe that highly selective MMP-2 responsive fluorescent nanoprobes have broad impact on biomedical applications including molecular imaging and labeling for tumor detection.

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Publication details

The article was received on 29 May 2018, accepted on 04 Aug 2018 and first published on 06 Aug 2018


Article type: Paper
DOI: 10.1039/C8BM00593A
Citation: Biomater. Sci., 2018, Accepted Manuscript
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    MMP-2 responsive fluorescent nanoprobes for enhanced selectivity of tumor cell uptake and imaging

    L. Sun, S. Xie, X. Ji, J. Zhang, D. Wang, S. J. Lee, H. Lee, H. He and V. Yang, Biomater. Sci., 2018, Accepted Manuscript , DOI: 10.1039/C8BM00593A

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