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

机译：MMP-2响应荧光纳米体纳压物，用于增强肿瘤细胞摄取和成像的选择性

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摘要

It is difficult to develop highly selective substrate-based fluorescent nanoprobes for specific matrix metalloproteinases (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 consisted of a fluorescent mCherry protein with a cell penetrating peptide (CPP) moiety. An 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. A cell-based assay demonstrated that the nano-probes could only be activated by tumor cells secreting soluble MMP-2, but not membrane-tethered MMP-14. To further evaluate the contribution of the steric hindrance effect on the nanoprobes, a truncated recombinant MMP-14 was employed to confer their cleavage activity as compared to native membrane-tethered MMP-14. Furthermore, a designed probe with a diminished steric hindrance effect was proved to be activated by membrane-tethered type MMP-14. The results indicated that the design of fluorescent nanoprobes employing the steric hindrance effect can greatly enhance the selectivity of MMP-responsive nanoprobes realizing the specific detection of soluble MMP-2 in a tumor microenvironment. We believe that highly selective MMP-2-responsive fluorescent nanoprobes have broad impacts on biomedical applications including molecular imaging and labeling for tumor detection.
机译：由于MMP酶系列中的底物特异性重叠，难以为特定基质金属蛋白酶（MMP）开发高精度基质基荧光纳米体。为了解决这个问题，我们开发了新型荧光纳米体，对可溶性MMP-2具有高度选择性。这里，通过通过HIS-TAG镍螯合机制将荧光融合蛋白固定在镍铁氧体纳米颗粒上的荧光融合蛋白来制备MMP-2响应纳米体。融合蛋白由具有细胞穿透肽（CPP）部分的荧光蛋白质组成。在融合蛋白内也引入MMP-2切割位点，其与镍铁氧体纳米颗粒直接连接。通过将MMP-2基质的切割位点深深地覆盖在系统内，可以调节纳米素的选择性，这可能导致纳米体和MMP之间的强空间阻断，特别是对于诸如MMP-14的膜系型MMP。基于细胞的测定证明纳米探针只能通过分泌可溶性MMP-2的肿瘤细胞激活，但不可用于膜系重膜-14。为了进一步评价空间阻断对纳米体抑制效应的贡献，与天然膜 - 系膜的MMP-14相比，使用截短的重组MMP-14赋予它们的切割活性。此外，证明具有减少的空间阻断效应的设计探针通过膜系重型MMP-14激活。结果表明，采用空间阻断效果的荧光纳米体的设计可以大大提高MMP响应纳米体的选择性，实现肿瘤微环境中可溶性MMP-2的特异性检测。我们认为，高精度的MMP-2响应荧光纳米体对生物医学应用具有广泛的影响，包括分子成像和肿瘤检测标记。

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  • 来源
    《Biomaterials Science》 |2018年第10期|共8页
  • 作者

    Sun Lu; Xie Shuping; Ji Xiuru; Zhang Jingming; Wang Dongmei; Lee Seung Jin; Lee Hyukjin; He Huining; Yang Victor C.;

  • 作者单位

    Tianjin Med Univ Sch Pharm Tianjin Key Lab Technol Enabling Dev Clin Therape Tianjin 300070 Peoples R China;

    Tianjin Med Univ Sch Pharm Tianjin Key Lab Technol Enabling Dev Clin Therape Tianjin 300070 Peoples R China;

    Tianjin Med Univ Sch Pharm Tianjin Key Lab Technol Enabling Dev Clin Therape Tianjin 300070 Peoples R China;

    Tianjin Med Univ Sch Basic Med Sci Tianjin 300070 Peoples R China;

    Tianjin Med Univ Sch Pharm Tianjin Key Lab Technol Enabling Dev Clin Therape Tianjin 300070 Peoples R China;

    Ewha Womans Univ Coll Pharm Grad Sch Pharmaceut Sci Seoul 13760 South Korea;

    Ewha Womans Univ Coll Pharm Grad Sch Pharmaceut Sci Seoul 13760 South Korea;

    Tianjin Med Univ Sch Pharm Tianjin Key Lab Technol Enabling Dev Clin Therape Tianjin 300070 Peoples R China;

    Tianjin Med Univ Sch Pharm Tianjin Key Lab Technol Enabling Dev Clin Therape Tianjin 300070 Peoples R China;

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  • 正文语种 eng
  • 中图分类 分子生物学;
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