<br>MMP-2 响应荧光纳米探针可增强肿瘤细胞摄取和成像的选择性,Biomaterials Science

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MMP-2 响应荧光纳米探针可增强肿瘤细胞摄取和成像的选择性
Biomaterials Science ( IF 5.8 ) Pub Date : 2018-08-06 00:00:00 , DOI: 10.1039/c8bm00593a
Lu Sun ₁ , Shuping Xie , Xiuru Ji , Jingming Zhang , Dongmei Wang , Seung Jin Lee , Hyukjin Lee , Huining He , Victor C Yang

Affiliation

由于 MMP 酶家族之间的底物特异性重叠，因此很难开发针对特定基质金属蛋白酶 (MMP) 的高选择性底物荧光纳米探针。为了解决这个问题，我们开发了新型荧光纳米探针，对可溶性 MMP-2 具有高度选择性。在此，通过His 标签镍螯合机制将荧光融合蛋白固定在铁氧体镍纳米粒子上，制备了 MMP-2 响应纳米探针。该融合蛋白由荧光 mCherry 蛋白和细胞穿透肽 (CPP) 部分组成。融合蛋白中还引入了 MMP-2 裂解位点，该位点直接连接到镍铁氧体纳米颗粒。通过将 MMP-2 底物的裂解位点隐藏在系统深处来调节纳米探针的选择性，这可能会导致纳米探针和 MMP 之间产生强烈的空间位阻，特别是对于膜束缚的 MMP，例如 MMP-14。基于细胞的测定表明，纳米探针只能被分泌可溶性 MMP-2 的肿瘤细胞激活，而不能被膜束缚的 MMP-14 激活。为了进一步评估空间位阻效应对纳米探针的贡献，与天然膜束缚 MMP-14 相比，采用截短的重组 MMP-14 来赋予其切割活性。此外，设计的空间位阻效应减弱的探针被证明可以被膜束缚型 MMP-14 激活。结果表明，利用空间位阻效应设计荧光纳米探针可以大大提高MMP响应纳米探针的选择性，实现肿瘤微环境中可溶性MMP-2的特异性检测。我们相信，高选择性 MMP-2 响应荧光纳米探针对生物医学应用具有广泛的影响，包括用于肿瘤检测的分子成像和标记。

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

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 nanoprobes 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.

更新日期：2018-08-06

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