Development of an optimized activatable MMP-14 targeted SPECT imaging probe.
Development of an optimized activatable MMP-14 targeted SPECT imaging probe.
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DOI：
10.1016/j.bmc.2008.11.078
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发表时间：
2009-01-15
影响因子：
3.5
通讯作者：
Franc, Benjamin L.
中科院分区：
文献类型：
--
作者：
Watkins, Gregory A.;Jones, Ella Fung;Shell, M. Scott;VanBrocklin, Henry F.;Pan, Mei-Hsiu;Hanrahan, Stephen M.;Feng, Jin Jin;He, Jiang;Sounni, Nor Eddine;Dill, Ken A.;Contag, Christopher H.;Coussens, Lisa M.;Franc, Benjamin L.
基质金属蛋白酶-14（MT 1-MMP或MMP-14）是一种膜相关蛋白酶，参与多种组织重塑过程，是选择性转移性癌症的分子标志。在体内检测MMP-14的能力将有助于研究其在病理过程中的作用，并可能作为靶向分子治疗的发展指南。使用AMBER力场方法模拟了四种MMP-14特异性探针，其含有与MMP-14肽底物连接的带正电荷的细胞穿透肽（CPP）d-精氨酸八聚体（r8）和具有谷氨酸（8 e，4 e）或谷氨酸-甘氨酸（4 eg和4 egg）重复单元的衰减序列。具有4 egg衰减序列的探针表现出最高的CPP/衰减剂相互作用，预测最小化的细胞摄取直到切割。使用人重组MMP-14催化结构域的体外MMP-14介导的切割研究揭示了与嵌入的肽底物序列的线性直接相关的增强的切割速率。在MMP-14转染的人乳腺癌细胞中证明了最佳探针的锝-99m标记版本的成功切割和摄取。在广谱MMP抑制剂存在下发现细胞摄取减少两倍。因此，计算化学，平行合成和生化筛选的组合，显示出作为一套工具，用于开发新的放射性标记的探针，是敏感的蛋白酶活性的承诺。
Matrix Metalloproteinase-14 (MT1-MMP or MMP-14) is a membrane-associated protease implicated in a variety of tissue remodeling processes and a molecular hallmark of select metastatic cancers. The ability to detect MMP-14 in vivo would be useful in studying its role in pathologic processes and may potentially serve as a guide for the development of targeted molecular therapies. Four MMP-14 specific probes containing a positively charged cell penetrating peptide (CPP) d-arginine octamer (r8) linked with a MMP-14 peptide substrate and attenuating sequences with glutamate (8e, 4e) or glutamate-glycine (4eg and 4egg) repeating units were modeled using an AMBER force field method. The probe with 4egg attenuating sequence exhibited the highest CPP/attenuator interaction, predicting minimized cellular uptake until cleaved. The in vitro MMP-14-mediated cleavage studies using the human recombinant MMP-14 catalytic domain revealed an enhanced cleavage rate that directly correlated with the linearity of the embedded peptide substrate sequence. Successful cleavage and uptake of a technetium-99m labeled version of the optimal probe was demonstrated in MMP-14 transfected human breast cancer cells. Two- fold reduction of cellular uptake was found in the presence of a broad spectrum MMP inhibitor. The combination of computational chemistry, parallel synthesis and biochemical screening, therefore, shows promise as a set of tools for developing new radiolabeled probes that are sensitive to protease activity.
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