Chemical design of a radiolabeled gelatinase inhibitor peptide for the imaging of gelatinase activity in tumors
Chemical design of a radiolabeled gelatinase inhibitor peptide for the imaging of gelatinase activity in tumors
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DOI：
10.1016/j.nucmedbio.2007.04.002
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发表时间：
2007-07-01
影响因子：
3.1
通讯作者：
Saji, Hideo
中科院分区：
文献类型：
--
作者：
Hanaoka, Hirofurni;Mukai, Takahiro;Saji, Hideo
由于明胶酶[基质金属蛋白酶（MMP）-2和MMP-9]水平升高与癌症患者的预后不良相关，因此这些酶是肿瘤成像的潜在靶点。在本研究中，选择环状十肽cCTTHWGFTLC（CTT）作为母体化合物，因为其对明胶酶的选择性抑制活性。为了成像肿瘤中的明胶酶活性，我们设计了基于CTT的放射性药物，考虑到（1）肽的HWGF基序对活性很重要，（2）亲水性放射性标记的肽在肝脏中显示低水平蓄积，（3）放射性标记的肽的负电荷增加可有效减少肾蓄积。因此，高度亲水性和带负电荷的放射性标记，铟-111-二乙三胺五乙酸（In-111-DTPA），连接到远离HWGF基序的N-末端残基（In-111-DTPA-CTT）。在MMP-2抑制试验中，In-DTPA-CTT以浓度依赖性方式显著抑制蛋白水解活性。当注射到正常小鼠体内时，In-111-DTPA-CTT在肝脏和肾脏中显示出低水平的放射性。In-111-DTPA-CTT的药代动力学特征与其他CTT衍生物具有不同的物理化学性质的比较表明，增加亲水性和负电荷引起的共轭1 In-111-DTPA降低放射性水平在肝脏和肾脏。在荷瘤小鼠中，观察到（111）InDTPA-CTT在肿瘤中的蓄积以及肿瘤-血液比与明胶酶活性之间存在显著相关性。这些发现支持In-111-DTPA-CTT化学设计的有效性，以减少在非靶组织中的蓄积并保持母体化合物的抑制活性。此外，In-111-DTPA-CTT衍生物将是用于体内转移性肿瘤中明胶酶活性成像的潜在放射性药物。(c)2007年爱思唯尔公司All rights reserved.
Since elevated levels of gelatinases [matrix metalloprotemase (MMP)-2 and MMP-9] are associated with a poor prognosis in cancer patients, these enzymes are potential targets for tumor imaging. In the present study, a cyclic decapeptide, cCTTHWGFTLC (CTT), was selected as a mother compound because of its selective inhibitory activity toward gelatinases. For imaging gelatinase activity in tumors, we designed a CTT-based radiopharmaceutical taking into consideration that (1) the HWGF motif of the peptide is important for the activity, (2) hydrophilic radiolabeled peptides show low-level accumulation in the liver and (3) an increase in the negative charge of radiolabeled peptides is effective in reducing renal accumulation. Thus, a highly hydrophilic and negatively charged radiolabel, indiun-111-diethylenctriaminepentaacetic acid (In-111-DTPA), was attached to an N-terminal residue distant from the HWGF motif (In-111-DTPA-CTT). In MMP-2 inhibition assays, In-DTPA-CTT significantly inhibited the proteolytic activity in a concentration-dependent fashion. When injected into nomal mice, In-111-DTPA-CTT showed low levels of radioactivity in the liver and kidney. A comparison of the pharmacokinetic characteristics of In-111-DTPA-CTT with those of other CTT derivatives having different physicochemical properties revealed that the increase in hydrophilicity and negative charge caused by the conjugation of 1 In-111-DTPA reduced levels of radioactivity in the liver and kidney. In tumor-bearing mice, a significant correlation was observed between the accumulation in the tumor as well as tumor-to-blood ratio of (111)InDTPA-CTT and gelatinase activity. These findings support the validity of the chemical design of In-111-DTPA-CTT for reducing accumulation in nontarget tissues and maintaining the inhibitory activity of the mother compound. Furthermore, In-111-DTPA-CTT derivatives would be potential radiophannaccuticals for the imaging of gelatinase activity in metastatic tumors in vivo. (c) 2007 Elsevier Inc. All rights reserved.