Imaging the Met Receptor Tyrosine Kinase (Met) and Assessing Tumor Responses to a Met Tyrosine Kinase Inhibitor in Human Xenograft Mouse Models with a [99mTc] (AH-113018) or Cy 5** (AH-112543) Labeled Peptide.

IF 2.2 4区 医学 Q3 BIOCHEMICAL RESEARCH METHODS
Molecular Imaging Pub Date : 2015-01-01
Elaine M Jagoda, Sibaprasad Bhattacharyya, Joseph Kalen, Lisa Riffle, Avrum Leeder, Stephanie Histed, Mark Williams, Karen J Wong, Biying Xu, Lawrence P Szajek, Osama Elbuluk, Fabiola Cecchi, Kristen Raffensperger, Meghana Golla, Donald P Bottaro, Peter Choyke
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Abstract

Developing an imaging agent targeting the hepatocyte growth factor receptor protein (Met) status of cancerous lesions would aid in the diagnosis and monitoring of Met-targeted tyrosine kinase inhibitors (TKIs). A peptide targeting Met labeled with [(99m)Tc] had high affinity in vitro (Kd = 3.3 nM) and detected relative changes in Met in human cancer cell lines. In vivo [(99m)Tc]-Met peptide (AH-113018) was retained in Met-expressing tumors, and high-expressing Met tumors (MKN-45) were easily visualized and quantitated using single-photon emission computed tomography or optical imaging. In further studies, MKN-45 mouse xenografts treated with PHA 665752 (Met TKI) or vehicle were monitored weekly for tumor responses by [(99m)Tc]-Met peptide imaging and measurement of tumor volumes. Tumor uptake of [(99m)Tc]-Met peptide was significantly decreased as early as 1 week after PHA 665752 treatment, corresponding to decreases in tumor volumes. These results were comparable to Cy5**-Met peptide (AH-112543) fluorescence imaging using the same treatment model. [(99m)Tc] or Cy5**-Met peptide tumor uptake was further validated by histologic (necrosis, apoptosis) and immunoassay (total Met, p Met, and plasma shed Met) assessments in imaged and nonimaged cohorts. These data suggest that [(99m)Tc] or Cy5**-Met peptide imaging may have clinical diagnostic, prognostic, and therapeutic monitoring applications.

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用[99mTc] (AH-113018) 或 Cy 5** (AH-112543) 标记的肽对人异种移植小鼠模型中的 Met 受体酪氨酸激酶 (Met) 进行成像,并评估肿瘤对 Met 酪氨酸激酶抑制剂的反应。
开发一种针对癌症病灶中肝细胞生长因子受体蛋白(Met)状态的成像剂将有助于诊断和监测以Met为靶点的酪氨酸激酶抑制剂(TKIs)。用[(99m)Tc]标记的靶向Met的多肽在体外具有高亲和力(Kd = 3.3 nM),并能检测到人类癌细胞系中Met的相对变化。体内[(99m)Tc]-Met 多肽(AH-113018)可保留在表达 Met 的肿瘤中,高表达 Met 的肿瘤(MKN-45)很容易通过单光子发射计算机断层扫描或光学成像进行观察和量化。在进一步研究中,用 PHA 665752(Met TKI)或药物治疗 MKN-45 小鼠异种移植物,每周通过[(99m)Tc]-Met 肽成像和肿瘤体积测量监测肿瘤反应。PHA 665752治疗1周后,肿瘤对[(99m)Tc]-Met肽的摄取就显著减少,这与肿瘤体积的减少相对应。这些结果与使用相同治疗模型的Cy5**-Met肽(AH-112543)荧光成像结果相当。组织学(坏死、凋亡)和免疫测定(总 Met、p Met 和血浆脱落 Met)评估进一步验证了成像和非成像队列中[(99m)Tc]或 Cy5**-Met 肽的肿瘤摄取。这些数据表明,[(99m)Tc]或Cy5**-Met肽成像可用于临床诊断、预后和治疗监测。
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来源期刊
Molecular Imaging
Molecular Imaging Biochemistry, Genetics and Molecular Biology-Biotechnology
自引率
3.60%
发文量
21
期刊介绍: Molecular Imaging is a peer-reviewed, open access journal highlighting the breadth of molecular imaging research from basic science to preclinical studies to human applications. This serves both the scientific and clinical communities by disseminating novel results and concepts relevant to the biological study of normal and disease processes in both basic and translational studies ranging from mice to humans.
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