Multiplexed Targeting of Barrett's Neoplasia with a Heterobivalent Ligand: Imaging Study on Mouse Xenograft in Vivo and Human Specimens ex Vivo.
Multiplexed Targeting of Barrett's Neoplasia with a Heterobivalent Ligand: Imaging Study on Mouse Xenograft in Vivo and Human Specimens ex Vivo.
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DOI：
10.1021/acs.jmedchem.8b00405
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发表时间：
2018-06-28
影响因子：
7.3
通讯作者：
Wang TD
中科院分区：
文献类型：
--
作者：
Chen J;Zhou J;Gao Z;Li X;Wang F;Duan X;Li G;Joshi BP;Kuick R;Appelman HD;Wang TD
食管腺癌(EAC)是一种分子异质性疾病，发病率上升迅速，预后不良。我们开发了一种异二价肽，通过将针对EGFR或ErbB2的单体七肽以异二聚体的配置组合在一起，靶向检测早期Barrett肿瘤。对三甘醇连接体的结构进行了优化，以最大限度地结合细胞表面受体。Cy5.5标记的异源二聚体QRH*-KSP*-E3-Cy5.5与每个靶点都有特异性结合，荧光强度是单体的3倍，亲和力是单体的2倍。异种移植瘤体内摄取高峰出现在注射后2小时，全身清除时间为24小时。此外，在体外对人食道标本的配体结合进行了评估，发现对高度异型增生(HGD)或EAC的检测灵敏度为88%，特异度为87%。这种多肽异源二聚体在临床研究中显示出对早期Barrett瘤的靶向检测的前景。
Esophageal adenocarcinoma (EAC) is a molecularly heterogeneous disease that is rising rapidly in incidence and has poor prognosis. We developed a heterobivalent peptide to target detection of early Barrett’s neoplasia by combining monomer heptapeptides specific for either EGFR or ErbB2 in a heterodimer configuration. The structure of a triethyleneglycol linker was optimized to maximize binding interactions to the surface receptors on cells. The Cy5.5-labeled heterodimer QRH*-KSP*-E3-Cy5.5 demonstrated specific binding to each target and showed 3-fold greater fluorescence intensity and 2-fold higher affinity compared with either monomer alone. Peak uptake in xenograft tumors was observed at 2 hours post-injection with systemic clearance by ~24 hours in vivo. Furthermore, ligand binding was evaluated on human esophageal specimens ex vivo, and 88% sensitivity and 87% specificity were found for detection of either high-grade dysplasia (HGD) or EAC. This peptide heterodimer shows promise for targeted detection of early Barrett’s neoplasia in clinical study.
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影响因子：
29.4
作者：
LEVINE, DS;HAGGITT, RC;REID, BJ
通讯作者：
REID, BJ
影响因子：
46.9
作者：
Becker, A;Hessenius, C;Grötzinger, C
通讯作者：
Grötzinger, C
影响因子：
4.9
作者：
Luo H;Hong H;Yang SP;Cai W
通讯作者：
Cai W
影响因子：
11.2
作者：
Dulak AM;Schumacher SE;van Lieshout J;Imamura Y;Fox C;Shim B;Ramos AH;Saksena G;Baca SC;Baselga J;Tabernero J;Barretina J;Enzinger PC;Corso G;Roviello F;Lin L;Bandla S;Luketich JD;Pennathur A;Meyerson M;Ogino S;Shivdasani RA;Beer DG;Godfrey TE;Beroukhim R;Bass AJ
通讯作者：
Bass AJ
影响因子：
4.7
作者：
Josan, Jatinder S.;Handl, Heather L.;Sankaranarayanan, Rajesh;Xu, Liping;Lynch, Ronald M.;Vagner, Josef;Mash, Eugene A.;Hruby, Victor J.;Gillies, Robert J.
通讯作者：
Gillies, Robert J.