A multimodal molecular imaging approach targeting urokinase plasminogen activator receptor for the diagnosis, resection and surveillance of urothelial cell carcinoma
A multimodal molecular imaging approach targeting urokinase plasminogen activator receptor for the diagnosis, resection and surveillance of urothelial cell carcinoma
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DOI：
10.1016/j.ejca.2021.01.001
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发表时间：
2021-02-06
影响因子：
8.4
通讯作者：
Sier, Cornelis F. M.
中科院分区：
文献类型：
--
作者：
Baart, Victor M.;van der Horst, Geertje;Sier, Cornelis F. M.
尿路上皮细胞癌（UCC）的5年复发率为30-78%，是所有实体恶性肿瘤中最高的。因此，经尿道切除术后，患者将终身接受内镜监测。多模态近红外（NIR）荧光成像策略可以改善诊断、切除和监测，从而提高生活质量。方法：采用免疫组织化学法和流式细胞术分别检测石蜡包埋的人UCC细胞中尿激酶纤溶酶原激活物受体（uPAR）和上皮细胞粘附分子（EpCAM）的表达。MNPR-101是一种靶向uPAR的人源化单克隆抗体，与IRDye800CW偶联，并通过表面等离子体共振和基于细胞的结合试验在体外验证其结合。对BALB/c裸鼠皮下培养的人UM-UC-31uc2细胞进行体内近红外荧光和光声三维成像。在转移性UM-UC-31uc2原位小鼠模型中证实了其翻译潜力。英夫利昔单抗和利妥昔单抗- irdye 800cw作为对照。结果：UCCs在瘤间质界面表达uPAR，上皮细胞表达EpCAM。uPAR和EpCAM分别在6/7和4/7 UCC细胞系中表达。在体外，mnpr -101- irdye - 800cw对uPAR结构域2-3具有皮摩尔亲和力。使用mnpr -101- irdye - 800cw进行体内荧光成像，特异性地描绘了皮下和原位肿瘤，肿瘤与背景比高达6.8，与对照组显著不同（p < 0.0001）。光声三维深度成像证实了mnpr -101- irdye - 800cw在肿瘤中的均匀分布。结论：mnpr -101- irdye - 800cw适用于UCC的多模态成像，有待临床推广。(C) 2021作者。Elsevier Ltd.出版。
With a 5-year recurrence rate of 30-78%, urothelial cell carcinoma (UCC) rates amongst the highest of all solid malignancies. Consequently, after transurethral resection, patients are subjugated to life-long endoscopic surveillance. A multimodal near-infrared (NIR) fluorescence-based imaging strategy can improve diagnosis, resection and surveillance, hence increasing quality of life.Methods: Expression of urokinase plasminogen activator receptor (uPAR) and epithelial cell adhesion molecule (EpCAM) are determined on paraffin-embedded human UCC using immunohistochemistry and on UCC cell lines by flow cytometry. MNPR-101, a humanised monoclonal antibody targeting uPAR is conjugated to IRDye800CW and binding is validated in vitro using surface plasmon resonance and cell-based binding assays. In vivo NIR fluorescence and photoacoustic three-dimensional (3D) imaging are performed with subcutaneously growing human UM-UC-31uc2 cells in BALB/c-nude mice. The translational potential is confirmed in a metastasising UM-UC-31uc2 orthotopic mouse model. InfliximabIRDye800CW and rituximab-IRDye800CW are used as controls.Results: UCCs show prominent uPAR expression at the tumour-stroma interface and EpCAM on epithelial cells. uPAR and EpCAM are expressed by 6/7 and 4/7 UCC cell lines, respectively. In vitro, MNPR-101-IRDye800CW has a picomolar affinity for domain 2-3 of uPAR. In vivo fluorescence imaging with MNPR-101-IRDye800CW, specifically delineates both subcutaneous and orthotopic tumours with tumour-to-background ratios reaching as high as 6.8, differing significantly from controls (p < 0.0001). Photoacoustic 3D in depth imaging confirms the homogenous distribution of MNPR-101-IRDye800CW through the tumour.Conclusions: MNPR-101-IRDye800CW is suitable for multimodal imaging of UCC, awaiting clinical translation. (C) 2021 The Author(s). Published by Elsevier Ltd.