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首页> 外文期刊>Bioconjugate Chemistry >Galactosyl Human Serum Albumin-NMP1 Conjugate: A Near Infrared (NIR)-Activatable Fluorescence Imaging Agent to Detect Peritoneal Ovarian Cancer Metastases
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Galactosyl Human Serum Albumin-NMP1 Conjugate: A Near Infrared (NIR)-Activatable Fluorescence Imaging Agent to Detect Peritoneal Ovarian Cancer Metastases

机译:半乳糖基人血清白蛋白-NMP1偶联:一种近红外(NIR)可激活的荧光成像剂,以检测腹膜卵巢癌转移。

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Patient survival depends on the completeness of resection of peritoneal ovarian cancer metastases (POCM), and therefore, it is important to develop methods to enhance detection. Previous probe designs based on activatable galactosyl human serum albumin (hGSA)-fluorophore pairs, which target lectin receptors expressed on POCM, have used only visible range dyes conjugated to hGSA. However, imaging probes emitting fluorescence in the NIR range are advantageous because NIR photons have deeper in vivo tissue penetration and result in lower background autofluorescence than those emitting in the visible ranee. A NIR-activatablehGSA fluorophore was synthesized using a bacteriochlorin-based dye, NMP1. NMP1 has two unique absorption peaks, one in the green range and the other in the NIR range, but emits at a NIR peak of 780 nm. NMP1, thus, has two different Stokes shifts that have the potential to allow imaging of POCM both at the peritoneal surface and just below it. hGSA was conjugated with 2 NMP1 molecules to create a self-quenching complex (hGSA-NMPl). The activation ratio of hGSA-NMPl was measured by the fluorescence intensity before and after exposure to 10% SDS. The activation ratio of hGSA-NMPl was ~100-fold in vitro. Flow cytometry, fluorescence microscopy, and in vivo spectral fluorescence imaging were carried out to compare hGSA-NMPl with hGSA-IR800 and hGSA-ICG (two always-on control agents with similar emission to NMP1) in terms of comparative fluorescence signal and the ability to detect POCM in mice models. The sensitivity and specificity of hGSA-NMPl for POCM implant detection were determined by colocalizing NMP1 emission spectra with red fluorescent protein (RFP) expressed constitutively in SHIN3 tumor implants at different depths below the peritoneal surface. In vitro, SHIN3 cells were easily detectable after 3 h of incubation with hGSA-NMPl. In vivo submillimeter POCM foci were clearly detectable with spectral fluorescence imaging using hGSA-NMPl. Among 555 peritoneal lesions, hGSA-NMP, using NIR and green excitation light, respectively, detect 75% of all lesions and 91% of lesions ~0.8 mm or greater in diameter. Few false positives were encountered. Nodules located at a depth below the small bowel surface were only depicted with hGSA-NMPl. We conclude that hGSA-NMPl is useful in imaging peritoneal ovarian cancer metastases, located both superficially and deep in the abdominal cavity.
机译:患者的生存取决于切除腹膜卵巢癌转移灶(POCM)的完整性,因此,开发增强检测的方法很重要。以前基于可激活的半乳糖基人血清白蛋白(hGSA)-荧光团对的探针设计,其靶向在POCM上表达的凝集​​素受体,仅使用了与hGSA偶联的可见范围染料。但是,在NIR范围内发射荧光的成像探针是有利的,因为NIR光子具有比在可见栅栏中发射的那些更深的体内组织穿透力,并导致较低的背景自发荧光。使用基于细菌二氯的染料NMP1合成了可激活NIR的hGSA荧光团。 NMP1有两个独特的吸收峰,一个在绿色范围内,另一个在NIR范围内,但在780 nm的NIR峰处发射。因此,NMP1具有两个不同的斯托克斯位移,它们有可能允许在腹膜表面及其正下方进行POCM成像。将hGSA与2个NMP1分子缀合以产生自猝灭复合物(hGSA-NMP1)。通过暴露于10%SDS之前和之后的荧光强度来测量hGSA-NMP1的活化率。在体外,hGSA-NMP1的活化率是约100倍。进行了流式细胞术,荧光显微镜和体内光谱荧光成像,以比较hGSA-NMP1与hGSA-IR800和hGSA-ICG(两种与NMP1发射相似的常开对照剂)的比较荧光信号和能力。检测小鼠模型中的POCM。通过将NMP1发射光谱与在腹膜表面以下不同深度组成性表达的SHIN3肿瘤植入物中表达的红色荧光蛋白(RFP)共定位,确定hGSA-NMP1对POCM植入物的敏感性和特异性。在体外,与hGSA-NMP1孵育3小时后,SHIN3细胞易于检测。使用hGSA-NMP1通过光谱荧光成像可以清楚地检测到体内亚毫米POCM病灶。在555个腹膜病变中,分别使用NIR和绿色激发光的hGSA-NMP可以检测到所有病变的75%和直径在〜0.8 mm或更大的病变的91%。很少遇到误报。仅在hGSA-NMP1中描述了位于小肠表面以下深度的结节。我们得出的结论是,hGSA-NMP1可用于对位于腹腔浅表和深处的腹膜卵巢癌转移进行成像。

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