Purpose: Evans Blue (EB) is an azo dye that binds quantitatively with serum albumin. With an albumin binding, NOTA conjugated truncated Evan's blue (NEB) dye derived PET tracer, we aimed to establish a strategy for evaluating vascular permeability in malignant tumors via non-invasive PET. Experimental design: Sixty-minute dynamic PET using [¹⁸F]FAl-NEB was performed in three xenograft tumor models including INS-1 rat insulinoma, UM-SCC-22B human head and neck carcinoma and U-87 MG human glioblastoma. Tumor vascular permeability was quantified by the difference of the slopes between tumor and blood time-activity curve (TACs, expressed as P_s). The method was further substantiated by EB extraction and colorimetric assay and correlates with that calculated from dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). The changes in tumor vasculature at different time points were assessed with NEB PET in U-87 MG and UM-SCC-22B tumor models after treatment with bevacizumab or doxorubicin. Result: The P_s values calculated from tumor and blood TACs from multiple time-point static images are consistent with those from dynamic images. Moreover, the P_s showed a positive and significant correlation with extracted EB concentration and K_PS-MRI generated from DCE-MRI, which further confirmed the soundness of this methodology. The antiangiogenic effect of bevacizumab could be revealed by NEB PET in U-87 MG tumors as early as 8 hrs after therapy, demonstrated by a substantial decrease of P_s. On the contrary, there was no significant change of P_s in bevacizumab treated UM-SCC-22B tumors, compared with control group. However, the significant changes of P_s were overestimated in doxorubicin treated UM-SCC-22B tumors. Conclusions: We successfully developed a relatively convenient and novel strategy to evaluate vascular permeability and blood volume using NEB PET. This method will be advantageous in evaluating vascular permeability, promoting drug delivery, and monitoring tumor response to therapeutics that affect tumor angiogenesis.

中文翻译：

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正电子发射断层扫描定量肿瘤血管通透性和血容量

目的：伊文思蓝（EB）是一种偶氮染料，可与血清白蛋白定量结合。通过白蛋白结合，NOTA结合的截短的埃文氏蓝（NEB）染料衍生的PET示踪剂，我们旨在建立一种通过无创PET评估恶性肿瘤中血管通透性的策略。实验设计：在[ INS]大鼠胰岛素瘤，UM-SCC-22B人头颈癌和U-87 MG人胶质母细胞瘤等三种异种移植肿瘤模型中，使用[ ¹⁸ F] FA1-NEB进行了60分钟动态PET 。肿瘤血管通透性通过肿瘤与血液时间-活动曲线（TACs，以P _s表示）之间的斜率之差来量化）。该方法通过EB提取和比色法进一步证实，并且与从动态对比增强磁共振成像（DCE-MRI）计算得出的方法相关。在用贝伐单抗或阿霉素治疗后，在U-87 MG和UM-SCC-22B肿瘤模型中，使用NEB PET评估了不同时间点的肿瘤脉管系统的变化。结果：从多个时间点静态图像中的肿瘤和血液TAC计算出的P _s值与动态图像中的P _s值一致。此外，P _s与提取的EB浓度和K _PS-MRI呈显着正相关。DCE-MRI产生的信号，进一步证实了这种方法的正确性。贝伐单抗的抗血管生成作用最早可在治疗后8小时通过NEB PET在U-87 MG肿瘤中揭示，证明P _s明显降低_。相反，与对照组相比，在贝伐单抗治疗的UM-SCC-22B肿瘤中P _s没有明显变化。但是，在阿霉素治疗的UM-SCC-22B肿瘤中，P _s 的显着变化被高估了。结论：我们成功开发了一种相对方便，新颖的策略，使用NEB PET评估血管通透性和血容量。该方法在评估血管渗透性，促进药物递送以及监测肿瘤对影响肿瘤血管生成的治疗剂的反应方面将是有利的。