A Pretargeted Imaging Strategy for EGFR-Positive Colorectal CarcinomaviaModulation of Tz-Radioligand Pharmacokinetics
A Pretargeted Imaging Strategy for EGFR-Positive Colorectal CarcinomaviaModulation of Tz-Radioligand Pharmacokinetics
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通过调节 Tz 放射性配体药代动力学的 EGFR 阳性结直肠癌的预靶向成像策略
DOI：
10.1007/s11307-020-01539-z
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发表时间：
2020-09-10
影响因子：
3.1
通讯作者：
Shi, Hongcheng
中科院分区：
文献类型：
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作者：
Qiu, Lin;Lin, Qingyu;Shi, Hongcheng
目的在此之前，我们成功地建立了一种预靶向成像策略(atezolizumab-TCO/[TC-99m]HYNIC-PEG(11)-tz)，用于评价程序性细胞死亡配体-1(PD-L1)在异种移植小鼠中的表达。然而，剩余的未点击的[TC-99m]HYNIC-PEG(11)-TZ通过肠道被清除得有些迟缓，这对于结直肠癌(CRC)成像不是理想的。为了将TZ放射性配体的排泄转移到肾脏系统，我们开发了一种新型的TZ放射性配体，在HYNIC和PEG(11)之间添加了一个多肽连接物。方法合成预靶向分子探针[TC-99m]HYNIC-多肽-PEG(11)-TZ和西妥昔单抗-TCO。考察了[TC-99m]HYNIC-多肽-PEG(11)-TZ的体外稳定性和体内药代动力学，并考察了[TC-99m]HYNIC-多肽-PEG(11)-TZ对西妥昔单抗-TCO的体外反应活性。通过生物分布测定和[TC-99m]HYNIC-多肽-PEG(11)-TZ显像法观察其排泄途径。在三个不同的蓄积间隔测量预靶向生物分布，以确定最佳预靶向间隔时间。比较预靶向(西妥昔单抗48h/[TC-99m]HYNIC-PEG(11)-TZ 6h)和(西妥昔单抗-TCO 48h/[TC-99m]HYNIC-多肽-PEG(11)-TZ 6h)显像对肿瘤显像的影响。结果[TC-99m]HYNIC-多肽-聚乙二醇(11)-TZ具有良好的体外稳定性和较快的小鼠血液清除能力。Sec-Hplc-HPLC显示西妥昔单抗-TCO与[TC-99m]HYNIC-多肽-PEG(11)-Tzin在体外几乎完全反应，8：1的TZ-to-mAb转化率为87.83+/-3.27%。生物分布和成像分析表明，TZ-放射性配基通过肾脏被清除。西妥昔单抗在HCT116肿瘤体内蓄积24、48、72h后，瘤血比分别为0.83+/-0.13、1.40+/-0.31、1.15+/-0.21。预靶向(西妥昔单抗48h/[TC-99m]HYNIC-PEG(11)-TZ 6h)和(西妥昔单抗48h/[TC-99m]HYNIC-多肽-PEG(11)-TZ 6h)均清楚地勾画出HCT116肿瘤的轮廓。使用cetuximab-TCO/[Tc-99m]HYNIC-polypeptide-PEG(11)-Tz的预靶向成像策略可用于结直肠癌的诊断，因为剩余的未点击的[TC-99m]HYNIC-多肽-聚乙二醇(11)-TZ可通过泌尿系统清除，导致腹部低摄取本底。结论新的预靶向成像策略(cetuximab-TCO/[Tc-99m]HYNIC-polypeptide-PEG(11)-Tz)可用于结直肠癌的成像，拓宽了预靶向成像策略的应用范围。预靶向成像策略清楚地勾勒出了HCT116肿瘤，表明它的用途可以扩展到选择内化抗体。
Purpose Previously, we successfully developed a pretargeted imaging strategy (atezolizumab-TCO/[Tc-99m]HYNIC-PEG(11)-Tz) for evaluating programmed cell death ligand-1 (PD-L1) expression in xenograft mice. However, the surplus unclicked [Tc-99m]HYNIC-PEG(11)-Tz is cleared somewhat sluggishly through the intestines, which is not ideal for colorectal cancer (CRC) imaging. To shift the excretion of the Tz-radioligand to the renal system, we developed a novel Tz-radioligand by adding a polypeptide linker between HYNIC and PEG(11). Procedures Pretargeted molecular probes [Tc-99m]HYNIC-polypeptide-PEG(11)-Tz and cetuximab-TCO were synthesized. [Tc-99m]HYNIC-polypeptide-PEG(11)-Tz was evaluated forin vitrostability andin vivoblood pharmacokinetics.In vitroligation reactivity of [Tc-99m]HYNIC-polypeptide-PEG(11)-Tz towards cetuximab-TCO was also tested. Biodistribution assay and imaging of [Tc-99m]HYNIC-polypeptide-PEG(11)-Tz were performed to observe its excretion pathway. Pretargeted biodistribution was measured at three different accumulation intervals to determine the optimal pretargeted interval time. Pretargeted (cetuximab-TCO 48 h/[Tc-99m]HYNIC-PEG(11)-Tz 6 h) and (cetuximab-TCO 48 h/[Tc-99m]HYNIC-Polypeptide-PEG(11)-Tz 6 h) imagings were compared to examine the effect of the excretion pathway on tumor imaging. Results [Tc-99m]HYNIC-polypeptide-PEG(11)-Tz showed favorablein vitrostability and rapid blood clearance in mice. SEC-HPLC revealed almost complete reaction between cetuximab-TCO and [Tc-99m]HYNIC-polypeptide-PEG(11)-Tzin vitro, with the 8:1 Tz-to-mAb reaction providing a conversion yield of 87.83 +/- 3.27 %. Biodistribution and imaging analyses showed that the Tz-radioligand was cleared through the kidneys. After 24, 48, and 72 h of accumulation in HCT116 tumor, the tumor-to-blood ratio of cetuximab-TCO was 0.83 +/- 0.13, 1.40 +/- 0.31, and 1.15 +/- 0.21, respectively. Both pretargeted (cetuximab-TCO 48 h/[Tc-99m]HYNIC-PEG(11)-Tz 6 h) and (cetuximab-TCO 48 h/[Tc-99m]HYNIC-polypeptide-PEG(11)-Tz 6 h) clearly delineated HCT116 tumor. Pretargeted imaging strategy using cetuximab-TCO/[Tc-99m]HYNIC-polypeptide-PEG(11)-Tz could be used for diagnosing CRC, as the surplus unclicked [Tc-99m]HYNIC-polypeptide-PEG(11)-Tz was cleared through the urinary system, leading to low abdominal uptake background. Conclusion Our novel pretargeted imaging strategy (cetuximab-TCO/[Tc-99m]HYNIC-polypeptide-PEG(11)-Tz) was useful for imaging CRC, broadening the application scope of pretargeted imaging strategy. The pretargeted imaging strategy clearly delineated HCT116 tumor, showing that its use could be extended to selection of internalizing antibodies.