Primary Preclinical and Clinical Evaluation of 68Ga-DOTA-TMVP1 as a Novel VEGFR-3 PET Imaging Radiotracer in Gynecological Cancer
Primary Preclinical and Clinical Evaluation of 68Ga-DOTA-TMVP1 as a Novel VEGFR-3 PET Imaging Radiotracer in Gynecological Cancer
复制标题
68Ga-DOTA-TMVP1 作为一种新型 VEGFR-3 PET 成像放射性示踪剂在妇科癌症中的初步临床前和临床评价。
DOI：
10.1158/1078-0432.ccr-19-1845
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发表时间：
2020-03-01
影响因子：
11.5
通讯作者：
Xi, Ling
中科院分区：
文献类型：
--
作者：
Li, Fei;Zhang, Zhenzhong;Xi, Ling
目的：肿瘤诱导的淋巴管生成的肿瘤周围和淋巴结常大量表达VEGFR-3。在我们之前的研究中，我们发现了一个名为TMVP1的5个氨基酸肽，它特异性地与VEGFR-3结合。本研究的目的是开发一种新的ga -68标记的TMVP1用于VEGFR-3 PET成像，并研究其在异种移植肿瘤模型和一小群复发性卵巢癌和宫颈癌患者中的安全性、生物分布和肿瘤定位功效。实验设计：用放射性核素Ga-68标记dota偶联的TMVP1肽。SPR和饱和结合试验用于受体结合研究。采用妇科异种肿瘤小动物PET显像及Ga-68-DOTA-TMVP1在体内的生物分布。在临床研究中，5名健康志愿者和8名妇科癌症患者在注射Ga-68-DOTA-TMVP1后进行了全身PET/CT检查。结果：Ga-68成功标记DOTA-TMVP1。LEC与Ga-68-DOTA-TMVP1的结合能力高于LEC（shVEGFR-3）和人脐静脉内皮细胞。在皮下移植C33-A和SKOV-3异种移植的小鼠中，示踪剂通过肾脏到膀胱迅速消除，小动物PET/CT有助于清晰地显示肿瘤。在复发性卵巢癌和宫颈癌患者中，在大多数已确定的疾病部位，示踪剂积累远高于背景水平；特别是对于复发性内皮窦肿瘤，Ga-68-DOTA-TMVP1的诊断价值与F-18-FDG PET/CT相当。结论：Ga-68-DOTA-TMVP1具有良好的药代动力学，是一种潜在的VEGFR-3显像PET示踪剂。
Purpose: Tumor periphery and lymph nodes of tumor-induced lymphangiogenesis often abundantly express VEGFR-3. In our previous study, we identified a 5-amino acid peptide named TMVP1, which binds specifically to VEGFR-3. The objective of this study was to develop a novel Ga-68-labeled TMVP1 for VEGFR-3 PET imaging and to investigate its safety, biodistribution, and tumor-localizing efficacy in xenograft tumor models and a small cohort of patients with recurrent ovarian and cervical cancer.Experimental Design: The DOTA-conjugated TMVP1 peptide was labeled with radionuclide Ga-68. SPR and saturation binding assays were used for the receptor-binding studies. Gynecologic xenograft tumors were employed for small-animal PET imaging and biodistribution of Ga-68-DOTA-TMVP1 in vivo. In the clinical study, 5 healthy volunteers and 8 patients with gynecologic cancer underwent whole-body PET/CT after being injected with Ga-68-DOTA-TMVP1.Results: DOTA-TMVP1 was successfully labeled with Ga-68. LECs showed higher binding capacity with Ga-68-DOTA-TMVP1 than LEC(shVEGFR-3)and human umbilical vein endothelial cells. In mice with subcutaneous C33-A and SKOV-3 xenografts, the tracer was rapidly eliminated through the kidney to the bladder, and the small-animal PET/CT helped to clearly visualize the tumors. In patients with recurrent ovarian cancer and cervical cancer, tracer accumulation well above the background level was demonstrated in most identified sites of disease; especially with recurrent endodermal sinus tumors, the diagnostic value of Ga-68-DOTA-TMVP1 was comparable with that of F-18-FDG PET/CT.Conclusions: Ga-68-DOTA-TMVP1 is a potential PET tracer for imaging VEGFR-3 with favorable pharmacokinetics.