86/90Y-Labeled Monoclonal Antibody Targeting Tissue Factor for Pancreatic Cancer Theranostics
86/90Y-Labeled Monoclonal Antibody Targeting Tissue Factor for Pancreatic Cancer Theranostics
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DOI：
10.1021/acs.molpharmaceut.0c00127
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发表时间：
2020-05-04
影响因子：
4.9
通讯作者：
Cai, Weibo
中科院分区：
文献类型：
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作者：
Ferreira, Carolina A.;Ehlerding, Emily B.;Cai, Weibo
胰腺癌具有高度侵袭性，中位生存时间不到6个月，5年总生存率约为7%。PaCa的预后不良主要是由于其诊断时的晚期和缺乏有效的治疗选择。因此，迫切需要开发一种高效、多功能的PaCa治疗诊断系统。组织因子（TF）的过表达与许多恶性肿瘤（包括胰腺癌）的肿瘤生长、血管生成和转移有关。在此，我们提出了TF靶向单克隆抗体（ALT 836）与Y-86（/）90偶联作为针对胰腺癌的治疗诊断剂的用途。对于方法，用（86）YDTPA-ALT 836进行系列PET成像以绘制示踪剂在BXPC-3荷瘤小鼠中的生物分布。Y-90-DTPA-ALT 836用作治疗剂，其还允许通过切伦科夫发光成像监测肿瘤负荷。结果是，Y-86-DTPA-ALT 836在BXPC-3异种移植肿瘤中的摄取高，并且随着时间的推移而增加，直至注射后48小时（p.i.），通过离体生物分布研究证实，并通过切伦科夫发光成像进一步证实。在治疗性研究中，发现Y-90-DTPA-ALT 836相对于对照组减缓肿瘤生长，并且在感染后1天具有显著较小（p < 0.05）的肿瘤体积。离体组织的组织学分析显示对治疗的肿瘤的显著损伤。结论是，使用Y-86（/90）治疗诊断对允许PET成像具有良好的肿瘤-背景对比度，并治疗表达TF的胰腺肿瘤，具有有希望的治疗结局。
Pancreatic cancer is highly aggressive, with a median survival time of less than 6 months and a 5-year overall survival rate of around 7%. The poor prognosis of PaCa is largely due to its advanced stage at diagnosis and the lack of efficient therapeutic options. Thus, the development of an efficient, multifunctional PaCa theranostic system is urgently needed. Overexpression of tissue factor (TF) has been associated with increased tumor growth, angiogenesis, and metastasis in many malignancies, including pancreatic cancer. Herein, we propose the use of a TFtargeted monoclonal antibody (ALT836) conjugated with the pair Y-86(/)90 as a theranostic agent against pancreatic cancer. For methods, serial PET imaging with (86)YDTPA-ALT836 was conducted to map the biodistribution the tracer in BXPC-3 tumor-bearing mice. Y-90-DTPA-ALT836 was employed as a therapeutic agent that also allowed tumor burden monitoring through Cherenkov luminescence imaging. The results were that the uptake of Y-86-DTPA-ALT836 in BXPC-3 xenograft tumors was high and increased over time up to 48 h postinjection (p.i.), corroborated through ex vivo biodistribution studies and further confirmed by Cherenkov luminescence Imaging. In therapeutic studies, Y-90-DTPA-ALT836 was found to slow tumor growth relative to the control groups and had significantly smaller (p < 0.05) tumor volumes 1 day p.i. Histological analysis of ex vivo tissues revealed significant damage to the treated tumors. The conclusion is that the use of the Y-86(/90) theranostic pair allows PET imaging with excellent tumor-to-background contrast and treatment of TF-expressing pancreatic tumors with promising therapeutic outcomes.