Development of Bispecific NT-PSMA Heterodimer for Prostate Cancer Imaging: A Potential Approach to Address Tumor Heterogeneity
Development of Bispecific NT-PSMA Heterodimer for Prostate Cancer Imaging: A Potential Approach to Address Tumor Heterogeneity
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DOI：
10.1021/acs.bioconjchem.9b00252
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发表时间：
2019-05-01
影响因子：
4.7
通讯作者：
Li, Zibo
中科院分区：
文献类型：
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作者：
Ma, Xiaofen;Wang, Mengzhe;Li, Zibo
前列腺癌是一种异质性疾病，晚期生存率较低。在本报告中，开发了一种双靶向PET剂来部分解决肿瘤异质性问题。异源二聚体F-BCN-PSMA-NT旨在靶向PSMA和神经紧张素受体1 (NTR1)，两者在前列腺癌治疗中都显示出巨大的潜力。该异二聚体通过将gluu -urea-lys(Ahx) （PSMA靶向基序）和NT20.3 （NTR1靶向基序）偶联到对称的三功能连接体上，并带有叠氮化物基团进行进一步修饰而合成。采用应变促进叠氮-炔咔嗒反应进行了高收率的放射性标记。基于细胞的实验表明，F-BCN-PSMA-NT与相应单体的结合亲和力相当或仅略有降低。小动物PET清楚地表明，异源二聚体探针不仅在NTR1阳性/PSMA阴性的PC-3肿瘤（1.4 +/- 0.3%ID/g）中有显著的摄取，在PSMA阳性/NTR1阴性的LnCap肿瘤（1.3 +/- 0.2% ID/g）中也有显著的摄取。示踪剂显示每个单体的肿瘤与背景比相当。总之，前列腺癌是一种异质性疾病，需要改进诊断和治疗。PSMA-NT异二聚体代表了一类新的分子，可用于靶向两种与前列腺癌相关的不同抗原。除了在本研究中显示的成像应用外，该药物在治疗异质性前列腺癌方面也具有很大的潜力。
Prostate cancer is a heterogeneous disease with a poor survival rate at late stage. In this report, a dual targeting PET agent was developed to partially address the tumor heterogeneity issue. The heterodimer F-BCN-PSMA-NT was designed to target PSMA and neurotensin receptor1 (NTR1), both of which have demonstrated great potential in prostate cancer management. The heterodimer was synthesized through the conjugation of Glu-urea-lys(Ahx) (PSMA targeting motif) and NT20.3 (NTR1 targeting motif) to a symmetric trifunctional linker, bearing an azide group for further modification. Radio-labeling was performed using strain promoted azide-alkyne click reaction with high yield. Cell based assays suggested that F-BCN-PSMA-NT has comparable or only slightly reduced binding affinity with the corresponding monomers. Small animal PET clearly demonstrated that the heterodimer probe has prominent uptake not only in NTR1 positive/PSMA negative PC-3 tumors (1.4 +/- 0.3%ID/g), but also in the PSMA positive/NTR1 negative LnCap tumors (1.3 +/- 0.2% ID/g). The tracer showed comparable tumor to background ratio with each monomer. In summary, prostate cancer is a heterogeneous disease in need of improved diagnostics and treatments. The PSMA-NT heterodimer represents a new class of molecules that can be used to target two distinct antigens related to prostate cancer. In addition to the imaging applications demonstrated in this study, the agent also holds great potential on the treatment of heterogeneous prostate cancer.