Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, Maryland, USA.
J Control Release. 2012 Jan 30;157(2):216-23. doi: 10.1016/j.jconrel.2011.09.076. Epub 2011 Sep 22.
Tumors expressing the chemokine receptor CXCR4 have been reported to be more aggressive and to produce more metastatic seeding in specific organs, such as the bone marrow. However, evaluation of tumors for CXCR4 expression requires testing of ex vivo biopsy samples, and is not routinely done in cancer management. In prior work to address this issue, we and others have developed tracers for positron emission tomography (PET) that targeted CXCR4, but in addition to binding to CXCR4 these tracers also bound to red blood cells (and to other unrelated targets) in vivo. Here we report two new tracers based on the CXCR4 peptide antagonist 4F-benzoyl-TN14003 (T140) that bind to CXCR4, but not to undesired targets. These tracers, NOTA-NFB and DOTA-NFB, show slight reductions in both 1) binding affinities for CXCR4 and 2) inhibition of CXCL12 induced migration, compared to T140, in vitro. Both NOTA-NFB and DOTA-NFB specifically accumulate in CXCR4-positive, but not CXCR4-negative, tumor xenografts in mice and allow clear visualization of CXCR4 expression by PET. Evaluation of NOTA-NFB and DOTA-NFB for their potential to mobilize immune cells and progenitor cells from the bone marrow to the peripheral blood revealed slightly reduced, but still comparable, results to the parent molecule T140. The tracers reported here may allow the evaluation of CXCR4 expression in primary tumors and metastatic nodules, and enable better informed, more personalized treatment for patients with cancer.
已经有报道称，表达趋化因子受体 CXCR4 的肿瘤在特定器官（如骨髓）中更具侵袭性，并产生更多的转移性播散。然而，评估肿瘤中 CXCR4 的表达需要对离体活检样本进行检测，而在癌症管理中通常不会这样做。在之前解决这个问题的工作中，我们和其他人开发了针对 CXCR4 的正电子发射断层扫描（PET）示踪剂，但除了与 CXCR4 结合外，这些示踪剂在体内还与红细胞（和其他无关的靶标）结合。在这里，我们报告了两种基于 CXCR4 肽拮抗剂 4F-苯甲酰-TN14003（T140）的新型示踪剂，它们与 CXCR4 结合，但不与不想要的靶标结合。这些示踪剂，NOTA-NFB 和 DOTA-NFB，与 T140 相比，在体外表现出 1）对 CXCR4 的结合亲和力略有降低，2）抑制 CXCL12 诱导的迁移。NOTA-NFB 和 DOTA-NFB 均特异性地在 CXCR4 阳性但 CXCR4 阴性的肿瘤异种移植小鼠中积聚，并允许通过 PET 清楚地可视化 CXCR4 表达。对 NOTA-NFB 和 DOTA-NFB 进行评估，以确定它们是否有潜力将免疫细胞和祖细胞从骨髓动员到外周血，结果显示与母体分子 T140 相比略有降低，但仍具有可比性。报告的示踪剂可能允许评估原发性肿瘤和转移性结节中的 CXCR4 表达，并为癌症患者提供更明智、更个性化的治疗。
