Targeted Molecular Radiotherapy of Pediatric Solid Tumors Using a Radioiodinated Alkyl-Phospholipid Ether Analog
Targeted Molecular Radiotherapy of Pediatric Solid Tumors Using a Radioiodinated Alkyl-Phospholipid Ether Analog
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DOI：
10.2967/jnumed.117.193748
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发表时间：
2018-02-01
影响因子：
9.3
通讯作者：
Otto, Mario
中科院分区：
文献类型：
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作者：
Baiu, Dana C.;Marsh, Ian R.;Otto, Mario
外照射在大多数儿童实体瘤的治疗中起着关键作用。尤其是在儿童中，实现最佳的治疗指数以避免对正常组织的损害是极其重要的。因此，在转移性疾病中，外照射的应用是有限的。使用肿瘤靶向放射性核素的分子放射治疗可能会克服其中的一些挑战，但到目前为止，还没有一种癌症选择性药物能够独立于组织病理学来源治疗各种儿科恶性肿瘤。我们测试了临床级烷基磷脂醚类似物CLR1404，18-(对碘苯基)十八烷基磷胆碱作为儿童恶性肿瘤肿瘤靶向放射治疗支架的治疗潜力。方法：用流式细胞仪检测体外培养的儿童实体瘤细胞对CLR1404的摄取，用PET/CT显像和剂量学方法检测体内摄取CLR1404的能力。在异种移植模型上评价I-131-CLR1404的治疗潜力。结果：在体外，与正常对照相比，荧光标记的CLR1404-BODIPY在多种儿科肿瘤细胞中有明显的选择性摄取。使用I-124-CLR1404的小鼠异种移植模型的体内肿瘤靶向摄取通过成像得到证实。单次静脉注射I-131-CLR1404显著延缓了所有啮齿动物儿童异种移植模型的肿瘤生长，延长了动物存活时间，同时显示出良好的副作用。结论：I-131-CLR1404有望成为一种具有广泛应用前景的肿瘤靶向放射治疗药物。由于I-131-CLR1404已进入成人临床试验，我们的数据保证为这一特别脆弱的患者群体开发儿科临床试验。
External-beam radiotherapy plays a critical role in the treatment of most pediatric solid tumors. Particularly in children, achieving an optimal therapeutic index to avoid damage to normal tissue is extremely important. Consequently, in metastatic disease, the utility of external-beam radiotherapy is limited. Molecular radiotherapy with tumor-targeted radionuclides may overcome some of these challenges, but to date there exists no single cancer-selective agent capable of treating various pediatric malignancies independently of their histopathologic origin. We tested the therapeutic potential of the clinical-grade alkyl-phospholipid ether analog CLR1404, 18-(p-iodophenyl) octadecyl phosphocholine, as a scaffold for tumortargeted radiotherapy of pediatric malignancies. Methods: Uptake of CLR1404 by pediatric solid tumor cells was tested in vitro by flow cytometry and in vivo by PET/CT imaging and dosimetry. The therapeutic potential of I-131-CLR1404 was evaluated in xenograft models. Results: In vitro, fluorescent CLR1404-BODIPY showed significant selective uptake in a variety of pediatric cancer lines compared with normal controls. In vivo tumor-targeted uptake in mouse xenograft models using I-124-CLR1404 was confirmed by imaging. Single-dose intravenous injection of I-131-CLR1404 significantly delayed tumor growth in all rodent pediatric xenograft models and extended animal survival while demonstrating a favorable side effect profile. Conclusion: I-131-CLR1404 has the potential to become a tumor-targeted radiotherapeutic drug with broad applicability in pediatric oncology. Because I-131-CLR1404 has entered clinical trials in adults, our data warrant the development of pediatric clinical trials for this particularly vulnerable patient population.