Targeted Radionuclide Therapy in Patient-Derived Xenografts Using (177)Lu-EB-RGD.
Targeted Radionuclide Therapy in Patient-Derived Xenografts Using (177)Lu-EB-RGD.
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DOI：
10.1158/1535-7163.mct-19-1098
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发表时间：
2020-10
影响因子：
5.7
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Zhao L;Chen H;Guo Z;Fu K;Yao L;Fu L;Guo W;Wen X;Jacobson O;Zhang X;Sun L;Wu H;Lin Q;Chen X
目前，大多数非小细胞肺癌(NSCLC)患者诊断为晚期，五年生存率较低。因此，旨在寻找新的治疗策略的密集研究一直在进行中；非常需要可靠地模拟非小细胞肺癌疾病的实验模型来预测对新疗法的反应。因此，我们建立了非小细胞肺癌患者来源的异种移植模型，并将其用于评估177Lu-EB-RGD的治疗效果。177Lu-EB-RGD是一种基于多肽的放射性药物，具有改善的药代动力学，靶向整合素αvβ3。在本研究中，成功地建立了三组不同的非小细胞肺癌-PDX细胞，它们都保持了与人类原发肿瘤相同的免疫组织化学和遗传学特征。选择整合素αvβ3高表达和低表达的两个非小细胞肺癌-pDx组(Pdxαvβ3+和Pdxαvβ3-)作为实验模型，评价177Lu-EB-RGd的体内生物学行为。在SPECT显像和生物分布研究中，177Lu-EB-RGD在Pdxαvβ3+和Pdxαvβ3-模型中的蓄积量显著高于其相应单体177Lu-RGD。单次注射18.5MBq177Lu-EB-RGD可完全清除Pdxαvβ3+中的肿瘤，观察期间未见肿瘤复发迹象。这种治疗在Pdxαvβ3-中也是有效的：与对照组或177Lu-RGD组相比，单次注射29.6MBq的177Lu-EB-RGD可显著延缓肿瘤的生长。使用该模型的临床前数据表明，177Lu-EB-RGD可能是治疗非小细胞肺癌的有效选择，应该在人体试验中进一步评估。
Currently, most patients with non-small cell lung cancer (NSCLC) are diagnosed in advanced stages with a poor five-year survival rate. Therefore, intensive research aimed at finding novel therapeutic strategies has been ongoing; experimental models that reliably emulate NSCLC disease are greatly needed to predict responses to novel therapeutics. Therefore, we developed patient-derived xenograft models of NSCLC, which we then used to evaluate the therapeutic efficacy of 177Lu-EB-RGD, a peptide-based radiopharmaceutical with improved pharmacokinetics that targets integrin αvβ3. In this study, three different groups of NSCLC-PDXs were successfully established, all of which maintained the same immunohistochemical and genetic characteristics of the human primary tumour. The two NSCLC-PDX groups with intense and low expression of integrin αvβ3 (denoted as PDXαvβ3+ and PDXαvβ3-) were chosen as the experimental models to evaluate the in vivo biological behaviour of 177Lu-EB-RGD. In SPECT imaging and biodistribution studies, 177Lu-EB-RGD showed significantly higher accumulation in PDXαvβ3+ and PDXαvβ3- models than its corresponding monomer 177Lu-RGD. A single dose of 18.5 MBq 177Lu-EB-RGD was enough to completely eradicate the tumours in PDXαvβ3+, with no sign of tumour recurrence during the observation period. Such treatment was also efficacious in PDXαvβ3-: a single dose of 29.6 MBq 177Lu-EB-RGD led to a significant delay in tumour growth as compared to that in the control or 177Lu-RGD group. The preclinical data from the use of this model suggest that 177Lu- EB-RGD may be an effective treatment option for NSCLC and should be further evaluated in human trials.