晚期非小细胞肺癌靶向αvβ3 “筛选-治疗”一体化放射性探针的构建及提高探针肿瘤摄取的新策略

Only 12-16% patients with advanced non-small cell lung cancer (NSCLC) can benefit from targeted therapy. Furthermore, secondary drug resistance has occurred in almost all patients with time and treatment. At this moment of challenge, tumor targeted radiotherapy with the radiolabeled peptide probe provides a new idea for the treatment of advanced NSCLC. However, most of peptide probes are characterized by the fast renal excretion and short half-life in blood, such unfavorable pharmaceutical properties leads to low tumor uptake and prevent their translation into clinical settings for being used as a radiotherapeutic agent. In this study, we are going to propose a novel platform for developing a long-lasting radiotherapeutic agent by conjugating a small molecular albumin binding moiety, truncated Evans blue (EB), to RGD peptide. Here, we will describe the novel EB derivative that, on conjugation with targeting agents, results in an enhanced half-life in blood. Through radiolabeling with 64Cu or 177Lu, we are going to evaluate whether the EB-conjugated RGD peptide (EB-RGD) could be of use as an imaging probe for the pre-treatment screening and a radiotherapeutic agent for the targeted radiotherapy of integrin αvβ3-expressing NSCLC. Through this investigation, we wish to establish the “prescreening-therapy” radiolabeled peptide probe for advanced NSCLC and propose a novel strategy for enhancing tumor uptake of αvβ3-targeted probe.

晚期非小细胞肺癌（NSCLC）患者中适于靶向治疗的不足20%，其中有效的占60-80%，总体获益比例仅为12-16%。此外，几乎所有患者都会随治疗的深入出现继发性耐药。以放射性核素标记多肽探针为载体的放射靶向治疗为晚期NSCLC的治疗提供了新的思路。但目前大部分肽类药物在体内的清除速率快、半衰期短，因此在肿瘤组织中摄取不高、滞留时间短，影响了其作为放射性治疗药物的临床转化。本研究针对以NSCLC高表达的整合素αvβ3为靶标，设计以结合伊文思蓝（EB）的RGD多肽（EB-RGD）为放射性靶向探针，通过EB与体内白蛋白的结合延长靶向探针在体内的循环时间，提高以RGD为载体的放射靶向治疗效果。本项目拟采用治疗核素177Lu标记EB-RGD构建内照射靶向治疗探针，进行NSCLC模型的放射靶向治疗；采用显像核素64Cu标记同一靶向分子构建诊断性显像筛选探针，实现“筛选-治疗”一体化放射性探针的构建。

目前，大多数非小细胞肺癌（NSCLC）患者诊断为晚期，5年生存率很低，寻找新的治疗策略的研究正在进行中，可靠地模拟非小细胞肺癌的实验模型是非常需要的，以预测对新疗法的反应。因此，我们开发了NSCLC的患者来源异种移植（PDX）模型，并利用该模型评估177Lu-EB-RGD的治疗效果。177Lu-EB-RGD是一种基于多肽的放射性药物，靶向整合素αvβ3，其药代动力学得到改进。本研究成功建立了三组不同的NSCLC-PDX模型，它们都保持了人类原发肿瘤相同的免疫组化和遗传特征。选取整合素αvβ3强阳性表达组和弱阳性表达组（PDXαvβ3+和PDXαvβ3-）作为实验模型，评价177Lu-EB-RGD的体内生物学行为。在SPECT成像和生物分布研究中，177Lu-EB-RGD在PDXαvβ3+和PDXαvβ3-模型中的积累显著高于其对应的单体177Lu-RGD。在PDXαvβ3+中单次注射18.5 MBq 177Lu-EB-RGD足以完全根除肿瘤，观察期间无肿瘤复发迹象。这种治疗对PDXαvβ3-也有效：与对照组或177Lu-RGD组相比，单剂量29.6 MBq 177Lu-EB-RGD可使肿瘤生长显著延迟。使用该模型的临床前数据表明，177Lu-EB-RGD可能是一种有效的非小细胞肺癌治疗选择，应该在临床试验中进一步评估。

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