Detection and therapy of neuroblastoma minimal residual disease using [(64/67)Cu]Cu-SARTATE in a preclinical model of hepatic metastases.
Detection and therapy of neuroblastoma minimal residual disease using [(64/67)Cu]Cu-SARTATE in a preclinical model of hepatic metastases.
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DOI：
10.1186/s13550-021-00763-0
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发表时间：
2021-02-25
期刊：
影响因子：
3.2
通讯作者：
Packard AB
中科院分区：
文献类型：
--
作者：
Dearling JLJ;van Dam EM;Harris MJ;Packard AB
神经母细胞瘤治疗长期成功的一个主要挑战是作为微小残留病（MRD）在初始治疗中存活的广泛转移。大多数神经母细胞瘤肿瘤表达SSTR 2受体，使其成为分子靶向放射性核素治疗的有吸引力的靶点。SARTATE由奥曲酸组成，奥曲酸靶向SSTR 2受体，与MeCOSar偶联，MeCOSar是一种对铜具有高亲和力的双功能螯合剂。Cu-SARTATE通过使用[64 Cu]Cu-SARTATE检测和监测疾病以及[67 Cu]Cu-SARTATE作为伴随治疗药物，提供了检测和治疗神经母细胞瘤MRD的潜力。在本研究中，我们在神经母细胞瘤MRD的临床前模型中测试了这种治疗诊断对。在裸鼠中使用IMR 32细胞建立转移性神经母细胞瘤的肝内模型。使用小动物PET和离体组织分析测量[64 Cu]Cu-SARTATE的生物分布。使用相同的模型进行存活研究：在肿瘤细胞接种后2周或4周，对小鼠（6-8只小鼠/组）给予单次剂量的生理盐水或9.25 MBq（250 µCi）或18.5 MBq（500 µCi）[67 Cu]Cu-SARTATE。PET成像和离体生物分布证实了[64 Cu]Cu-SARTATE的肿瘤摄取和从其他组织的快速清除。主要清除组织为肾脏（注射后24 h为15.6 ± 5.8% IA/g，48 h为11.5 ± 2.8% IA/g，n = 3/4）。放射自显影和组织学分析证实了存活的SSTR 2阳性肿瘤区域中的[64 Cu]Cu-SARTATE摄取，24 h时平均肿瘤摄取为14.1-25.0% IA/g。[67 Cu]Cu-SARTATE治疗在肿瘤细胞接种后2周开始时有效，与未治疗组相比，存活期平均延长13天（30%）（对照组的平均存活期为43.0 ± 8.1天，治疗组为55.6 ± 9.1天; p = 0.012）。当肿瘤细胞接种后4周开始[67 Cu]Cu-SARTATE时，未观察到显著的治疗效果，此时肿瘤将更大（对照组14.6 ± 8.5天; 9.25 MBq组9.5 ± 1.6天; 18.5 MBq组15.6 ± 4.1天; p = 0.064）。肽受体放射性核素治疗转移性疾病的临床经验令人鼓舞。本研究证明了使用[64/67 Cu]Cu-SARTATE检测和治疗SSTR 2阳性神经母细胞瘤MRD的治疗诊断方法的潜力。
A major challenge to the long-term success of neuroblastoma therapy is widespread metastases that survive initial therapy as minimal residual disease (MRD). The SSTR2 receptor is expressed by most neuroblastoma tumors making it an attractive target for molecularly targeted radionuclide therapy. SARTATE consists of octreotate, which targets the SSTR2 receptor, conjugated to MeCOSar, a bifunctional chelator with high affinity for copper. Cu-SARTATE offers the potential to both detect and treat neuroblastoma MRD by using [64Cu]Cu-SARTATE to detect and monitor the disease and [67Cu]Cu-SARTATE as the companion therapeutic agent. In the present study, we tested this theranostic pair in a preclinical model of neuroblastoma MRD. An intrahepatic model of metastatic neuroblastoma was established using IMR32 cells in nude mice. The biodistribution of [64Cu]Cu-SARTATE was measured using small-animal PET and ex vivo tissue analysis. Survival studies were carried out using the same model: mice (6–8 mice/group) were given single doses of saline, or 9.25 MBq (250 µCi), or 18.5 MBq (500 µCi) of [67Cu]Cu-SARTATE at either 2 or 4 weeks after tumor cell inoculation. PET imaging and ex vivo biodistribution confirmed tumor uptake of [64Cu]Cu-SARTATE and rapid clearance from other tissues. The major clearance tissues were the kidneys (15.6 ± 5.8% IA/g at 24 h post-injection, 11.5 ± 2.8% IA/g at 48 h, n = 3/4). Autoradiography and histological analysis confirmed [64Cu]Cu-SARTATE uptake in viable, SSTR2-positive tumor regions with mean tumor uptakes of 14.1–25.0% IA/g at 24 h. [67Cu]Cu-SARTATE therapy was effective when started 2 weeks after tumor cell inoculation, extending survival by an average of 13 days (30%) compared with the untreated group (mean survival of control group 43.0 ± 8.1 days vs. 55.6 ± 9.1 days for the treated group; p = 0.012). No significant therapeutic effect was observed when [67Cu]Cu-SARTATE was started 4 weeks after tumor cell inoculation, when the tumors would have been larger (control group 14.6 ± 8.5 days; 9.25 MBq group 9.5 ± 1.6 days; 18.5 MBq group 15.6 ± 4.1 days; p = 0.064). Clinical experiences of peptide-receptor radionuclide therapy for metastatic disease have been encouraging. This study demonstrates the potential for a theranostic approach using [64/67Cu]Cu-SARTATE for the detection and treatment of SSTR2-positive neuroblastoma MRD.
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影响因子：
1.2
作者：
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通讯作者：
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影响因子：
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通讯作者：
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作者：
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