用于鼻咽癌的肽受体放射性核素治疗的[Lu]Lu-LNC1010 的开发。
Development of [Lu]Lu-LNC1010 for peptide receptor radionuclide therapy of nasopharyngeal carcinoma.
机构信息
Department of Nuclear Medicine and Minnan PET Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Department of Radiation Oncology, Xiamen Cancer Center, Xiamen Key Laboratory of Radiation Oncology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
出版信息
Eur J Nucl Med Mol Imaging. 2024 Dec;52(1):247-259. doi: 10.1007/s00259-024-06874-9. Epub 2024 Aug 15.
PURPOSE
Somatostatin Receptor 2 (SSTR2)-targeted radiopharmaceutical [Ga]Ga-DOTATATE has potential advantages in the diagnosis of nasopharyngeal carcinoma (NPC). This study introduces a novel long-lasting SSTR2 analogue, LNC1010, based on DOTATATE, a truncated Evans blue-binding moiety, and a polyethylene-glycol linker. We hypothesised that peptide receptor radionuclide therapy (PRRT) is more effective with [Lu]Lu-LNC1010 than with [Lu]Lu-DOTATATE in treating metastatic NPC.
METHODS
We assessed binding characteristics of LNC1010 in vitro using C666-1 NPC cells and in-vivo pharmacokinetics of [Ga]Ga/[Lu]Lu-LNC1010 in C666-1 NPC xenografts via PET and SPECT imaging, biodistribution studies, and PRRT, and compared them with [Ga]Ga/[Lu] Lu-labelled DOTATATE. Furthermore, a proof-of-concept approach for imaging and therapy was conducted in a patient with metastatic NPC.
RESULTS
LNC1010 exhibited strong uptake and specific affinity for SSTR2 in C666-1 NPC cells. PET and SPECT imaging demonstrated higher uptake and longer tumour retention of [Ga]Ga/[Lu]Lu-LNC1010 than [Ga]Ga/[Lu]Lu-DOTATATE in C666-1 NPC xenografts, indicating its suitability for PRRT applications in NPCs. Biodistribution studies confirmed the higher uptake and prolonged retention of [Lu]Lu-LNC1010 than [Lu]Lu-DOTATATE. In preclinical PRRT studies, [Lu]Lu-LNC1010 showed greater inhibition of tumour growth in C666-1 NPC xenografts than [Lu]Lu-DOTATATE. In a subsequent pilot clinical study, PRRT with [Lu]Lu-LNC1010 achieved favourable therapeutic and negligible side effects in a patient with metastatic NPC.
CONCLUSION
[Lu]Lu-LNC1010 demonstrated increased tumour uptake and prolonged retention in SSTR2-positive NPCs, with superior anti-tumour efficacy to that of [Lu]Lu-DOTATATE in preclinical studies. These findings suggest that PRRT with [Lu]Lu-LNC1010 is a promising treatment for advanced NPC, extending the clinical scope of PRRT beyond neuroendocrine tumours.
目的
基于 DOTATATE（一种截短的 Evans 蓝结合部分）和聚乙二醇连接子，我们开发了一种新型的长效生长抑素受体 2（SSTR2）靶向放射性药物[Ga]Ga-DOTATATE，其在鼻咽癌（NPC）的诊断中具有潜在优势。本研究引入了一种新型的长效 SSTR2 类似物 LNC1010，用于治疗转移性 NPC。我们假设肽受体放射性核素治疗（PRRT）用[Lu]Lu-LNC1010 比用[Lu]Lu-DOTATATE 治疗效果更好。
方法
我们使用 C666-1 NPC 细胞评估 LNC1010 的体外结合特性，并通过 PET 和 SPECT 成像、生物分布研究以及 PRRT 评估[Ga]Ga/[Lu]Lu-LNC1010 在 C666-1 NPC 异种移植瘤中的体内药代动力学，同时将其与[Ga]Ga/[Lu]Lu-标记的 DOTATATE 进行比较。此外，我们还在一名转移性 NPC 患者中进行了成像和治疗的概念验证方法。
结果
LNC1010 在 C666-1 NPC 细胞中表现出对 SSTR2 的强烈摄取和特异性亲和力。PET 和 SPECT 成像显示，与[Ga]Ga/[Lu]Lu-DOTATATE 相比，[Ga]Ga/[Lu]Lu-LNC1010 在 C666-1 NPC 异种移植瘤中的摄取更高，肿瘤保留时间更长，表明其适用于 NPC 的 PRRT 应用。生物分布研究证实，[Lu]Lu-LNC1010 的摄取更高，保留时间更长。在临床前 PRRT 研究中，[Lu]Lu-LNC1010 在 C666-1 NPC 异种移植瘤中的肿瘤生长抑制作用强于[Lu]Lu-DOTATATE。随后的一项临床研究表明，在一名转移性 NPC 患者中，[Lu]Lu-LNC1010 的 PRRT 治疗取得了良好的治疗效果，且副作用极小。
结论
[Lu]Lu-LNC1010 在 SSTR2 阳性 NPC 中表现出更高的肿瘤摄取和更长的保留时间，与临床前研究中的[Lu]Lu-DOTATATE 相比，具有更好的抗肿瘤疗效。这些发现表明，[Lu]Lu-LNC1010 的 PRRT 治疗是晚期 NPC 的一种很有前途的治疗方法，将 PRRT 的临床应用范围扩展到神经内分泌肿瘤之外。
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