Peptide Receptor Radionuclide Therapy with 67Cu-CuSarTATE Is Highly Efficacious Against a Somatostatin-Positive Neuroendocrine Tumor Model
Peptide Receptor Radionuclide Therapy with 67Cu-CuSarTATE Is Highly Efficacious Against a Somatostatin-Positive Neuroendocrine Tumor Model
复制标题
DOI：
10.2967/jnumed.120.243543
复制
发表时间：
2020-12-01
影响因子：
9.3
通讯作者：
Donnelly, Paul S.
中科院分区：
文献类型：
--
作者：
Cullinane, Carleen;Jeffery, Charmaine M.;Donnelly, Paul S.
利用放射性标记的奥曲酸进行肽受体放射性核素治疗（PRRT）是治疗生长抑素受体2表达的神经内分泌肿瘤的有效方法。Cu-64和Cu-67的诊断和治疗潜力分别提供了使用单一生长抑素受体靶向肽偶联物作为治疗剂的可能性。石棺笼胺配体MeCO-Sar（5-(8-甲基-3,6,10,13,16,19- hexaza - bicycloo [6.6.6]icosan-1-ylamino)-5-oxopentanoic acid）与(Tyr(3))- octreoate （Cu-64-CuSarTATE）偶联，在10例神经内分泌肿瘤患者中被证明是一种显像剂和潜在的前瞻性剂量测定工具。本研究旨在探讨Cu-67-CuSarTATE在神经内分泌肿瘤临床前模型中的抗肿瘤效果，并与标准PRRT药物Lu-177-LuDOTA-Tyr(3)-octreotate （Lu-177-LuTATE）进行比较。方法：比较不同剂量Cu-67-CuSarTATE对AR42J（大鼠胰腺外分泌）荷瘤小鼠的抗肿瘤效果。结果：单次给药Cu-67-CuSarTATE (5 MBq) 7天后，与对照相比，肿瘤生长被抑制了75%。给予Lu-177-LuTATE （5 MBq）抑制肿瘤生长89%。Cu-67-CuSarTATE和Lu-177-LuTATE治疗组的生存期从对照组的12 d延长至21 d。在第二项研究中，评估了PRRT分次递送的疗效，比较了30 MBq的Cu-67-CuSarTATE或Lu-177-LuTATE的疗效，无论是单次静脉注射还是两次15 MBq的分次静脉注射，间隔2周。2组分治疗肿瘤比单组分治疗显著提高生存率（67Cu-CuSarTATE: 47 vs. 36 d [P = 0.036]; Lu-177-LuTATE: 46 vs. 29 d [P = 0.040]）。结论：本研究表明，Cu-67-CuSarTATE在BALB/c裸鼠体内耐受性良好，对AR42J肿瘤具有较高的体内抗肿瘤活性。Cu-67-CuSarTATE和Lu-177-LuTATE分2份给药2周内比单份给药更有效。Cu-67-CuSarTATE在AR42J肿瘤模型中的抗肿瘤活性证明了这种新型药物治疗生长抑素受体2表达神经内分泌肿瘤的临床适用性。
Peptide receptor radionuclide therapy (PRRT) using radiolabeled octreotate is an effective treatment for somatostatin receptor 2-expressing neuroendocrine tumors. The diagnostic and therapeutic potential of Cu-64 and Cu-67, respectively, offers the possibility of using a single somatostatin receptor-targeted peptide conjugate as a theranostic agent. A sarcophagine cage amine ligand, MeCO-Sar (5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid), conjugated to (Tyr(3))-octreotate, called Cu-64-CuSarTATE, was demonstrated to be an imaging agent and potential prospective dosimetry tool in 10 patients with neuroendocrine tumors. This study aimed to explore the antitumor efficacy of Cu-67-CuSarTATE in a preclinical model of neuroendocrine tumors and compare it with the standard PRRT agent, Lu-177-LuDOTA-Tyr(3)-octreotate (Lu-177-LuTATE). Methods: The antitumor efficacy of various doses of Cu-67-CuSarTATE in AR42J (rat pancreatic exocrine) tumor-bearing mice was compared with Lu-177-LuTATE. Results: Seven days after a single administration of Cu-67-CuSarTATE (5 MBq), tumor growth was inhibited by 75% compared with vehicle control. Administration of Lu-177-LuTATE (5 MBq) inhibited tumor growth by 89%. Survival was extended from 12 d in the control group to 21 d after treatment with both Cu-67-CuSarTATE and Lu-177-LuTATE. In a second study, the efficacy of fractionated delivery of PRRT was assessed, comparing the efficacy of 30 MBq of Cu-67-CuSarTATE or Lu-177-LuTATE, either as a single intravenous injection or as two 15-MBq fractions 2 wk apart. Treatment of tumors with 2 fractions significantly improved survival over delivery as a single fraction (67Cu-CuSarTATE: 47 vs. 36 d [P = 0.036]; Lu-177-LuTATE: 46 vs. 29 d [P = 0.040]). Conclusion: This study demonstrates that Cu-67-CuSarTATE is well tolerated in BALB/c nude mice and highly efficacious against AR42J tumors in vivo. Administration of Cu-67-CuSarTATE and Lu-177-LuTATE divided into 2 fractions over 2 wk was more efficacious than administration of a single fraction. The antitumor activity of Cu-67-CuSarTATE in the AR42J tumor model demonstrated the suitability of this novel agent for clinical assessment in the treatment of somatostatin receptor 2-expressing neuroendocrine tumors.