Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
J Nucl Med. 2019 Aug;60(8):1124-1133. doi: 10.2967/jnumed.118.217240. Epub 2019 Feb 7.
New effective therapies are greatly needed for metastatic uveal melanoma, which has a very poor prognosis with a median survival of less than 1 y. The melanocortin 1 receptor (MC1R) is expressed in 94% of uveal melanoma metastases, and a MC1R-specific ligand (MC1RL) with high affinity and selectivity for MC1R was previously developed. The Ac-DOTA-MC1RL conjugate was synthesized in high radiochemical yield and purity and was tested in vitro for biostability and for MC1R-specific cytotoxicity in uveal melanoma cells, and the lanthanum-DOTA-MC1RL analog was tested for binding affinity. Non-tumor-bearing BALB/c mice were tested for maximum tolerated dose and biodistribution. Severe combined immunodeficient mice bearing uveal melanoma tumors or engineered MC1R-positive and -negative tumors were studied for biodistribution and efficacy. Radiation dosimetry was calculated using mouse biodistribution data and blood clearance kinetics from Sprague-Dawley rat data. High biostability, MC1R-specific cytotoxicity, and high binding affinity were observed. Limiting toxicities were not observed at even the highest administered activities. Pharmacokinetics and biodistribution studies revealed rapid blood clearance (<15 min), renal and hepatobillary excretion, MC1R-specific tumor uptake, and minimal retention in other normal tissues. Radiation dosimetry calculations determined pharmacokinetics parameters and absorbed α-emission dosages from Ac and its daughters. Efficacy studies demonstrated significantly prolonged survival and decreased metastasis burden after a single administration of Ac-DOTA-MC1RL in treated mice relative to controls. These results suggest significant potential for the clinical translation of Ac-DOTA-MC1RL as a novel therapy for metastatic uveal melanoma.
新型有效疗法对于转移性葡萄膜黑色素瘤极为重要，这种疾病预后极差，中位生存期不足 1 年。黑素皮质素 1 受体（MC1R）在 94%的葡萄膜黑色素瘤转移瘤中表达，之前已开发出一种对 MC1R 具有高亲和力和选择性的 MC1R 特异性配体（MC1RL）。AC-DOTA-MC1RL 缀合物以高放射化学产率和纯度合成，并在体外进行了生物稳定性测试以及对葡萄膜黑色素瘤细胞的 MC1R 特异性细胞毒性测试，镧-DOTA-MC1RL 类似物用于测试结合亲和力。未携带肿瘤的 BALB/c 小鼠用于测试最大耐受剂量和生物分布。严重联合免疫缺陷小鼠携带葡萄膜黑色素瘤肿瘤或工程化的 MC1R 阳性和阴性肿瘤，用于研究生物分布和疗效。使用小鼠生物分布数据和 Sprague-Dawley 大鼠数据的血液清除动力学计算辐射剂量学。观察到高生物稳定性、MC1R 特异性细胞毒性和高结合亲和力。即使给予最高的放射性活度，也没有观察到限制毒性。药代动力学和生物分布研究显示，放射性药物在血液中迅速清除（<15 分钟），经肾脏和肝胆排泄，MC1R 特异性肿瘤摄取，以及在其他正常组织中最小保留。辐射剂量学计算确定了 Ac 和其子体的药代动力学参数和吸收的α-发射剂量。疗效研究表明，与对照组相比，单次给予 Ac-DOTA-MC1RL 可显著延长治疗小鼠的存活时间并减少转移瘤负担。这些结果表明，Ac-DOTA-MC1RL 作为转移性葡萄膜黑色素瘤的新型治疗方法具有重要的临床转化潜力。
