Purpose: Radionuclide therapy directed against tumors that express somatostatin receptors (SSTRs) has proven effective for the treatment of advanced, low- to intermediate-grade neuroendocrine tumors in the clinic. In clinical usage, somatostatin peptide-based analogs, labeled with therapeutic radionuclides, provide an overall response rate of about 30%, despite the high cumulative activity injected per patient. We set out to improve the effectiveness of somatostatin radiotherapy by preparing a chemical analog that would clear more slowly through the urinary tract and, concomitantly, have increased blood circulation half-life and higher targeted accumulation in the tumors. Experimental Design: We conjugated a common, clinically-used SST peptide derivative, DOTA-octreotate, to an Evans blue analog (EB), which reversibly binds to circulating serum albumin. The resulting molecule was used to chelate ⁸⁶Y and ⁹⁰Y, a diagnostic and a therapeutic radionuclide, respectively. The imaging capabilities and the radiotherapeutic efficacy of the resulting radioligand was evaluated in HCT116/SSTR2, HCT116, and AR42J cell lines that express differing levels of SST2 receptors. Results: The synthesized radiopharmaceutical retained affinity and specificity to SSTR2. The new molecule also retained the high internalization rate of DOTA-octreotate, and therefore, showed significantly higher accumulation in SSTR2-positive tumors. Labeling of our novel EB-octreotate derivative with the therapeutic, pure beta emitter, ⁹⁰Y, resulted in improved tumor response and survival rates of mice bearing SSTR2 xenografts and had long term efficacy when compared to DOTA-octreotate itself. Conclusions: The coupling of a targeted peptide, a therapeutic radionuclide, and the EB‑based albumin binding provides for effective treatment of SSTR2-containing tumors.

中文翻译：

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埃文斯蓝色附件增强生长抑素受体亚型2成像和放射治疗。

目的：针对表达生长抑素受体（SSTRs）的肿瘤的放射性核素疗法已被证明可有效治疗临床上的晚期，中低级神经内分泌肿瘤。在临床使用中，尽管每位患者注射了高累积活性，但以治疗性放射性核素标记的生长抑素肽基类似物仍可提供约30％的总缓解率。我们着手通过制备化学类似物来提高生长抑素放疗的有效性，该化学类似物在尿道中的清除速度较慢，并因此增加了血液循环半衰期，并在肿瘤中具有更高的靶向蓄积性。实验设计：我们将一种临床上常用的SST肽衍生物DOTA-octreotate偶联到了Evans blue类似物（EB）上，该Evans blue类似物可逆地结合到循环的血清白蛋白上。所得分子被用于螯合⁸⁶ Y和⁹⁰ Y，诊断和治疗用放射性核素，分别。在表达不同水平的SST2受体的HCT116 / SSTR2，HCT116和AR42J细胞系中评估了所得放射性配体的成像能力和放射治疗功效。结果：合成的放射性药物保留了对SSTR2的亲和力和特异性。该新分子还保留了DOTA-奥曲肽的高内在化率，因此在SSTR2阳性肿瘤中显示出明显更高的积累。与治疗性纯β发射体⁹⁰ Y标记我们的新型EB-奥古斯丁衍生物，与带有SSTR2异种移植物的小鼠相比，可改善小鼠的肿瘤反应和存活率，并且与DOTA-奥古斯丁本身相比具有长期疗效。结论：靶向肽，治疗性放射性核素和基于EB的白蛋白结合的结合可有效治疗含SSTR2的肿瘤。