Orano Med SAS, Paris, France; and
Orano Med LLC, Plano, Texas.
J Nucl Med. 2024 Nov 1;65(11):1769-1775. doi: 10.2967/jnumed.124.268101.
The role of gastrin-releasing peptide receptor (GRPR) in various diseases, including cancer, has been extensively studied and has emerged as a promising therapeutic target. In this study, we successfully achieved the use of [Pb]Pb-DOTAM-GRPR1, comprising the α-particle generator, Pb, combined with a GRPR-targeting peptide, GRPR1, in a prostate cancer model. Pharmacokinetics, toxicity, radiation dosimetry, and efficacy were assessed in GRPR-positive prostate tumor-bearing mice after intravenous administration of [Pb]Pb-DOTAM-GRPR1 (where DOTAM is 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane). Preclinical studies have shown tumor targeting of up to 5 percent injected dose per gram over 24 h, and optimization of the drug formulation and quantity has led to minimized oxidation and off-target binding, respectively. Particularly, an increase in peptide amount from 28 to 280 ng was shown to reduce off-target uptake, especially at the level of the pancreas, by about 30%. Furthermore, dosimetry studies confirmed the kidney as the dose-limiting organ, and toxicity studies revealed that a nontoxic dose of up to 1,665 kBq could be injected into mice. Efficacy studies indicated a median survival time of 9 wk in the control group, which received only a buffer solution, compared with 19 wk in the group that received 4 injections of 370 kBq at 3-wk intervals. Taken together, these combined data demonstrate the safety, tolerability, and efficacy of [Pb]Pb-DOTAM-GRPR1, thus warranting further exploration in clinical trials.
胃泌素释放肽受体（GRPR）在包括癌症在内的各种疾病中的作用已得到广泛研究，并已成为有前途的治疗靶点。在这项研究中，我们成功地实现了使用[Pb]Pb-DOTAM-GRPR1，该物质由α-粒子发生器 Pb 与 GRPR 靶向肽 GRPR1 组成，用于前列腺癌模型。在 GRPR 阳性前列腺肿瘤荷瘤小鼠中，静脉注射[Pb]Pb-DOTAM-GRPR1（其中 DOTAM 是 1,4,7,10-四（氨基甲酰甲基）-1,4,7,10-四氮杂环十二烷）后，评估了其药代动力学、毒性、辐射剂量学和疗效。临床前研究表明，在 24 小时内，肿瘤靶向达到每克注射剂量的 5%，并且对药物配方和数量的优化分别导致最小化的氧化和非靶标结合。特别是，肽量从 28 增加到 280ng，被证明可以减少非靶标摄取，特别是在胰腺水平，减少约 30%。此外，剂量学研究证实肾脏是限制剂量的器官，毒性研究表明，高达 1665 kBq 的非毒性剂量可注射到小鼠体内。疗效研究表明，在仅接受缓冲液的对照组中，中位生存时间为 9 周，而在接受 4 次 370 kBq 注射的组中，中位生存时间为 19 周，间隔 3 周。综上所述，这些综合数据表明[Pb]Pb-DOTAM-GRPR1 的安全性、耐受性和疗效，因此值得进一步在临床试验中探索。
