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 [²¹²Pb]Pb-DOTAM-GRPR1, comprising the α-particle generator, ²¹²Pb, combined with a GRPR-targeting peptide, GRPR1, in a prostate cancer model. Methods: Pharmacokinetics, toxicity, radiation dosimetry, and efficacy were assessed in GRPR-positive prostate tumor–bearing mice after intravenous administration of [²¹²Pb]Pb-DOTAM-GRPR1 (where DOTAM is 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane). Results: 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. Conclusion: Taken together, these combined data demonstrate the safety, tolerability, and efficacy of [²¹²Pb]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，并已成为一个有前途的治疗靶点。在这项研究中，我们成功地在前列腺癌模型中实现了 [²¹²Pb]Pb-DOTAM-GRPR1 的使用，包括α粒子发生器 ²¹²Pb，结合 GRPR 靶向肽 GRPR1。方法：静脉注射 [²¹²Pb]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，在 GRPR 阳性荷瘤小鼠中评估药代动力学、毒性、辐射剂量测定和疗效。结果：临床前研究表明，在 24 小时内，肿瘤靶向性为每克注射剂量高达 5%，并且药物配方和数量的优化分别导致氧化和脱靶结合最小化。特别是，将肽量从 28 ng 增加到 280 ng 可减少脱靶摄取，尤其是在胰腺水平，减少约 30%。此外，剂量学研究证实肾脏是剂量限制器官，毒性研究表明，可以向小鼠注射高达 1,665 kBq 的无毒剂量。功效研究表明，仅接受缓冲溶液的对照组的中位生存时间为 9 周，而以 3 周的间隔接受 4 次 370 kBq 注射的组为 19 周。结论：综上所述，这些综合数据证明了 [²¹²Pb]Pb-DOTAM-GRPR1 的安全性、耐受性和有效性，因此值得在临床试验中进一步探索。