The targeting of gastrin-releasing peptide receptors (GRPR) was recently proposed for targeted therapy, e.g., radiotherapy. Multiple and frequent injections of peptide-based therapeutic agents would be required due to rapid blood clearance. By conjugation of the GRPR antagonist RM26 (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH₂) to an ABD (albumin-binding domain), we aimed to extend the blood circulation of peptides. The synthesized conjugate DOTA-ABD-RM26 was labelled with indium-111 and evaluated in vitro and in vivo. The labelled conjugate was stable in PBS and retained specificity and its antagonistic function against GRPR. The half-maximal inhibitory concentration (IC₅₀) of ^natIn-DOTA-ABD-RM26 in the presence of human serum albumin was 49 ± 5 nM. [¹¹¹In]In-DOTA-ABD-RM26 had a significantly longer residence time in blood and in tumors (without a significant decrease of up to 144 h pi) than the parental RM26 peptide. We conclude that the ABD-RM26 conjugate can be used for GRPR-targeted therapy and delivery of cytotoxic drugs. However, the undesirable elevated activity uptake in kidneys abolishes its use for radionuclide therapy. This proof-of-principle study justified further optimization of the molecular design of the ABD-RM26 conjugate.

中文翻译：

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与白蛋白结合域缀合的 GRPR 靶向拮抗剂 RM26 用于 GRPR 靶向癌症治疗的临床前评估


最近提出以胃泌素释放肽受体(GRPR)为目标进行靶向治疗，例如放射治疗。由于快速的血液清除，需要多次和频繁地注射基于肽的治疗剂。通过将 GRPR 拮抗剂 RM26 (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH ₂ ) 与 ABD（白蛋白结合结构域）结合，我们旨在延长肽的血液循环。合成的缀合物 DOTA-ABD-RM26 用 indium-111 标记并进行体外和体内评估。标记的缀合物在 PBS 中稳定，保留了对 GRPR 的特异性及其拮抗功能。在人血清白蛋白存在下， ^nat In-DOTA-ABD-RM26 的半最大抑制浓度 (IC ₅₀ ) 为 49 ± 5 nM。与亲本RM26肽相比，[ ¹¹¹ In]In-DOTA-ABD-RM26在血液和肿瘤中的停留时间显着更长（注射后没有显着减少，最多144小时）。我们的结论是，ABD-RM26 缀合物可用于 GRPR 靶向治疗和细胞毒性药物的递送。然而，肾脏中不良的活性摄取升高使其无法用于放射性核素治疗。这项原理验证研究证明了 ABD-RM26 缀合物分子设计的进一步优化。