The gastrin‐releasing peptide receptor (GRPR) is part of the bombesin receptor family and a well‐known target in cancer diagnosis and therapy. In the last decade, promising results have been achieved by using peptide‐drug conjugates, which allow selective targeting of GRPR expressing tumor cells. Most ligands, however, have been antagonists even though agonists can lead to higher tumor uptake owing to their internalization. So far, only a few studies focused on the identification of small GRPR‐selective agonists that are metabolically stable. Here, we developed novel bombesin analogs with high selectivity for the GRPR and improved blood plasma stability. The most promising analog [d‐Phe⁶, β‐Ala¹¹, NMe‐Ala¹³, Nle¹⁴]Bn(6‐14) displays an activity of 0.3nM at the GRPR, a more than 4000‐fold selectivity over the other two bombesin receptors and more than 75% stability in human blood plasma after 24 hours. This analog is proposed as a promising drug shuttle for the intracellular delivery of different payloads in targeted tumor therapy approaches.

中文翻译：

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鉴定和稳定的高选择性胃泌素释放肽受体激动剂。

胃泌素释放肽受体（GRPR）是蛙皮素受体家族的一部分，是癌症诊断和治疗中众所周知的靶标。在过去的十年中，使用肽-药物结合物已经取得了可喜的成果，该结合物可以选择性靶向GRPR表达肿瘤细胞。然而，即使激动剂由于其内在化而导致更高的肿瘤吸收，大多数配体仍是拮抗剂。到目前为止，只有很少的研究集中于识别代谢稳定的小GRPR选择性激动剂。在这里，我们开发了对GRPR具有高选择性并改善了血浆稳定性的新型蛙皮素类似物。最有前途的类似物[ ð -Phe ⁶，β丙氨酸¹¹，NME丙氨酸¹³，NLE ¹⁴] Bn（6-14）在GRPR上显示出0.3nM的活性，比其他两个蛙皮素受体的选择性高4000倍，并且24小时后在人血浆中的稳定性超过75％。该类似物被提议作为有希望的药物穿梭剂，用于靶向肿瘤治疗方法中不同有效载荷的细胞内递送。