Zavvar Taraneh Sadat, Hörmann Anton Amadeus, Klingler Maximilian, Summer Dominik, Rangger Christine, Desrues Laurence, Castel Hélène, Gandolfo Pierrick, von Guggenberg Elisabeth
Department of Nuclear Medicine, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Inserm U1245, University Rouen Normandie, 76000 Rouen, France.
Pharmaceuticals (Basel). 2023 Feb 13;16(2):278. doi: 10.3390/ph16020278.
Different attempts have been made in the past two decades to develop radiolabeled peptide conjugates with enhanced pharmacokinetic properties in order to improve the application for tumor imaging and peptide receptor radionuclide therapy (PRRT), which targets the cholecystokinin-2 receptor (CCK2R). In this paper, the influence of different side chain and peptide bond modifications has been explored for the minigastrin analog DOTA-DGlu-Ala-Tyr-Gly-Trp-(-Me)Nle-Asp-1Nal-NH (DOTA-MGS5). Based on this lead structure, five new derivatives were synthesized for radiolabeling with trivalent radiometals. Different chemical and biological properties of the new derivatives were analyzed. Receptor interaction of the peptide derivatives and cell internalization of the radiolabeled peptides were studied in A431-CCK2R cells. The stability of the radiolabeled peptides in vivo was investigated using BALB/c mice. Tumor targeting of all In-labeled peptide conjugates, and of a selected compound radiolabeled with gallium-68 and lutetium-177, was evaluated in BALB/c nude mice xenografted with A431-CCK2R and A431-mock cells. All In-labeled conjugates, except [In]In-DOTA-[Phe]MGS5, showed a high resistance against enzymatic degradation. A high receptor affinity with IC values in the low nanomolar range was confirmed for most of the peptide derivatives. The specific cell internalization over time was 35.3-47.3% for all radiopeptides 4 h after incubation. Only [In]In-DOTA-MGS5[NHCH] exhibited a lower cell internalization of 6.6 ± 2.8%. An overall improved resistance against enzymatic degradation was confirmed in vivo. Of the radiopeptides studied, [In]In-DOTA-[(-Me)1Nal]MGS5 showed the most promising targeting properties, with significantly increased accumulation of radioactivity in A431-CCK2R xenografts (48.1 ± 9.2% IA/g) and reduced accumulation of radioactivity in stomach (4.2 ± 0.5% IA/g). However, in comparison with DOTA-MGS5, a higher influence on the targeting properties was observed for the change of radiometal, resulting in a tumor uptake of 15.67 ± 2.21% IA/g for [Ga]Ga-DOTA-[(-Me)1Nal]MGS5 and 35.13 ± 6.32% IA/g for [Lu]Lu-DOTA-[(-Me)1Nal]MGS5.
在过去二十年中，人们进行了不同的尝试来开发具有增强药代动力学特性的放射性标记肽缀合物，以改善其在肿瘤成像和肽受体放射性核素治疗（PRRT）中的应用，PRRT靶向胆囊收缩素-2受体（CCK2R）。在本文中，研究了不同侧链和肽键修饰对小胃泌素类似物DOTA-DGlu-Ala-Tyr-Gly-Trp-(-Me)Nle-Asp-1Nal-NH（DOTA-MGS5）的影响。基于该先导结构，合成了五种新的衍生物用于与三价放射性金属进行放射性标记。分析了新衍生物的不同化学和生物学性质。在A431-CCK2R细胞中研究了肽衍生物的受体相互作用以及放射性标记肽的细胞内化。使用BALB/c小鼠研究了放射性标记肽在体内的稳定性。在接种了A431-CCK2R和A431-对照细胞的BALB/c裸鼠中评估了所有铟标记的肽缀合物以及一种用镓-68和镥-177放射性标记的选定化合物的肿瘤靶向性。除了[铟]铟-DOTA-[苯丙氨酸]MGS5外，所有铟标记的缀合物都表现出对酶降解的高抗性。大多数肽衍生物的受体亲和力在低纳摩尔范围内，IC值较高得到证实。孵育4小时后，所有放射性肽的特异性细胞内化随时间为35.3-47.3%。只有[铟]铟-DOTA-MGS5[NHCH]的细胞内化较低，为6.6±2.8%。在体内证实了对酶降解的总体抗性有所提高。在所研究的放射性肽中，[铟]铟-DOTA-[(-甲基)1-萘丙氨酸]MGS5表现出最有前景的靶向特性，A431-CCK2R异种移植瘤中的放射性积累显著增加（48.1±9.2%IA/g），胃中的放射性积累减少（4.2±0.5%IA/g）。然而，与DOTA-MGS5相比，放射性金属的变化对靶向特性的影响更大，[镓]镓-DOTA-[(-甲基)1-萘丙氨酸]MGS5的肿瘤摄取为15.67±2.21%IA/g，[镥]镥-DOTA-[(-甲基)I-萘丙氨酸]MGS5的肿瘤摄取为35.13±6.32%IA/g。
