通过优化基于放射杂交技术的小胃泌素类似物的连接序列,显著降低其在肾脏中的活性保留。

IF 3.1 3区 医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING
Nadine Holzleitner, Sebastian Fischer, Isabel Maniyankerikalam, Roswitha Beck, Constantin Lapa, Hans-Jürgen Wester, Thomas Günther
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引用次数: 0

摘要

背景:我们最近推出了基于放射杂交(rh)技术的小胃泌素类似物,如 DOTA-rhCCK-18 (DOTA-D-Dap(p-SiFA)-(D-γ-Glu)8-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) ,它们在肿瘤中的活性保持率大大提高。然而,这些基于第一代rh的胆囊收缩素-2受体(CCK-2R)配体的一个主要缺点是它们在肾脏中的活性水平升高,尤其是在较晚的时间点(24 h p.i.)。因此,本研究旨在通过不同长度((PEG)4 至 (PEG)11)的亲水性不带电荷的聚乙二醇 (PEG) 连接体取代带负电荷的 D-谷氨酸分子,从而减少肾脏对治疗用途的滞留。此外,还评估了带不同电荷的硅氟受体(SiFA)分子(p-SiFA:中性,SiFA-ipa:带负电荷,SiFAlin:带正电荷)对小胃泌素类似物体外特性的影响。在体外评估的所有化合物中,对两种最有前景的小胃泌素类似物进行了进一步的体内研究:结果:大多数被评估化合物的 CCK-2R 亲和力在 8-20 nM 之间(通过表观 IC50 值),而含有 SiFA-ipa 分子的配体显示出更高的 IC50 值。在 D-Dap(SiFA)单元旁边含有 D-γ-谷氨酸(D-γ-Glu)分子的化合物的亲油性明显低于不含额外负电荷的化合物。在本研究中,结合最有利的 CCK-2R 亲和力和亲油性,[177/natLu]Lu-DOTA-rhCCK-70(DOTA-D-Dap(p-SiFA)-D-γ-Glu-(PEG)7-D-γ-Glu-(PEG)3-Trp-(N-Me)Nle-Asp-1-Nal-NH2;IC50:12.6 ± 2.0 nM;logD7.4:- 1.67 ± 0.08)和[177/natLu]Lu-DOTA-rhCCK-91(DOTA-D-Dap(SiFAlin)-D-γ-Glu-(PEG)4-D-γ-Glu-(PEG)3-Trp-(N-Me)Nle-Asp-1-Nal-NH2;IC50:8.6 ± 0.7 nM;logD7.4 = - 1.66 ± 0.07)进行了进一步的体内评估。这两种化合物的生物分布数据显示,尽管肿瘤摄取率较低,但在24小时后,(p 177Lu]Lu-DOTA-rhCCK-18的摄取率明显降低,导致肿瘤与肾脏的比值升高。然而,新型化合物的总体肿瘤-背景比低于[177Lu]Lu-DOTA-rhCCK-18:我们可以证明,减少基于放射性杂交的小胃泌素类似物的连接部分的负电荷会降低其在肾脏中的活性水平(24 h p.i.),同时保持良好的肿瘤摄取率。因此,在体内实现了良好的肿瘤-肾脏比率。不过,还需要进一步优化,以提高肿瘤保留率和总体生物分布状况。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Significant reduction of activity retention in the kidneys via optimized linker sequences in radiohybrid-based minigastrin analogs.

Background: We recently introduced radiohybrid (rh)-based minigastrin analogs e.g., DOTA-rhCCK-18 (DOTA-D-Dap(p-SiFA)-(D-γ-Glu)8-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2), that revealed substantially increased activity retention in the tumor. However, one major drawback of these first generation rh-based cholecystokinin-2 receptor (CCK-2R) ligands is their elevated activity levels in the kidneys, especially at later time points (24 h p.i.). Therefore, this study aimed to reduce kidney retention with regard to a therapeutic use via substitution of negatively charged D-glutamic acid moieties by hydrophilic uncharged polyethylene glycol (PEG) linkers of various length ((PEG)4 to (PEG)11). Furthermore, the influence of differently charged silicon-based fluoride acceptor (SiFA)-moieties (p-SiFA: neutral, SiFA-ipa: negatively charged, and SiFAlin: positively charged) on in vitro properties of minigastrin analogs was evaluated. Out of all compounds evaluated in vitro, the two most promising minigastrin analogs were further investigated in vivo.

Results: CCK-2R affinity of most compounds evaluated was found to be in a range of 8-20 nM (by means of apparent IC50), while ligands containing a SiFA-ipa moiety displayed elevated IC50 values. Lipophilicity was noticeably lower for compounds containing a D-γ-glutamate (D-γ-Glu) moiety next to the D-Dap(SiFA) unit as compared to their counterparts lacking the additional negative charge. Within this study, combining the most favorable CCK-2R affinity and lipophilicity, [177/natLu]Lu-DOTA-rhCCK-70 (DOTA-D-Dap(p-SiFA)-D-γ-Glu-(PEG)7-D-γ-Glu-(PEG)3-Trp-(N-Me)Nle-Asp-1-Nal-NH2; IC50: 12.6 ± 2.0 nM; logD7.4: - 1.67 ± 0.08) and [177/natLu]Lu-DOTA-rhCCK-91 (DOTA-D-Dap(SiFAlin)-D-γ-Glu-(PEG)4-D-γ-Glu-(PEG)3-Trp-(N-Me)Nle-Asp-1-Nal-NH2; IC50: 8.6 ± 0.7 nM; logD7.4 =  - 1.66 ± 0.07) were further evaluated in vivo. Biodistribution data of both compounds revealed significantly reduced (p < 0.0001) activity accumulation in the kidneys compared to [177Lu]Lu-DOTA-rhCCK-18 at 24 h p.i., leading to enhanced tumor-to-kidney ratios despite lower tumor uptake. However, overall tumor-to-background ratios of the novel compounds were lower than those of [177Lu]Lu-DOTA-rhCCK-18.

Conclusion: We could show that the reduction of negative charges within the linker section of radiohybrid-based minigastrin analogs led to decreased activity levels in the kidneys at 24 h p.i., while maintaining a good tumor uptake. Thus, favorable tumor-to-kidney ratios were accomplished in vivo. However, further optimization has to be done in order to improve tumor retention and general biodistribution profile.

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来源期刊
EJNMMI Research
EJNMMI Research RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING&nb-
CiteScore
5.90
自引率
3.10%
发文量
72
审稿时长
13 weeks
期刊介绍: EJNMMI Research publishes new basic, translational and clinical research in the field of nuclear medicine and molecular imaging. Regular features include original research articles, rapid communication of preliminary data on innovative research, interesting case reports, editorials, and letters to the editor. Educational articles on basic sciences, fundamental aspects and controversy related to pre-clinical and clinical research or ethical aspects of research are also welcome. Timely reviews provide updates on current applications, issues in imaging research and translational aspects of nuclear medicine and molecular imaging technologies. The main emphasis is placed on the development of targeted imaging with radiopharmaceuticals within the broader context of molecular probes to enhance understanding and characterisation of the complex biological processes underlying disease and to develop, test and guide new treatment modalities, including radionuclide therapy.
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