一种用于乳腺癌分子成像中靶向血管内皮生长因子受体的新型DOTA肽的合成、放射性标记及生物分布研究

Synthesis, Radiolabeling, and Biodistribution Study of a Novel DOTA-Peptide for Targeting Vascular Endothelial Growth Factor Receptors in the Molecular Imaging of Breast Cancer.

作者信息

Ebrahimi Fatemeh, Zargari Nooshin Reisi, Akhlaghi Mehdi, Asghari S Mohsen, Abdi Khosrou, Balalaie Saeed, Asadi Mahboobeh, Beiki Davood

机构信息

Department of Nuclear Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran.

University Campus II, University of Guilan, Rasht 4144784475, Iran.

出版信息

Pharmaceutics. 2024 Jul 4;16(7):899. doi: 10.3390/pharmaceutics16070899.

Abstract

As angiogenesis plays a pivotal role in tumor progression and metastasis, leading to more cancer-related deaths, the angiogenic process can be considered as a target for diagnostic and therapeutic applications. The vascular endothelial growth factor receptor-1 (VEGR-1) and VEGFR-2 have high expression on breast cancer cells and contribute to angiogenesis and tumor development. Thus, early diagnosis through VEGFR-1/2 detection is an excellent strategy that can significantly increase a patient's chance of survival. In this study, the VEGFR1/2-targeting peptide VGB3 was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), using 6-aminohexanoic acid (Ahx) as a spacer to prevent steric hindrance in binding. DOTA-Ahx-VGB3 was radiolabeled with Gallium-68 (Ga) efficiently. An in vitro cell binding assay was assessed in the 4T1 cell line. The tumor-targeting potential of [Ga]Ga-DOTA-Ahx-VGB3 was conducted for 4T1 tumor-bearing mice. Consequently, high radiochemical purity [Ga]Ga-DOTA-Ahx-VGB3 (RCP = 98%) was prepared and stabilized in different buffer systems. Approximately 17% of the radiopeptide was internalized after 2 h incubation and receptor binding as characterized by the IC value being about 867 nM. The biodistribution and PET/CT studies revealed that [Ga]Ga-DOTA-Ahx-VGB3 reached the tumor site and was excreted rapidly by the renal system. These features convey [Ga]Ga-DOTA-Ahx-VGB3 as a suitable agent for the noninvasive visualization of VEGFR-1/2 expression.

摘要

由于血管生成在肿瘤进展和转移中起关键作用,导致更多与癌症相关的死亡,因此血管生成过程可被视为诊断和治疗应用的靶点。血管内皮生长因子受体-1(VEGR-1)和VEGFR-2在乳腺癌细胞上高表达,促进血管生成和肿瘤发展。因此,通过检测VEGFR-1/2进行早期诊断是一种极佳的策略,可显著提高患者的生存几率。在本研究中,将靶向VEGFR1/2的肽VGB3与1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)偶联,使用6-氨基己酸(Ahx)作为间隔物以防止结合时的空间位阻。DOTA-Ahx-VGB3用镓-68(Ga)高效标记。在4T1细胞系中评估体外细胞结合试验。对荷4T1肿瘤的小鼠进行了[Ga]Ga-DOTA-Ahx-VGB3的肿瘤靶向潜力研究。结果,制备了高放射化学纯度的[Ga]Ga-DOTA-Ahx-VGB3(RCP = 98%)并在不同缓冲系统中稳定。孵育2小时后,约17%的放射性肽被内化,受体结合的IC值约为867 nM。生物分布和PET/CT研究表明,[Ga]Ga-DOTA-Ahx-VGB3到达肿瘤部位并通过肾脏系统迅速排泄。这些特性表明[Ga]Ga-DOTA-Ahx-VGB3是一种用于VEGFR-1/2表达无创可视化的合适试剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad5/11279866/b723f2aa190e/pharmaceutics-16-00899-g001.jpg

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