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3D肿瘤细胞球体是否是用于诊断放射性示踪剂体外评估的有用系统？

Are 3D Tumor Cell Spheroids a Utile System for the In Vitro Evaluation of Diagnostic Radiotracers?

作者信息

Judmann Benedikt, Keller Florian, Wängler Björn, Schirrmacher Ralf, Rudolf Rüdiger, Wängler Carmen

机构信息

Heidelberg University, Medical Faculty Mannheim, Biomedical Chemistry, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.

Medical Faculty Mannheim, Research Campus MOLIE, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.

出版信息

ACS Omega. 2024 Dec 16;9(52):51349-51362. doi: 10.1021/acsomega.4c08214. eCollection 2024 Dec 31.

DOI:10.1021/acsomega.4c08214
PMID:39758651
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11696429/
Abstract

By possibly bridging the gap between 2D cell assays and applications, tumor cell spheroid cultures offer promising avenues for advancing innovation in nuclear medicine. Regarding the evaluation of therapeutic radioligands, tumor cell spheroids have been successfully used to assess the therapeutic efficacy against human tumors. However, studies employing spheroids for testing diagnostic tracers are missing. The present work investigated the receptor interaction of a diagnostic radioligand with different tumor cell spheroids and compared the results to those received from a standard 2D cell assay to validate the usefulness of 3D cell systems for diagnostic radiotracer testing. For this purpose, a new agent-[Ga]Ga-NODAGA-PEG-c(RGDfK)-was developed. In competitive displacement assays against [I]I-echistatin in human U87MG glioblastoma cell monolayers, NODAGA-PEG-c(RGDfK) demonstrated specific binding and IC values of 3.08 ± 0.12 and 10.39 ± 0.89 μM in the absence and presence of basal membrane extract (BME), respectively. Compared to cell monolayers, the 3D cell aggregates yielded considerably higher IC values of 16.46 ± 2.88, 20.52 ± 4.41, and 18.44 ± 6.06 μM in spheroids generated without additive, collagen-1, and BME supplementation and showed considerable unspecific binding. The obtained data were contextualized by investigating differences in morphology, cell viability, and integrin content per cell of the 2D and 3D cell models as well as the influence of ECM composition. Integrin expression per cell was stable, while spheroid density and the associated radioligand uptake were varying, depending on the culture conditions. This suggests a correlation between the NODAGA-PEG-c(RGDfK)-integrin αβ-interaction and cell model compactness. Further, a considerable influence of matrix components on ligand-receptor interaction could be demonstrated. Overall, the results showed profound differences between the 2D and 3D radiotracer assays investigated, and further work is warranted to verify the expected added value of 3D tumor cell spheroids for the evaluation of diagnostic radioligands.

摘要

肿瘤细胞球体培养可能弥合二维细胞分析与应用之间的差距，为推动核医学创新提供了有前景的途径。关于治疗性放射性配体的评估，肿瘤细胞球体已成功用于评估对人类肿瘤的治疗效果。然而，缺乏使用球体测试诊断示踪剂的研究。本研究调查了一种诊断性放射性配体与不同肿瘤细胞球体的受体相互作用，并将结果与标准二维细胞分析的结果进行比较，以验证三维细胞系统在诊断放射性示踪剂测试中的实用性。为此，开发了一种新型试剂——[镓]Ga-NODAGA-PEG-c(RGDfK)。在针对人U87MG胶质母细胞瘤细胞单层中[碘]I-echistatin的竞争性置换试验中，NODAGA-PEG-c(RGDfK)在不存在和存在基底膜提取物（BME）的情况下分别表现出特异性结合，IC值分别为3.08±0.12和10.39±0.89μM。与细胞单层相比，在不添加添加剂、补充胶原蛋白-1和BME的情况下生成的球体中，三维细胞聚集体产生的IC值显著更高，分别为16.46±2.88、20.52±4.41和18.44±6.06μM，并且显示出相当大的非特异性结合。通过研究二维和三维细胞模型在形态、细胞活力和每个细胞整合素含量方面的差异以及细胞外基质组成的影响，对获得的数据进行了背景分析。每个细胞的整合素表达是稳定的，而球体密度和相关的放射性配体摄取则根据培养条件而变化。这表明NODAGA-PEG-c(RGDfK)与整合素αβ相互作用和细胞模型紧密性之间存在相关性。此外，可以证明基质成分对配体-受体相互作用有相当大的影响。总体而言，结果显示所研究的二维和三维放射性示踪剂分析之间存在深刻差异，需要进一步开展工作来验证三维肿瘤细胞球体在评估诊断放射性配体方面预期的附加值。

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