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采用正电子发射断层扫描技术研究源自不同人体细胞来源的细胞外囊泡的体内生物分布。

Investigating the In Vivo Biodistribution of Extracellular Vesicles Isolated from Various Human Cell Sources Using Positron Emission Tomography.

机构信息

Departments of Medical Physics and Radiology, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, Wisconsin 53705, United States.

Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, 1685 Highland Avenue, Madison, Wisconsin 53705, United States.

出版信息

Mol Pharm. 2024 Sep 2;21(9):4324-4335. doi: 10.1021/acs.molpharmaceut.4c00298. Epub 2024 Aug 20.

DOI:10.1021/acs.molpharmaceut.4c00298
PMID:39164886
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11891749/
Abstract

Positron emission tomography (PET) is a powerful tool for investigating the in vivo behavior of drug delivery systems. We aimed to assess the biodistribution of extracellular vesicles (EVs), nanosized vesicles secreted by cells isolated from various human cell sources using PET. EVs were isolated from mesenchymal stromal cells (MSCs) (MSC EVs), human macrophages (Mϕ EVs), and a melanoma cell line (A375 EVs) by centrifugation and were conjugated with deferoxamine for radiolabeling with Zr-89. PET using conjugated and radiolabeled EVs evaluated their in vivo biodistribution and tissue tropisms. Our study also investigated differences in mouse models, utilizing immunocompetent and immunocompromised mice and an A375 xenograft tumor model. Lastly, we investigated the impact of different labeling techniques on the observed EV biodistribution, including covalent surface modification and membrane incorporation. PET showed that all tested EVs exhibited extended in vivo circulation and generally low uptake in the liver, spleen, and lungs. However, Mϕ EVs showed high liver uptake, potentially attributable to the intrinsic tissue tropism of these EVs from the surface protein composition. MSC EV biodistribution differed between immunocompetent and immunodeficient mice, with increased spleen uptake observed in the latter. PET using A375 xenografts demonstrated efficient tumor uptake of EVs, but no preferential tissue-specific tropism of A375 EVs was found. Biodistribution differences between labeling techniques showed that surface-conjugated EVs had preferential blood circulation and low liver, spleen, and lung uptake compared to membrane integration. This study demonstrates the potential of EVs as effective drug carriers for various diseases, highlights the importance of selecting appropriate cell sources for EV-based drug delivery, and suggests that EV tropism can be harnessed to optimize therapeutic efficacy. Our findings indicate that the cellular source of EVs, labeling technique, and animal model can influence the observed biodistribution.

摘要

正电子发射断层扫描（PET）是研究药物传递系统体内行为的有力工具。我们旨在评估细胞外囊泡（EVs）的生物分布，EVs 是从小鼠骨髓间充质干细胞（MSC）、人巨噬细胞（Mϕ）和黑素瘤细胞系（A375）中分离出来的纳米级囊泡。通过离心从各种人源细胞来源中分离出 EVs，并用去铁胺进行共轭以用 Zr-89 进行放射性标记。使用共轭和放射性标记的 EVs 进行 PET 评估其体内生物分布和组织趋向性。我们的研究还调查了在免疫功能正常和免疫功能低下的小鼠模型以及 A375 异种移植肿瘤模型中存在的差异。最后，我们调查了不同标记技术对观察到的 EV 生物分布的影响，包括共价表面修饰和膜结合。PET 显示，所有测试的 EV 都表现出延长的体内循环，并且在肝脏、脾脏和肺部的摄取通常较低。然而，Mϕ EVs 表现出较高的肝脏摄取，这可能归因于这些 EVs 从表面蛋白组成上具有固有组织趋向性。MSC EV 生物分布在免疫功能正常和免疫缺陷小鼠之间存在差异，后者观察到脾脏摄取增加。使用 A375 异种移植的 PET 显示 EV 对肿瘤的摄取效率很高，但未发现 A375 EVs 具有特定的组织趋向性。标记技术之间的生物分布差异表明，与膜整合相比，表面共轭的 EVs 具有优先的血液循环和较低的肝脏、脾脏和肺部摄取。本研究证明了 EVs 作为各种疾病有效药物载体的潜力，强调了选择合适的细胞来源用于基于 EV 的药物传递的重要性，并表明 EV 趋向性可用于优化治疗效果。我们的研究结果表明，EVs 的细胞来源、标记技术和动物模型会影响观察到的生物分布。

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