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首页> 外文期刊>Biomaterials Science >Strategic reconstruction of macrophage-derived extracellular vesicles as a magnetic resonance imaging contrast agent
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Strategic reconstruction of macrophage-derived extracellular vesicles as a magnetic resonance imaging contrast agent

机译：巨噬细胞衍生细胞外囊泡的战略重建作为磁共振成像造影剂

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摘要

A contrast agent (CA) in magnetic resonance imaging (MRI) is now an essential add-on to obtain high-quality contrast-enhanced anatomical images for disease diagnosis and monitoring the treatment response. However, the rapid elimination of CAs by the immune system and excretion by the renal route has limited its application. As a result, the CA dose for effective contrast is ever-increasing, resulting in toxic side effects such as gadolinium (Gd) related nephrogenic systemic fibrosis (NSF) toxicity. Considering the widespread application of Gd-based CAs, it is now very important to revisit their formulation in order to improve their local concentration and minimize their dose while achieving clinical goals. Therefore, we have adapted a unique strategy to maximize Gd delivery to the target site using macrophage cell-derived extracellular vesicles (EVs) reconstructed with a Gd-conjugated liposomal system herein called gadolinium infused hybrid EVs (Gd-HEVs). We hypothesize that Gd-HEVs, owing to the presence of immune cell-derived EV protein cargo, can effectively disguise themselves as a biological entity, prolong the retention time for contrast enhancement, and show tumor specificity. Incorporation of Gd into nanoformulations can enhance the longitudinal relaxivity r(1) by reducing the tumbling rate of paramagnetic metal complexes. Here, Gd-HEVs showed a higher r(1) relaxivity of 9.86 mM(-1) s(-1) compared to 3.98 mM(-1) s(-1) of Magnevist (R) at an equivalent Gd concentration, when measured by clinical 3T MRI. This will allow us to reduce the clinically used Gd concentration about three-fold while maintaining contrast in the clinical window thereby supporting our hypothesis. Furthermore, Gd-HEVs showed a preferential cellular interaction and accumulation towards cancer cells compared to non-cancer cells, both in vitro and in vivo. More importantly, Gd-HEVs showed excellent contrast enhancement in the blood vasculature with a higher retention time compared to its counterpart, Magnevist (R). Our study successfully showed that the incorporation of Gd in the EV framework can help to enhance the contrast ability, and therefore it can be a platform technology for the development of safer MRI contrast agents.
机译：磁共振成像（MRI）中的造影剂（CA）现在是获得高质量对比增强解剖图像的基本加载项，用于疾病诊断和监测治疗反应。然而，肾脏途径的免疫系统和排泄的快速消除CAS并排泄有限。结果，有效对比的Ca剂量是不断增加的，导致毒副作用如钆（GD）相关的肾上纤维化（NSF）毒性。考虑到基于GD的CA的广泛应用，现在重新审视其配方非常重要，以提高其局部浓度并在实现临床目标的同时最小化它们的剂量。因此，我们已经改编了一种独特的策略，以使用与本文称为钆注入的杂交EVS（GD-HEV）重建的巨噬细胞衍生的细胞外囊泡（EVS）来最大化GD输送到靶位点。我们假设Gd-HEV由于存在免疫细胞衍生的EV蛋白质货物，可以有效地将自己伪装为生物实体，延长保留时间以进行对比增强，并显示出肿瘤特异性。将Gd掺入纳米氧化物可以通过降低顺磁金属配合物的翻滚速率来增强纵向松弛率R（1）。这里，与等效GD浓度的比较，GD-HEV显示为9.86mm（-1）S（-1）的升高（-1）（-1）的比例（-1）的饲料（-1），当时通过临床3T MRI测量。这将使我们能够将临床使用的GD浓度降低三倍，同时保持临床窗口中的对比度，从而支持我们的假设。此外，与在体外和体内的非癌细胞相比，GD-HEV显示出优先细胞相互作用和朝向癌细胞的积累。更重要的是，与其对应物，血管系统的血液脉管系统中，GD-HEV呈现出优异的对比增强，与其对应物，更高的保留时间是较高的保留时间。我们的研究成功地表明，EV框架中的GD融合可以帮助提高对比能力，因此它可以是开发更安全的MRI造影剂的平台技术。

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