Hydrogels Incorporating GdDOTA: Towards Highly Efficient Dual T1/T2 MRI Contrast Agents
Hydrogels Incorporating GdDOTA: Towards Highly Efficient Dual T1/T2 MRI Contrast Agents
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DOI：
10.1002/anie.201203190
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发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Chuburu, Francoise
中科院分区：
文献类型：
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作者：
Courant, Thomas;Roullin, Valerie Gaelle;Chuburu, Francoise
由于其亚毫米空间分辨率，检查的非侵入性性质，以及没有电离辐射，磁共振成像（MRI）是一种重要的诊断成像工具。然而，该技术的检测灵敏度较低。为了改善这方面，通常在检查前给予毫摩尔浓度的顺磁性造影剂（CA），以增强图像对比度，从而突出病变区域。最常用的CA是钆络合物（GdCA）。[1，2] GdCA不直接提供信号，但它们缩短组织中水质子的T1和/或T2弛豫时间。[1]它们的效率是根据弛豫率r1来测量的，弛豫率r1被定义为每毫摩尔金属离子的水质子的弛豫速率增强。直到最近，所有GdCA都被认为是安全的;不幸的是，已经证明其中一些可能会引发肾衰竭患者发生肾源性系统性纤维化（NSF）。[3]因此，需要改进以增加已知的低风险GdCA的弛豫性以减少注射剂量。SBM理论的解释[4]给出了一些关于如何放大r1的指导。对于0.5-1.5 T的应用，高弛豫率可以通过高有效载荷的活性磁中心，通过控制GdCA的翻滚运动，并通过确保最佳的水在钆配位球的驻留时间来实现。[5]在这一具有挑战性的领域，最近的进展已经取得了整合的钆螯合物到纳米粒子。为此，已经开发了许多纳米颗粒（改性天然纳米颗粒，[6]脂质体纳米颗粒，[6]胶束，[6]金属有机框架，[7]富勒烯，[8]无机纳米颗粒[9]），但很少获得预测的高弛豫率（约为100 mm 3/s）。[9 c-e]在这方面，我们在此的目标是开发用于MRI应用的高弛豫率钆纳米颗粒的新的和直接的合成，同时具有优化的纳米颗粒生产特性、钆负载和弛豫率。考虑到NSF疾病的风险，我们选择封装一种众所周知的低风险CA，[GdDOTA] β（DOTA= 1，4，7，10-四氮杂环十二烷-1，4，7，10-四乙酸; DOTAREM的GdCA）。由于其亲水性，在亲水性聚合物基质中进行[GdDOTA]-N的包封。出于生物相容性原因，选择壳聚糖（CH）[10]和透明质酸（HA）[11]作为聚合物基质。CH是一种带正电荷的生物相容性多糖，由N-乙酰葡糖胺和葡糖胺残基组成。HA是一种天然、无毒、带负电荷的聚合物，由葡萄糖醛酸和N-乙酰葡糖胺残基组成。本文
Because of its sub-millimeter spatial resolution, the noninvasive nature of the examinations, and the absence of ionizing radiation, magnetic resonance imaging (MRI) is an important diagnostic imaging tool. However, this technique suffers from low detection sensitivity. To improve this aspect, millimolar concentrations of paramagnetic contrast agents (CAs) are often administered prior to examination, to enhance the image contrast and thus, to highlight pathological areas. The most commonly used CAs are gadolinium complexes (GdCAs).[1, 2] GdCAs do not directly provide a signal, but they shorten the T1 and/or T2 relaxation times of water protons in the tissues.[1] Their efficiency is measured in terms of relaxivity r1, which is defined as the relaxation rate enhancement of the water proton per millimolar metal ion. Until recently, all GdCAs were considered safe; unfortunately, it has been demonstrated that some of them may trigger the development of nephrogenic systemic fibrosis (NSF) in patients with renal failure.[3] Improvement is therefore needed to increase the relaxivity of known, low-risk GdCAs to decrease the injected doses. The interpretation of SBM theory [4] gives some guidelines on how to amplify r1. For applications at 0.5–1.5 T, high relaxivity can be achieved by high payload of active magnetic centers, by controlling the tumbling motion of the GdCAs, and by ensuring optimal water residency times in the gadolinium coordination sphere.[5] In this challenging area, recent progress has been achieved with the integration of gadolinium chelates into nanoparticles. For this purpose, many nanoparticles have been developed (modified natural nanoparticles,[6] liposomal nanoparticles,[6] micelles,[6] metal–organic frameworks,[7] fullerenes,[8] inorganic nanoparticles [9]) but the predicted high relaxivities (on the order of 100 mmÀ1 sÀ1) have rarely been obtained.[9c–e]In this respect, our goal herein was to develop a new and straightforward synthesis of high-relaxivity gadolinium nanoparticles for MRI applications, with optimized nanoparticle production characteristics, gadolinium loading, and relaxivity at the same time. To take the risk of NSF disease into account, we choose to encapsulate a well-known, low-risk CA,[GdDOTA] À(DOTA= 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid; the GdCA of DOTAREM). Because of its hydrophilic nature, the encapsulation of [GdDOTA] À was made in a hydrophilic polymer matrix. For biocompatibility reasons, chitosan (CH)[10] and hyaluronic acid (HA)[11] were chosen for the polymer matrix. CH is a positively charged, biocompatible polysaccharide composed of N-acetylglucosamine and glucosamine residues. HA is a natural, non-toxic, negatively charged polymer composed of glucuronic acid and N-acetylglucosamine residues. Herein, the