Hydrogels Incorporating GdDOTA: Towards Highly Efficient Dual T₁/T₂ MRI Contrast Agents

Abstract

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 T 1 and/or T 2 relaxation times of water protons in the tissues. [1] Their efficiency is measured in terms of relaxivity r 1 , 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 r 1 . 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 mm À1 s À1 ) 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

High Relaxivity Gd(III)–DNA Gold Nanostars: Investigation of Shape Effects on Proton Relaxation

“…Many recent examples of nanoconjugate CAs appear to support this hypothesis, though in many cases we find that it is not described explicitly. 15,19,48,49 …”

“…In particular, for CAs that bear extended hydrophilic polymer or protein surfaces, the chemical environment surrounding the lanthanide center is believed to slow water diffusion in the second-sphere of the Gd(III) complexes. 15,19,37,48,49 The result of this hydrogen-bonding-rich environment is that each metal center has incrementally longer contact with second-sphere water molecules. In extensive work to study the effects of second-sphere relaxivity ( r 1 SS ), chelates of Gd(III) were synthesized using pendant phosphate groups.…”

“…36 Although second- and outer-sphere contributions to relaxivity are generally considered insignificant due to the high rate of water diffusion past the Gd(III), this phenomenon is sometimes cited to explain unexpectedly high values of r 1 in nanoconjugate systems. 6,19,30,37,38 …”

Dual-Enzyme-Loaded Multifunctional Hybrid Nanogel System for Pathological Responsive Ultrasound Imaging andT2-Weighted Magnetic Resonance Imaging

“…[28][29][30][31] The immobilization (encapsulation) of enzymes within the gel matrix provides protection from structural alterations and subsequent deactivation of the enzymes, ensuring higher loadings and better substrate mobility for efficient catalysis. [32][33][34] In addition, 6 the unique hydrophilic environment and water-rich structure of this nanogel make it an ideal probe for MR imaging, [35][36][37] where the signal detected is directly related to relaxation time. 38 In this work, focused on exploiting the structure-function relationships of hydrogel, the dual-enzyme loaded multifunctional magnetic nanogel can be developed to be an efficient and safe probe for dual-modality pathological responsive US and T 2 -weighted MR imaging.…”

Iron oxide/manganese oxide co-loaded hybrid nanogels as pH-responsive magnetic resonance contrast agents

“…Compared to macro-hydrogels [22e24], the "killer application" of nanogels has not emerged yet [25]. In the field of MRI, this specific nanogel structure facilitates a perfect interaction of functional species with proximal water molecules that strongly contribute to the T 1 or T 2 contrast effect of MRI [26]. Concurrently, sufficient water exchange between T 1 and T 2 contrast agents will, in turn, strongly perturb the relaxation process between them.…”