Water-Mediated Nanostructures for Enhanced MRI: Impact of Water Dynamics on Relaxometric Properties of Gd-DTPA (original) (raw)
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Polymer cross-linking a nanogel approach to enhancing the relaxivity of MRI contrast agents
Polymer cross-linking was explored as an approach for increasing the relaxivity of macromolecular contrast agents for magnetic resonance imaging. Poly(ethylene glycol) methyl ether methacrylate, N-(2-aminoethyl) methacrylamide hydrochloride, and the cross-linker ethylene glycol dimethacrylate were copolymerized under free radical conditions. By tuning the cross-linker content and reaction concentration, it was possible to obtain 10 nm nanogels in a single synthetic step. The pendant amine moieties were functionalized with an isothiocyanate derivative of diethylenetriaminepentaacetic acid (DTPA) and Gd(III) was chelated. In comparison with a linear control polymer prepared under the same conditions in the absence of the cross-linking agent, the nanogel contrast agent did exhibit enhanced relaxivity with an r 1 of 20.8 AE 0.2 at 20 MHz and 17.5 AE 0.4 at 60 MHz (corresponding to the clinical field strength of 1.5 T).
Impact of biopolymer matrices on relaxometric properties of contrast agents
Interface Focus, 2016
Properties of water molecules at the interface between contrast agents (CAs) for magnetic resonance imaging and macromolecules could have a valuable impact on the effectiveness of metal chelates. Recent studies, indeed, demonstrated that polymer architectures could influence CAs' relaxivity by modifying the correlation times of the metal chelate. However, an understanding of the physico-chemical properties of polymer/CA systems is necessary to improve the efficiency of clinically used CAs, still exhibiting low relaxivity. In this context, we investigate the impact of hyaluronic acid (HA) hydrogels on the relaxometric properties of Gd-DTPA, a clinically used CA, to understand better the determining role of the water, which is crucial for both the relaxation enhancement and the polymer conformation. To this aim, water self-diffusion coefficients, thermodynamic interactions and relaxometric properties of HA/Gd-DTPA solutions are studied through time-domain NMR relaxometry and isoth...
Polymer Chemistry, 2014
In this work, we studied the influence of the structure of macromolecular ligands on the relaxivity of gadolinium contrast agents constructed as nanoparticle systems. Macromolecular ligands were assembled as single-molecule nanoparticles in the form of either discrete core cross-linked star polymers or hyperbranched polymers. 1-(5-Amino-3-aza-2-oxypentyl)-4,7,10-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraaza-cyclododecane (DO3A-tBu-NH 2) chelate was incorporated into different parts (arms, cores, and end-groups) of the polymeric structures using activated ester/amine nucleophilic substitutions, deprotected and complexed with Gd 3+. The relaxivity properties of the ligated Gd 3+ agents were then studied to evaluate the effect of macromolecular architecture and Gd 3+ placement on their behavior as discrete nanoparticle magnetic resonance imaging (MRI) contrast agents. The precise placement of Gd 3+ in the polymeric structures (and therefore in the nanoparticles) proved to be critical in optimizing the performance of the nanoparticles as MRI contrast agents. The relaxivity was measured to vary from 11 to 22 mM À1 s À1 , 2-5 times higher than that of a commercial DOTA-Gd contrast agent when using a magnetic field strength of 0.47 T. The relaxivity of these nanoparticles was examined at different magnetic fields from 0.47 T to 9.4 T. Finally, the residence time of the coordinated water (s M) and the rotational correlation time of the final molecule (s R) were evaluated for these different nanostructures and correlated with the polymeric architecture.
Journal of Nanoscience and Nanotechnology, 2006
In this article, we use a nanotemplate engineering approach to prepare biodegradable nanoparticles composed of FDA-approved materials and possessing accessible gadolinium (Gd) atoms and demonstrate their potential as a Magnetic Resonance Imaging (MRI) contrast agent. Nanoparticles containing dimyristoyl phosphoethanolamine diethylene triamine penta acetate (PE-DTPA) were prepared using 3.5 mg of Brij 78, 2.0 mg of emulsifying wax and 0.5 mg of PE-DTPA/ml from a microemulsion precursor. After the addition of GdCl 3 , the presence of Gd on the surface of nanoparticles was characterized using inductively coupled plasma atomic emission spectroscopy and Scanning Transmission Electron Microscopy (STEM). The in vitro relaxivities of the PE-DTPA-Gd nanoparticles in different media were assessed at different field strengths. The conditional stability constant of Gd binding to the nanoparticles was determined using competitive spectrophotometric titration. Transmetallation kinetics of the gadolinium ion from PE-DTPA-Gd nanoparticles with zinc as the competing ionic was measured using the relaxivity evolution method. Nanoparticles with a diameter of ∼130 nm possessing surface chelating functions were made from GRAS (Generally Regarded As Safe) materials. STEM demonstrated the uniform distribution of Gd 3+ on the surface of the nanoparticles. The thermodynamic binding constant for Gd 3+ to the nanoparticles was ∼10 18 M −1 and transmetallation studies with Zn 2+ yielded kinetic constants K 1 and K −1 of 0.033 and 0.022 1/h, respectively, with an equilibrium constant of 1.5. A payload of ∼10 5 Gd/nanoparticle was achieved; enhanced relaxivities were observed, including a pH dependence of the transverse relaxivity (r 2). Nanoparticles composed of materials that have been demonstrated to be hemocompatible and enzymatically metabolized and possessing accessible Gd ions on their surface induce relaxivities in the bulk water signal that make them potentially useful as next-generation MRI tumor contrast enhancement agents.
Magnetic Resonance in Medicine, 2011
Here we show a study of the efficiency as Contras Agents (CA) for Magnetic Resonance Imaging (MRI) of a series of maghemite/polymer composite ferrofluids with different particle size. The ferrofluids are made of biocompatible components, contain anchoring groups for biofunctionalization, can incorporate fluorescent dyes, and have shown low cellular toxicity in previous studies. The maghemite particle sizes ranks between 7.4 and 15 nm while the range of hydrodynamic sizes is 59-93 nm. The magnetic properties of the samples have been determined by means of magnetization and ac susceptibility measurements as a function of temperature and frequency. To cover most of the working frequencies in clinical NMR Imagers we have performed 1 H nuclear magnetic resonance (NMR) experiments in the frequency range 10KHz ≤ ν ≤ 200MHz for T 1 and 4MHz ≤ ν ≤ 80MHz for T 2. It is found that both r 1 and r 2 (in mM Fe-1 s-1) strongly increases with the particle size. This behaviour is mostly due to an increase of the magnetic moment μ SP of the nanoparticles with size, being well described by the model of proton relaxation induced by superparamagnetic nanoparticles proposed by A. Roch and R.N. Muller, where the low frequency r 1 and r 2 values are essentially proportional to μ SP 2 •N SP /R (where N SP the nanoparticles density and R is the nanoparticles radius). A change in the relative contribution of magnetic anisotropy and water diffusion on the longitudinal relaxation was found for particle sizes over 8 nm. The NMR-dispersion (NMRD) profile shows that r 2 values for samples with sizes > 10 nm are comparable with or better than the ones of commercial samples, the best results obtained in particles with bigger magnetic cores (isn't it the ratio r2/r1 what matters?). These results are corroborated by MRI experiments at ν=8.5MHz, thus suggesting our samples as novel negative MRI contrast agents.
Scientific Reports, 2016
Recent advancements in imaging diagnostics have focused on the use of nanostructures that entrap Magnetic Resonance Imaging (MRI) Contrast Agents (CAs), without the need to chemically modify the clinically approved compounds. Nevertheless, the exploitation of microfluidic platforms for their controlled and continuous production is still missing. Here, a microfluidic platform is used to synthesize crosslinked Hyaluronic Acid NanoParticles (cHANPs) in which a clinically relevant MRI-CAs, gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA), is entrapped. This microfluidic process facilitates a high degree of control over particle synthesis, enabling the production of monodisperse particles as small as 35 nm. Furthermore, the interference of Gd-DTPA during polymer precipitation is overcome by finely tuning process parameters and leveraging the use of hydrophilic-lipophilic balance (HLB) of surfactants and pH conditions. For both production strategies proposed to design Gd-loaded cHANPs, a boosting of the relaxation rate T 1 is observed since a T 1 of 1562 is achieved with a 10 μM of Gd-loaded cHANPs while a similar value is reached with 100 μM of the relevant clinical Gd-DTPA in solution. The advanced microfluidic platform to synthesize intravascularly-injectable and completely biocompatible hydrogel nanoparticles entrapping clinically approved CAs enables the implementation of straightforward and scalable strategies in diagnostics and therapy applications. The Magnetic Resonance Imaging (MRI) represents the first-line diagnostic imaging modality for numerous indications. It is a clinically well-established, non-invasive technique that leverages the magnetic properties of water protons present in the body to produce three-dimensional whole body anatomical and functional images 1,2. High magnetic fields (1.5 T and above) are clinically favoured because of their higher signal-to-noise ratio, capability for MR spectroscopy 3 and other forms of functional MRI, such as high-speed imaging and high-resolution imaging. MRI signal intensity is related to the relaxation rate of in vivo water protons and can be enhanced by the administration of a contrast agent (CA) prior to scanning. These CAs utilize paramagnetic metal ions to enhance the contrast in an MR image by positively influencing the relaxation rates of water protons in the immediate surroundings of the tissue in which they localize. The ability of CAs to effectively enhance image contrast depends on their relaxivity (longitudinal r 1 ; transversal r 2) and the level of accumulation at the target site 4. Among different CAs, Gadolinium-based ones, used in up to 30% of clinical MRI scans 5 , consist of polyamino carboxylate complexes of Gd ions, where Gd ions cytotoxicity is sequestered via chelation with ligands such as diethylenetriaminepentaacetic acid (DTPA) and tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) 6-8. However, despite its certain role, Gadolinium-based CAs, like most of other clinically relevant CAs, suffer from poor sensitivity 6 and rapid renal clearance, requiring long scan times, thus severely limiting the time window for MRI. In addition, they present low tissue specificity, leading to concerns in linking the use of these CAs with nephrogenic systemic fibrosis (NSF) 9 and progressive accumulation in various central nervous system (CNS) structures following repeated gadolinium administration 10 .
Mémoire ocompatible nanoparticles and gadolinium complexes for MRI plications
2013
Performances of double-emulsion techniques (W/O/W and W/O/O) and ionotropic gelation process were compared to achieve encapsulation of gadolinium MRI contrast agents (GdCAs) into biocompatible polymeric nanoparticles (NPs) with high Gd-loadings. The better approach proved to be ionotropic gelation with H[Gd(DOTA)] as GdCA. Relaxometry evaluation of H[Gd(DOTA)] NPs efficiency demonstrated that incorporation of H[Gd(DOTA)] inside an hydrogel matrix highly improved H[Gd(DOTA)] relaxivity. Particle efficacy as MR contrast agents was further demonstrated on a 3 T clinical imager: a significant improvement of T1and T2MR signals was obtained at doses much lower than the currently used. 2012 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Nano Letters, 2016
4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid, N-(2-hydroxyethyl)piperazine-N′-(2ethanesulfonic acid)) were purchased from Sigma Aldrich Co., Ltd. at highest purity available and used as received. PEO 6k-b-PAA 3k was purchased from Polymer Source TM and used as received. Other polymers (PAA, PEO) were obtained from Sigma Aldrich Co., Ltd. Water was purified through a filter and ion exchange resin using a Purite device (resistivity 18.2 MΩ•cm). Characterization Fluorescence measurements were performed on a PTI® (Photon Technology International) apparatus with a xenon lamp EIMAC of 175 W (slits at 4 nm, integration time of 0.5 s, steps of 1 nm). Dynamic light scattering (DLS) measurements were conducted using a Zetasizer Nano-ZS (Malvern Instruments, Ltd, UK) with integrated 4 mW He-Ne laser, λ = 633 nm. Light scattering intensity (at 173°) was measured with instrumental parameters set to constant values for all the samples. The correlation function was analyzed via the cumulant method to get the Z-average size of the colloids and by the general purpose method (NNLS) to obtain the distribution of diffusion coefficients of the