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Lumazine Synthase Protein Nanoparticle-Gd(III)-DOTA Conjugate as a T1 contrast agent for high-field MRI.

ABSTRACT: With the applications of magnetic resonance imaging (MRI) at higher magnetic fields increasing, there is demand for MRI contrast agents with improved relaxivity at higher magnetic fields. Macromolecule-based contrast agents, such as protein-based ones, are known to yield significantly higher r1 relaxivity at low fields, but tend to lose this merit when used as T1 contrast agents (r1/r2 = 0.5 ~ 1), with their r1 decreasing and r2 increasing as magnetic field strength increases. Here, we developed and characterized an in vivo applicable magnetic resonance (MR) positive contrast agent by conjugating Gd(III)-chelating agent complexes to lumazine synthase isolated from Aquifex aeolicus (AaLS). The r1 relaxivity of Gd(III)-DOTA-AaLS-R108C was 16.49 mM(-1)s(-1) and its r1/r2 ratio was 0.52 at the magnetic field strength of 7 T. The results of 3D MR angiography demonstrated the feasibility of vasculature imaging within 2 h of intravenous injection of the agent and a significant reduction in T1 values were observed in the tumor region 7 h post-injection in the SCC-7 flank tumor model. Our findings suggest that Gd(III)-DOTA-AaLS-R108C could serve as a potential theranostic nanoplatform at high magnetic field strength.

SUBMITTER: Song Y

PROVIDER: S-EPMC4616051 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Lumazine Synthase Protein Nanoparticle-Gd(III)-DOTA Conjugate as a T1 contrast agent for high-field MRI.

Song YoungKyu Y Kang Young Ji YJ Jung Hoesu H Kim Hansol H Kang Sebyung S Cho HyungJoon H

Scientific reports 20151023

With the applications of magnetic resonance imaging (MRI) at higher magnetic fields increasing, there is demand for MRI contrast agents with improved relaxivity at higher magnetic fields. Macromolecule-based contrast agents, such as protein-based ones, are known to yield significantly higher r1 relaxivity at low fields, but tend to lose this merit when used as T1 contrast agents (r1/r2 = 0.5 ~ 1), with their r1 decreasing and r2 increasing as magnetic field strength increases. Here, we developed ...[more]

PMID: 26493381

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Project description:A linear polyamidoamine (PAA) named BAC-EDDS, containing metal chelating repeat units composed of two tert-amines and four carboxylic groups, has been prepared by the aza-Michael polyaddition of ethylendiaminodisuccinic (EDDS) with 2,2-bis(acrylamido)acetic acid (BAC). It was characterized by size exclusion chromatography (SEC), FTIR, UV-Vis and NMR spectroscopies. The pKa values of the ionizable groups of the repeat unit were estimated by potentiometric titration, using a purposely synthesized molecular ligand (Agly-EDDS) mimicking the structure of the BAC-EDDS repeat unit. Dynamic light scattering (DLS) and ζ-potential analyses revealed the propensity of BAC-EDDS to form stable nanoaggregates with a diameter of approximately 150 nm at pH 5 and a net negative charge at physiological pH, in line with an isoelectric point <2. BAC-EDDS stably chelated Gd (III) ions with a molar ratio of 0.5:1 Gd (III)/repeat unit. The stability constant of the molecular model Gd-Agly-EDDS (log K = 17.43) was determined as well, by simulating the potentiometric titration through the use of Hyperquad software. In order to comprehend the efficiency of Gd-BAC-EDDS in contrasting magnetic resonance images, the nuclear longitudinal (r1) and transverse (r2) relaxivities as a function of the externally applied static magnetic field were investigated and compared to the ones of commercial contrast agents. Furthermore, a model derived from the Solomon-Bloembergen-Morgan theory for the field dependence of the NMR relaxivity curves was applied and allowed us to evaluate the rotational correlation time of the complex (τ = 0.66 ns). This relatively high value is due to the dimensions of Gd-BAC-EDDS, and the associated rotational motion causes a peak in the longitudinal relaxivity at ca. 75 MHz, which is close to the frequencies used in clinics. The good performances of Gd-BAC-EDDS as a contrast agent were also confirmed through in vitro magnetic resonance imaging experiments with a 0.2 T magnetic field.

Project description:BackgroundMRI is very important for guiding the diagnosis and treatment of brachial plexus diseases. The most used type of MRI brachial plexus imaging is the 3D Short Term Inversion Recovery (STIR) sequence with contrast agent. This study aimed to investigate the effect of three contrast agents; gadobenate dimeglumine (Gd-BOPTA), gadopentetate dimeglumine (Gd-DTPA), and Gadoteric Acid Meglumine (Gd-DOTA) on brachial plexus magnetic resonance imaging (MRI).MethodsWe recruited 60 patients with suspected brachial plexus injury randomly into three groups. MRI images were obtained from each patient. Prior to scanning, the first group was injected with GD-BOPTA, the second group with Gd-DTPA, and the third with Gd-DOTA. The amount of contrast agent was 0.1 mmol/kg according to the weight of each patient, the injection rate was 1.5 mL/s, and 20 mL saline was injected at the same rate with a high-pressure injector. Immediately after the injection of contrast agent and saline, a 3D Sampling perfection with application optimized contrasts using different flip angle evolutions (SPACE) STIR sequence was used for scanning. The Signal Intensity (SI) and Standard Deviation (SD) of Maximal intensity projection (MIP) images for regions outside the anatomy (ROI background) with area of 17 mm2 on both sides of the C6 peripheral nerves (ROI nerve), and tissue adjacent to the peripheral nerves (ROI tissue) were obtained. Signal to noise ratio (SNR) and contrast to noise ratio (CNR) were then calculated.ResultsThe SNR was 40.66±25.27, 34.65±14.86, and 44.63±30.79 for Gd-BOPTA, Gd-DTPA, and Gd-DOTA, respectively and the CNR was 20.24±15.17, 16.07±7.50, and 20.84±15.53 for Gd-BOPTA, Gd-DTPA, and Gd-DOTA, respectively. In addition, there was no statistical difference in the SNR or CNR of brachial plexus nerves using the three contrast agents to enhance the 3D SPACE sequence χ2=1.877, P=0.391>0.05 and χ2=1.717, P=0.424, respectively.ConclusionsThere were no significant differences in the efficacy of three contrast agents in imaging the brachial plexus.

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Dataset Information

Lumazine Synthase Protein Nanoparticle-Gd(III)-DOTA Conjugate as a T1 contrast agent for high-field MRI.

Publications

Lumazine Synthase Protein Nanoparticle-Gd(III)-DOTA Conjugate as a T1 contrast agent for high-field MRI.

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