Elsevier

Magnetic Resonance Imaging

Volume 49, June 2018, Pages 16-24
Magnetic Resonance Imaging

Original contribution
A new class of cubic SPIONs as a dual-mode T1 and T2 contrast agent for MRI

https://doi.org/10.1016/j.mri.2017.09.013Get rights and content

Highlights

  • 11 nm cubic SPIONs simultaneously enhanced both positive and negative contrast in MR images.

  • Various SPIONs in defined crystallinity and size were synthesized to study the magnetic characteristics of the particles.

  • Complementary T1- and T2-weighted in vivo MRI experiments obtained using 11 nm cubic SPIONs contrast agent.

Abstract

Superparamagnetic iron oxide nanoparticles (SPIONs) are widely used as a robust negative contrast agent on conventional MRI. In this study, we (a) synthesized a new class of cubic SPIONs as a dual-mode contrast agent in MRI and (b) showed the in-vivo feasibility of these nanaoparticles as a simultaneous positive and negative contrast agent. Relaxation properties and contrast enhancement analysis of the synthesized SPIONs with two different shapes (cubic vs. spherical) and three different sizes 7 nm, 11 nm, and 14 nm were investigated to evaluate contrast enhancement in-vitro. In-vivo MRI experiments were performed on a 3T MR scanner, where a healthy anesthetized rat was imaged before, and from 20 to 80 min after intravenous injection of 1 mg/kg of contrast agent. Representative transmission electron microscopy (TEM) images of the synthesized nanoparticles reveal that the particles are well dispersed in a solvent and do not aggregate. The in-vitro relaxivity and contrast enhancement analysis show that, among all six SPIONs tested, 11-nm cubic SPIONs possess optimal molar relaxivities and contrast enhancement values, which can shorten the spin-lattice and spin-spin relaxation times, simultaneously. No noticeable toxicity is observed during in-vitro cytotoxicity analysis. In-vivo T1-and T2-weighted acquisitions at 60-min post-injection of 11-nm cubic SPIONs result in 64% and 48% contrast enhancement on the T1-and T2-weighted images, respectively. By controlling the shape and size of SPIONs, we have introduced a new class of cubic SPIONs as a synergistic (dual-mode) MRI contrast agent. 11-nm cubic SPIONs with smaller size and high positive and negative contrast enhancements were selected as a promising candidate for dual-mode contrast agent. Our proof-of-concept MRI experiments on rat demonstrate the in-vivo dual-mode contrast enhancement feasibility of these nanoparticles.

Graphical abstract

In this study, we synthesized a new class of cubic SPIONs as a dual-mode contrast agent in MRI. In vivo MRI experiments were performed on a 3T MR scanner, where healthy anesthetized rat was imaged before, and after intravenous injection of contrast agent. By controlling the shape and size of SPIONs, we have introduced a new class of cubic SPIONs as a synergistic MRI contrast agent. 11-nm cubic SPIONs were selected as a promising candidate for dual-mode contrast agent.

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Introduction

Superior soft tissue contrast is a major advantage of magnetic resonance imaging (MRI) over alternative medical imaging modalities such as computed tomography (CT) and X-ray [1], [2]. The difference of spin-lattice (T1) and spin-spin (T2) relaxation times among tissues, is the origin of the unique soft tissue contrast in MRI. However, in some applications, difference in relaxation parameters may be insufficient to provide reliable discrimination of tissue structure. In these instances, the use of contrast agents that alter relaxivity can significantly enhance the contrast between target tissues and the background. These contrast agents are usually in the form of T1 or T2 contrast agents [3], [4], [5], [6]. T1 agents are commonly paramagnetic materials that increase longitudinal relaxivity and thereby yield higher signal levels [7], [8]. While superparamagnetic iron oxide nanoparticles (SPIONs) with ultrasmall size (e.g., around 36 nm diameter) can also be used as T1 contrast agents, currently the Gadolinium species with seven unpaired electrons are the dominant positive contrast agent used in clinical applications [9], [10]. On the other hand, T2 agents are typically SPIONs that induce magnetic field perturbations and increase transverse relaxivity, which in turn reduces signal levels [11], [12], [13]. However, the difficulty in distinguishing a region of weak signal due to SPIONs from regions that suffer from other sources of signal loss (e.g., susceptibility differences among tissues, B0 field inhomogeneity) is a drawback of T2 contrast agents [14], [15], [16]. One solution to this problem is to utilize SPIONs as dual-modal contrast agents. In MRI, T1-weighted images typically provide better spatial resolution, while T2-weighted images can provide enhanced detection of lesions [17]. Hence, a synergistic combination of T1- and T2-contrast-enhanced imaging can potentially provide more comprehensive imaging information and lead to higher diagnostic accuracy [18].

To date, numerous studies have considered developing methods for synthesizing simultaneous T1 and T2 contrast agents. For this purpose, hybrid nanoparticles have recently been developed, where the Gadolinium species integrated with iron oxide nanoparticles in a core-shell format systematically demonstrated the feasibility of such hybrid probes [19]. In another study, Mn-Fe heterodoped ZnSe tetrapod nanocrystals were proposed to simultaneously enhance contrast in both T1- and T2-weighted MRI [20]. However, the use of hybrid materials as in these two examples may cause magnetic interactions of nanoparticles, which in turn result in the perturbation of the relaxation process [21]. An alternative method for achieving dual-mode contrast agent is to utilize a single material for enabling multiple contrasts. For example, Jung et al. generated both negative and positive image contrasts by manipulating the pulse sequences together with the use of size-controlled SPIONs [22]. In another study, T1-weighted positive contrast obtained from SPIONs using ultrashort-echo-time was reported by Kwon et al. [23]. In the clinic, Ferumoxytol (an ultrasmall SPION) can be utilized to obtain regional T1 and T2 signal enhancement or loss with conventional pulse sequences [24]. However, SPION's performance as MRI contrast agents strongly depends on their size and shape. Hence, as dual-mode contrast agents are gaining interest, there is a strong need to investigate both features to reach a high performance synergistic contrast agent.

In this study, by taking advantage of the strong shape and size dependence of SPION's performance, we synthesized a new class of cubic SPIONs as a synergistic T1- and T2-contrast-enhancement agent for MRI. We compared the performance of these cubic SPIONs with their spherical counterparts via measurements of molar relaxivities (r1 and r2) on a 3T MRI scanner. Here, we used silica for surface modification, since previous reports showed negligible toxicity level for nano-sized silica shells. As a feasibility study, both positive and negative contrast effects of 11-nm cubic SPIONs were demonstrated in-vivo on T1- and T2-weighted spin-echo MRI images obtained before and after intravenous injection of 1 mg/kg contrast agent trough the tail vein of a Sprague-Dawley rat.

Section snippets

Theory

The magnetic properties of SPIONs are affected by their crystallinity and size, which in turn significantly affects the MR relaxivity properties of the SPIONs. Accordingly, as the particle size increases the corresponding saturation magnetization increases, enhancing the T2 (transverse) relaxation of the surrounding tissue. On the other hand, as the particle size decreases, both the surface-to-volume ratio and the percentage of unpaired electrons on the particle surface increases. The

Synthesis of silica-coated SPION and characterization

Spherical and cubic SPIONs with the size of 7 nm, 11 nm, and 14 nm were synthesized using the thermal decomposition method. TEM was utilized for the morphological and structural characterizations of iron oxide nanocrystals. Representative TEM images and a comparison of core sizes of the synthesized SPIONs reveal that the particles are monodisperse, well separated in a solvent, and do not aggregate. An example TEM image corresponding to the 11-nm cubic SPIONs is shown in Fig. 1a. DLS measurements

Discussion

The need for a synergistic positive and negative contrast enhancing and safe MRI contrast agent that can be utilized in clinical diagnosis has attracted the interest of many research groups [18], [19]. The combination of both T1-contrast-enhanced image with high spatial resolution and T2-contrast-enhanced image with increased lesion detection capability allows complementary anatomic and pathologic information [20]. In this study, by controlling the shape and size of the SPIONs, we targeted a

Conclusion

In this study, by controlling the shape and size of SPIONs, we have synthesized a new class of synergistic (dual-mode) MRI contrast agent. The in-vitro contrast enhancement analysis showed that the synthesized 11-nm cubic SPIONs with small size have high dual-contrast effect, suitable for use during in-vivo imaging. Results of the toxicity analysis showed that the antagonistic effects of the 11-nm cubic SPIONs on the L929 line cell were very low even at high concentrations of the contrast

Acknowledgment

We gratefully acknowledge Dr. Gamze Aykut, Department of Molecular Biology and Genetics, Bilkent University, Ankara, Taner Demir and Dr. Volkan Acikel, Bilkent University, Ankara, for their assistance in in-vivo experiments, and all UMRAM staff for providing technical support. The authors also gratefully thank scientific discussion of Dr. Tolga Cukur. We would like to acknowledge Biomaten (METU) for the cytotoxicity experiments.

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