Design of a nanoprobe for high field magnetic resonance imaging, dual energy X-ray computed tomography and luminescent imaging
Graphical abstract
Introduction
Bioimaging techniques including X-ray computed tomography (CT), magnetic resonance imaging (MRI) and optical imaging (OI), have been extensively employed for clinical diagnosis during the last few decades. These single imaging modalities have different capabilities and limits. CT has high penetration depth and provides excellent 3D anatomical information of dense tissues, but it fails for soft tissue discrimination. MRI is an excellent imaging technique to study soft tissues. A common limitation for clinical MRI and CT is related to their spatial resolution, which makes them not adequate for cellular imaging and molecular detail. OI and in particular photoluminescence (PL), offers high resolution for imaging at the cellular level thus providing functional information such as metabolic or biochemical processes, but suffers from limited penetration depth of light into tissues. The limitations of the three commented imaging techniques hinder the use of just one of them to diagnose difficult miscellaneous diseases while the combination of two or three of these techniques (multimodal bioimaging) can provide sufficient anatomical and functional information to meet the high demands for the accuracy at clinical diagnostics [1].
Contrast agents (CAs) are commonly used in bioimaging techniques to enhance the visibility of the target region against the surrounding. In multimodal bioimaging, a unique multimodal CA is preferred over the combination of single-mode ones to avoid the risk of toxicity and collateral effects. Lanthanide(Ln)-doped rare-earth nanoparticles (NPs) have become a fascinating area in this respect because of their interesting and tunable optical, magnetic and X-ray attenuation properties [2], [3]. Along with the large anti-Stokes shift, low background interference, and excellent photostability, Ln-doped rare earth NPs have largely demonstrated superior capabilities as PL imaging bioprobes [4]. Moreover, some lanthanides, as Gd3+, Ho3+ and Dy3+, are able to relax the water protons thus enhancing the contrast in MRI images [5]. In addition, because of the high atomic number of lanthanides, Ln-doped rare earth NPs have demonstrated their ability to attenuate X-rays more strongly than commercially available X-ray CAs [6].
A large number of matrices for Ln-doped rare-earth NPs have been reported such as fluorides [7], [8], [9], phosphates [10], oxides [11], vanadates [12], tungstates [13], and molybdates [14], but the first is by far the most commonly proposed for bioapplications. Specifically, extensive research has been carried out on multimodal Ln-doped fluoride NPs using the so-called core-shell (CS) architecture adequate for PL, MRI and CT imaging [15]. They are generally based on a luminescent core coated with a Gd3+-containing shell, which gives the NP its contrast capacity in MRI [16], [17], [18].
The rapid development of technology in the field of diagnostic medical imaging demands exogenous contrast agents that properly work in the conditions imposed by the latest equipment. For example, MRI instruments used at present in clinics range between 0.5 and 3.0 T but the current trend in MRI technology involves the application of higher magnetic fields (up to 9.4 T) to obtain better signal-to-noise ratios [19]. While Gd3+-based MRI CAs have shown their ability to relax water protons at low fields (optimum at 1 T), they show low performance at higher fields due to the long electronic relaxation times of Gd3+ ions [20]. Paramagnetic lanthanide ions, especially Dy3+ and Ho3+, with short electronic relaxation times and high magnetic moments, increase however their capacity to relax water proton with increasing the strength of the external magnetic field [21]. In fact, several Dy3+ and Ho3+ containing fluoride NPs have already been reported in the literature as single-mode CAs for high field MRI [22], [23], [24], [25] and as bimodal (PL/high filed MRI) bioprobes [26], [27], [28], [29]. The literature is, however, very scarce on Ln-based fluoride bioprobes that have proved good performance as trimodal PL/high filed MRI/CT CAs [30], [31].
On the other hand, great efforts have also been done in the last years to improve the contrast efficacy and imaging performance of CT scanners. Tungsten is used as the X-ray tube target material in CT medical equipment which is classically operated at 140 kVp. A current trend in CT is the use of dual-energy CT, which uses two beams, at a lower and higher tube voltage (typically at 80 and 150 kV), to scan the subject. Both beams are differently absorbed by the different human tissues and those differences are the basis for which dual-energy CT identifies, enhances, or subtracts signals corresponding to different tissue types [32]. Therefore, using a single CT CA having high contrast efficacy at different operating voltages would be very beneficial for both patients and doctors. To the best of our knowledge, only one study has been carried out in this respect using Ln NPs, which demonstrates the efficacy of BaYbF5 NPs as CT CAs at both high and low voltage, due to the different K-edge values of Ba and Yb [33].
In the present study we have designed and synthesized, for first time, a multimodal nanoprobe for luminescent imaging, high field MRI and dual-energy CT. The nanoprobe is based on uniform core-shell Eu3+:(Ba0.3Lu0.7)F2.7@(Ba0.3Lu0.7)F2.7@HoF3 NPs. Our design strategy involved selecting Ba and Lu as the two main X-ray absorbers that, due to their different K-edge values (37.4 keV and 63.3 keV, respectively), are able to efficiently absorb X-rays of different energies generated at two different tube voltages, thus allowing dual-energy CT contrast. Eu3+-doping was used as a proof of concept to demonstrate the photoluminescent capability of the nanoprobe. The intermediate (Ba0.3Lu0.7)F2.7 shell was necessary to avoid the known cross-relaxation effect between Ho3+ and Eu3+ [34]. Finally, the NPs were conferred with MRI contrast capacity by adding an external HoF3 shell, which is expected to produce high contrast under a high magnetic field. To the best of our knowledge, this is the first report concerning with the development of a trimodal nanoprobe for luminescent imaging, dual energy CT and high field MRI.
Section snippets
Materials
Reagents used in the present study were: Barium nitrate (Ba(NO3)2, ≥99%), lutetium acetate hydrate (Lu(OAc)3, (CH3CO2)3 Lu·xH2O, 99.9%), europium nitrate hydrate (Eu(NO3)3·5H2O, 99.9%), holmium nitrate hydrate (Ho(NO3)3·5H2O, 99.9%), 1-butyl-2-methylimidazolium tetrafluoroborate ([BMIM]BF4, C8H15BF4N ≥ 97%), ethylene glycol (EG, C2H6O2, 99.5%) and Iohexol (≥95%). All of them were purchased from Sigma Aldrich.
Synthesis of core NPs (Eu3+:Ba0.3Lu0.7F2.7).
Synthesis of core-shell NPs was carried out using the seed-mediated heat-up method [15]
Results and discussion
The core-shell Eu3+:Ba0.3Lu0.7F2.7@Ba0.3Lu0.7F2.7@HoF3 NPs (CS NPs) were synthesized following the preparation process schematized in Fig. 1 and described in the experimental section. The synthesis of the CS NPs was carried out using the seed-mediated heat-up method, where the core of the CS NP must exist first and is utilized as seed nuclei for the growth of the outer shell layers.15
Conclusions
In summary, we developed a multimodal 80 nm sized nanoplatform composed of a Eu3+:Ba0.3Lu0.7F2.7 core and an outer HoF3 shell, separated by a Ba0.3Lu0.7F2.7 to prevent any Ho3+-Eu3+ cross relaxation. The core-shell NPs exhibit intense orange red photoluminescence during UV excitation. The outer shell conferred the NPs with a high transversal relaxivity value (r2 = 237 mM−1s−1) at 9.4 T, the highest reported for core-shell NPs at this field strength [28], [30]. The presence of Ba and Lu, with
CRediT authorship contribution statement
Daniel González Mancebo: Investigation. Ana Isabel Becerro: Methodology, Formal analysis, Writing - original draft, Writing - review & editing. Ariadna Corral: Investigation. Sonia García-Embid: Investigation. Marcin Balcerzyk: Validation. Maria Luisa García: Validation, Formal analysis. Jesús M. de la Fuente: Validation, Formal analysis. Manuel Ocaña: Conceptualization, Supervision, Writing - review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This research was funded by the Spanish Ministry of Science, Innovation, and Universities (RTI2018-094426-B-I00). Siemens Healthcare S.L.U. also supported part of the research. We also acknowledge the use of the CNA’s ICTS NanoCT facilities and support from DGA and Fondos Feder for funding Bionanosurf (E15_17R) research group. S. Garcia-Embid acknowledges the Ministerio de Educación, Cultura y Deportes of Spanish Government for a FPU grant (FPU15/04482).
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