Core–shell Fe₃O₄@NaLuF₄:Yb,Er/Tm nanostructure for MRI, CT and upconversion luminescence tri-modality imaging

Abstract

Core–shell Fe₃O₄@NaLuF₄:Yb,Er/Tm nanostructure (MUCNP) with multifunctional properties has been developed using a step-wise synthetic method. The successful fabrication of MUCNP has been confirmed by transmission electron microscopy, powder X-ray diffraction, energy-dispersive X-ray analysis and X-ray photoelectron spectroscopy. The MUCNP exhibits superparamagnetic property with saturation magnetization of 15 emu g⁻¹, and T₂-enhanced magnetic resonance (MR) effect with an r₂ value of 21.63 s⁻¹ mM⁻¹ at 0.5 T, resulting from the Fe₃O₄ cores. Moreover, the NaLuF₄-based MUCNP provides excellent X-ray attenuation and upconversion luminescence (UCL) emission under excitation at 980 nm. In vivo MR, computed tomography (CT) and UCL images of tumor-bearing mice show that the MUCNP can be successfully used in multimodal imaging. In vitro tests reveal that the MUCNP is non-cytotoxic. These results suggest that the developed MUCNP could be served as an MR, CT and UCL probe for tri-modality imaging.

Introduction

Recent years have witnessed the rapid pace of research and development of rare earth upconversion nanophosphors (RE-UCNPs) as potential bioimaging agents because of their distinct optical and chemical properties, such as sharp emission lines, long lifetimes, superior photostability and non-photoblinking [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33]. The upconversion luminescence (UCL) process involves the conversion of low-energy light in the near-infrared (NIR) region to higher energy visible light through multiple photon absorption or energy transfer [1], [2], [3], [4], [5], [6], [7], [8]. This special photoluminescence mechanism excludes both conventional luminescent materials (such as QDs and organic dyes) and endogenous fluorescent substances. As a result, RE-UCNPs for photoluminescence bioimaging exhibit many advantages, such as the use of non-invasive NIR radiation and the absence of autofluorescence of biological tissues [11], [12]. In particular, Yb³⁺ and Tm³⁺ co-doped RE-UCNPs show intense UCL emission at 800 nm under continuous-wave excitation at 980 nm, and are therefore ideal candidates for high contrast whole-body small-animal imaging [10], [12], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28]. For example, we have recently reported that the detection limit for the UCL imaging of a whole-body mouse is only 50 cells [28].

Usually, photoluminescent imaging has one shortcoming of the low penetration depth of the excitation and emission light, which can be solved by magnetic resonance imaging (MRI) [34], [35] and X-ray computed tomography (CT). To combine the merits of these imaging modalities, multimodal imaging based on RE-UCNPs has been developed. For example, by introducing Gd³⁺ in the host matrix or on the nanoparticle surface, magnetic-luminescent RE-UCNPs have successfully been fabricated for dual-modal imaging of T₁-enhanced MRI and UCL imaging [36], [37], [38], [39]. CT gives high spatial resolution and 3D tomography information about deep anatomic structures due to the high penetration of X-rays, whilst MRI provides comparable resolution but with far better contrast. Considering the different spatial resolution, imaging penetration depth, and areas of application of these different imaging modalities, a combination of CT, MRI and luminescence imaging using a sole probe is urgently required.

Owing to their large magnetic moment, superparamagnetic Fe₃O₄ nanoparticles have been combined with RE-UCNPs together for fabricating magnetic operation, T₂-enhanced MR imaging and UCL imaging [40]. For example, Liu et al. developed multifunctional nanoparticles, NaYF₄:Yb,Er@Fe₃O₄@Au, which combined optical and magnetic properties useful for multimodality imaging [41]. Recently, our group reported an imaging agent with NaYF₄:Yb,Tm@Fe_xO_y core–shell nanostructure for T₂ MRI and UCL bimodal lymphatic imaging [42]. It should be noted that the intensity of UCL emission will be weaker in the presence of the Fe₃O₄-shielding, because both excitation and emission light are absorbed by the Fe₃O₄ shell. Therefore, it is expected that a different core–shell nanostructure with Fe₃O₄ nanoparticles as core and RE-UCNPs as shell might show excellent upconversion luminescent and magnetic properties.

NaLuF₄ may be an ideal building block for multimodal bioimaging probes since RE-UCNPs based on the NaLuF₄ host have high UCL quantum yield [10], [28]. Furthermore, owing to the large atomic number and high X-ray absorption coefficient of lutetium, NaLuF₄ can be used as a contrast agent for CT imaging. In this work, core–shell Fe₃O₄@NaLuF₄:Yb,Er/Tm nanostructure (MUCNP) with Fe₃O₄ as the core and NaLuF₄:Yb,Er/Tm as the shell layer has been designed and synthesized by a step-wise method. The core–shell structure was characterized by transmission electron microscopy (TEM), powder X-ray diffraction (XRD), energy-dispersive X-ray (EDX) analysis and X-ray photoelectron spectroscopy (XPS). The upconversion luminescent, magnetic and X-ray attenuation properties of these nanoparticles were investigated in detail. Moreover, we have also investigated the multimodal performance for MR, CT and UCL imaging following an intratumoral injection of MUCNP. Finally, the cytotoxicity of the MUCNP is described.