Functionalized Lanthanide Oxide Nanoparticles: Comparison
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Functionalized lanthanide oxide (Ln2O3) nanoparticles has been used for tumor targeting, medical imaging, and therapy. Among the medical imaging techniques, magnetic resonance imaging (MRI) is an important noninvasive imaging tool for tumor diagnosis due to its high spatial resolution and excellent imaging contrast, especially when contrast agents are used. However, commercially available low-molecular-weight MRI contrast agents exhibit several shortcomings, such as nonspecificity for the tissue of interest and rapid excretion in vivo. Recently, nanoparticle-based MRI contrast agents have become a hot research topic in biomedical imaging due to their high performance, easy surface functionalization, and low toxicity. Among them, functionalized Ln2O3 nanoparticles are applicable as MRI contrast agents for tumor-targeting and nontumor-targeting imaging and image-guided tumor therapy. Primarily, Gd2O3 nanoparticles have been intensively investigated as tumor-targeting T1 MRI contrast agents. T2 MRI is also possible due to the appreciable paramagnetic moments of Ln2O3 nanoparticles (Ln = Dy, Ho, and Tb) at room temperature arising from the nonzero orbital motion of 4f electrons. In addition, Ln2O3 nanoparticles are eligible as X-ray computed tomography contrast agents because of their high X-ray attenuation power. 

  • imaging agent
  • lanthanide oxide nanoparticle
  • tumor targeting
  • toxicity

1. Introduction

Medical imaging plays an important role in the pre-detection, diagnosis, and treatment of tumors [1]. Among the currently available medical imaging techniques, magnetic resonance imaging (MRI) allows whole-body imaging and outstanding microsoft tissue contrast and image resolution to reveal morphological and anatomical details of tissues [2,3][2][3]. As imaging agents, various nanoparticles have been developed due to their remarkable physical and chemical properties, which are superior to those of small molecules [4,5,6,7][4][5][6][7]. Moreover, nanoparticles can be easily surface-functionalized for advanced imaging and tumor targeting [8,9][8][9]. They can also provide longer blood circulation times than small molecules, which is conducive to tumor targeting and drug delivery to specific tumor cells [10,11][10][11].
Lanthanide oxide (Ln2O3) nanoparticles (Ln = Gd, Tb, Dy, and Ho) are of special interest because they have appreciable magnetic moments at room temperature, which is useful for MRI [12[12][13][14][15],13,14,15], and high X-ray attenuation power, which is useful for X-ray computed tomography (CT) [16,17,18][16][17][18]. In addition, surface-modified Ln2O3 nanoparticles exhibit improved properties, such as high-water proton spin relaxivities, high colloidal stabilities, and low toxicities [12,13,14][12][13][14]. For in vivo applications, nanoparticles should have an ultrasmall particle diameter (<3 nm) to allow their excretion from the body via the urinary system after intravenous injection [19,20][19][20]. Ln2O3 nanoparticles meet such requirements, displaying excellent MRI and CT imaging properties at ultrasmall particle diameters [12,13,14,15][12][13][14][15].
The development of tumor-targeting Ln2O3 nanoparticles is challenging. Especially when compared with commercial molecular Gd-chelates [21[21][22][23],22,23], Gd2O3 nanoparticles are more efficient longitudinal relaxation promoters [12,13,14,15][12][13][14][15] because their longitudinal relaxivity (r1) values are higher than those (i.e., 3–5 s‒1mM‒1) [21,22,23][21][22][23] of commercial molecular MRI contrast agents. Therefore, Gd2O3 nanoparticles can provide very high contrast T1 MR images and thus, are ideal candidates for tumor-targeting T1 MRI contrast agents. In particular, their r1 value is optimal at ultrasmall nanoparticle size (1.0–2.5 nm) [24,25][24][25]. Meanwhile, other Ln2O3 nanoparticles (Ln = Dy, Tb, and Ho) are eligible as T2 MRI contrast agents [12,13,15][12][13][15].
Nanoparticles alone accumulate nonspecifically in tumors via passive targeting, i.e., the enhanced permeability and retention (EPR) effect [26]. The accumulation amount and specificity to tumors can be enhanced by active targeting, which is commonly achieved by modifying contrast agents with tumor-targeting ligands that can selectively bind to receptors overexpressed on tumor-cell membranes. Such tumor-targeting ligands include small molecules, such as arginylglycylaspartic acids (Arg-Gly-Asp or RGDs) [27,28,29][27][28][29] and folic acid [30[30][31],31], peptides, such as chlorotoxin (CTX) [32[32][33],33], and biological molecules, such as antibodies [34]. Nanoparticles can provide a flexible platform to attach tumor-targeting ligands, thereby improving their specificity and effectiveness for tumor treatment. In addition, anticancer drugs can also be attached to nanoparticle surfaces for chemotherapy. Generally, in this type of treatment, most anticancer drugs cannot differentiate between tumor and normal cells, causing toxic side effects [35,36][35][36]. However, such side effects can be minimized or eliminated by delivering drugs via tumor-targeting nanoparticles. However, the cytotoxicity and biocompatibility of lanthanides during and after endocytosis by cells are still largely unknown, although numerous reports describe lanthanides as relatively non-toxic elements [37,38][37][38].

2. Synthesis and Surface Functionalization of Ln2O3 Nanoparticles

Among the various methods currently available for the synthesis of ultrasmall Ln2O3 nanoparticles, the synthesis in a polyol solvent is preferred for biomedical applications because ultrasmall nanoparticles are obtained (average particle diameter = 2.0 nm) and subsequent surface coating of the nanoparticles with hydrophilic and biocompatible ligands can be performed in one pot [17,31][17][31]. A general reaction scheme for the polyol synthesis is provided in Figure 1.
Pharmaceutics 13 01890 g001
Figure 1. Reaction scheme for the one-pot polyol synthesis of hydrophilic and biocompatible polymer-coated ultrasmall Ln2O3 nanoparticles. TEG = triethylene glycol.
Nanoparticle contrast agents possess an additional advantage over molecular agents because cancer-targeting ligands and drugs can be easily attached to the nanoparticle surfaces. Small molecular ligands are less efficient in providing good colloidal stability to nanoparticles compared with polymer ligands, which is due to the presence of many hydrophilic binding groups in the polymers for attachment to the nanoparticles [39,40,41,42,43][39][40][41][42][43]. In addition, hydrophilic polymers can provide higher r1 values than small molecular ligands [39,40,41][39][40][41] because they can attract more water molecules around the nanoparticles. Examples of these polymers are polyacrylic acid (PAA), polymethyl vinyl ether-alt-maleic acid (PMVEMA), and polyacrylic acid-co-maleic acid (PAAMA) having numerous COOH groups (Figure 1) [39[39][40][41],40,41], which can serve as anchor groups of functional molecules, such as cancer-targeting ligands and drugs. For example, RGD-conjugated PAA-coated Gd2O3 nanoparticles were reported by Ho et al. [44] (Figure 2). Pharmaceutics 13 01890 g002
Figure 2. Two-step synthesis of RGD-PAA-Gd2O3 nanoparticles. (a) Step 1: PAA-Gd2O3 nanoparticles and (b) step 2: conjugation of RGD with PAA-Gd2O3 nanoparticles. EDC = N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, NHS = N-hydroxysuccinimide, and UGNP = ultrasmall gadolinium oxide nanoparticle. Adapted with permission from [44], The Royal Society of Chemistry, 2020.
Ln2O3 nanoparticles can also be synthesized in organic solvents via the thermal decomposition method. The synthesized nanoparticles can be further coated with hydrophilic ligands and then conjugated with cancer-targeting ligands. For example, CTX-poly(ethylene glycol)-N-(trimethoxysilylpropyl) ethylenediamine triacetic acid silane-coated Gd2O3 nanoparticles (CTX-PEG-TETT-Gd2O3) were reported by Gu et al. [45] as tumor-targeting contrast agents (Figure 3). Here, the biocompatible poly(ethylene glycol) (PEG) layer is known to stabilize the Gd2O3 nanoparticles, enhance blood circulation blood times, and improve colloidal stability [11]. Pharmaceutics 13 01890 g003 Figure 3. Schematic illustration for the synthesis of CTX-PEG-TETT-Gd2O3 nanoparticles. TETT = N-(trimethoxysilylpropyl) ethylenediamine triacetic acid trisodium salt and OA = oleic acid. Reproduced from [45], The Royal Society of Chemistry, 2014.

3. Ln2O3 Nanoparticle Toxicity

As shown in Figure 174a, bare Gd2O3 nanoparticles exhibit toxicities in both NCTC1469 normal and U87MG tumor-cell lines, whereas PAA-coated Gd2O3 nanoparticles are nearly non-toxic up to 500 μM Gd with cell viabilities of ∼93% in DU145, ∼99% in NCTC1469, and ∼80% in U87MG cell lines (Figure 174b) [83][46]. Other PAA-coated Ln2O3 nanoparticles (Ln = Dy, Tb, and Ho) also exhibit very low cytotoxicities in both DU145 and NCTC1469 cell lines (Figure 174c–e) [42[42][43],43], showing good biocompatibilities. These examples demonstrate that Ln2O3 nanoparticles must be well protected with water-soluble and biocompatible ligands for biomedical applications. Pharmaceutics 13 01890 g017
Figure 174. In vitro cytotoxicities of (a) uncoated Gd2O3 nanoparticles in NCTC1469 and U87MG cell lines and (b) PAA-coated Gd2O3 nanoparticles in DU145, NCTC1469, and U87MG cell lines [83][46]. PAA-coated Ln2O3 nanoparticles (Ln = (c) Dy, (d) Tb, and (e) Ho) in DU145 and NCTC1469 cell lines [42,43][42][43]. Adapted from [42,43,83][42][43][46]. Copyrights 2018, 2020 and 2021 The Royal Society of Chemistry, Wiley & MDPI.
Lanthanides are relatively non-toxic elements [37,38][37][38]. For example, for lanthanide chlorides, the lethal dose causing the death of 50% of a group of 10 animals (LD50) is higher than 10 and 450 mg per kg bodyweight for intravenous and intraperitoneal injections, respectively [84][47]. In the case of Ln2O3 nanoparticles, other properties, either alone or in concert, must be considered to evaluate the possible toxic effects of the nanoparticles. These properties include chemical composition, doping, hydrodynamic size, shape, redox properties, tendency for aggregation, composition of the shell or coating material, surface modifications, colloidal stability, solubility, biodegradability, concentration, and duration of exposure [85][48]. Although several studies have investigated the toxicity of lanthanide-based nanoparticles having different properties, such as chemical composition, size, surface ligands, and lanthanide concentration [86[49][50][51],87,88], the lack of literature data has prevented drawing firm conclusions for the assessment of the potential toxicity of Ln2O3 nanoparticles. Furthermore, several aspects of the biological interaction of Ln2O3 nanoparticles in living systems still need to be unveiled. For example, despite in vitro cytotoxicity studies being conducted using various cell cultures, these studies did not provide information about long-term safety and cytotoxicity [89[52][53],90], for which in vivo cytotoxicity studies would be needed. Nevertheless, several important conclusions can be extracted from the currently available literature data. In the case of biomedical applications, Ln2O3 nanoparticles are usually introduced into the body by intravenous injections and circulated by the bloodstream primarily to organs, such as the liver and spleen, kidneys, heart, lungs, and brain [91][54]. The possible retention or uptake in blood and organs strongly depends on the surface properties of the nanoparticles. Ligand coating can promote the interaction of the Ln2O3 nanoparticles with the cell membranes, favoring the internalization of the nanoparticles by various types of cells. However, biologically inert coating ligands, such as PEG, may prolong the circulation in the bloodstream of nanoparticles [11]. In addition, nanoparticle size is an important factor for the excretion route [92,93][55][56]. Thus, nanoparticles smaller than 3 nm can be excreted by renal filtration [19,20][19][20], whereas those larger than 3 nm are enclosed by a phagocyte system. As a part of the immune system, the phagocyte system is composed of several types of phagocytic cells in the reticular tissue within the body, whose main function is to remove undesired species, such as bacteria, viruses, and foreign materials, including nanoparticles. The toxicity of Ln2O3 nanoparticles differs depending on the lanthanide ions. For example, Er2O3 shows higher toxicity than Gd2O3 and La2O3 and is highly toxic to zebrafish embryos at a concentration of 50 ppm Er, causing significant mortality and morphological malformations [93][56]. Meanwhile, the toxicity of Gd2O3 nanoparticles is primarily attributed to the release of Gd3+ ions [94,95,96][57][58][59]. The toxicity of Gd3+ ions has been addressed not only for Gd2O3 nanoparticles but also for a variety of molecular Gd3+-chelates. In the case of Gd2O3 nanomaterials, Eu3+-doped Gd2O3 (Gd2O3:Eu3+) nanotubes can adversely affect bone marrow stromal cells (BMSCs) [97][60]. Yang et al. reported the application of 153Sm-doped Gd(OH)3 nanorods as a potential MRI contrast agent [98][61]. In vitro cell toxicity tests revealed that Gd(OH)3 nanorods have no toxic effect on cellular proliferation and viability. Furthermore, an in vivo toxicity test using Kunming mice showed that injection up to 100 mg/kg of Gd(OH)3 nanorods had no toxic effect up to 150 days after exposure. However, this in vivo test investigated the short-term toxic effect of Gd(OH)3 nanorods. In contrast, the long-term toxicity of clinically used Gd3+-chelates was reported. When used in patients with severely compromised kidney function, Gd3+-chelates promoted the development of nephrogenic systemic fibrosis (NSF), which is a rare disease affecting different parts of the body that can lead to thickening or hardening of the skin and deposits [99][62] (Figure 185). Moreover, NSF is a progressive condition that can be fatal because it may cause multiple organ failure [99,100,101,102][62][63][64][65]. Gd3+ retention in the body, which is greater with linear structured Gd3+-chelates than with macrocyclic structured Gd3+-chelates, was demonstrated to be associated with NSF. Pharmaceutics 13 01890 g018
Figure 185. Clinical pictures of the legs of two patients with NSF for (a) about three years and (b) four weeks. Adapted from [99][62]. Copyright 2007 International Society of Nephrology.
Compared with clinically used Gd3+-chelates, the toxicity of Ln2O3 nanoparticles, including Gd2O3 nanoparticles, has been less explored. For instance, the extent, mechanism, chemical form, and clinical implications of chronic lanthanide retention for Ln2O3 nanoparticles remain unknown. Therefore, more comprehensive investigations are required to improve our understanding of Ln2O3 nanoparticle toxicity and its clinical importance. In this context, the development of new experimental techniques may play a significant role in unveiling lanthanide nanotoxicity. For example, nanotoxicogenomics [103][66], which uses DNA microarray technologies to investigate the impact of nanoparticles on global gene expression profiles of cells and tissues, has emerged as a new field of toxicology to provide new and important insights into the toxicity of Ln2O3 nanoparticles.

4. Conclusions and Perspectives

Recent studies on the synthesis, surface modification, tumor-targeting ligand conjugation, toxicity, and novel biomedical applications to tumor-targeting T1 MRI and image-guided tumor therapy of Ln2O3 nanoparticles were introduced here. In addition, T2 MRI and CT imaging applications were also discussed. High-quality Ln2O3 nanoparticles can be synthesized via the polyol method and organic-phase thermal decomposition method and then surface-coated with hydrophilic and biocompatible ligands for colloidal stability and biocompatibility. Polymers are more efficient than small molecules as surface-coating ligands because of their many –COOH, –NH2, –OH groups, which can be attached to nanoparticles and conjugated with tumor-targeting ligands and drugs.
The interest in Ln2O3 nanoparticles in the field of medical imaging lies principally in the excellent imaging properties of lanthanides, which arises from their appreciable paramagnetic moments at room temperature; Gd3+ has the highest 4f-electron spin magnetic moment (s = 7/2) among the elements in the periodic table, which is extremely useful for T1 MRI, and other Ln3+ ions (Ln = Tb, Dy, and Ho) have a very high 4f-electron spin–orbital magnetic moment, which is suitable for T2 MRI. In addition, lanthanide elements possess higher X-ray attenuation coefficients than iodine, which is currently used as a CT contrast agent in its organic compound forms. The potential of Ln2O3 nanoparticles as CT contrast agents has been confirmed by recording in vivo CT images. In the case of tumor targeting, Gd2O3 nanoparticles are the most widely investigated Ln2O3 nanoparticles due to their very high T1 MRI sensitivity. Various tumor-targeting ligands have been conjugated to Gd2O3 nanoparticles for tumor imaging and T1 MRI-guided tumor therapy. Especially, the enhanced accumulation of tumor-targeting ligand-coated Gd2O3 nanoparticles at tumor cells compared with that at normal cells allowed the development of precise image-guided tumor therapies via clear distinction and delineation of tumors from normal tissues.
Further intensive research is essential to achieve the ultimate goal of using Ln2O3 nanoparticles for tumor-targeting diagnosis and therapy and nontumor-targeting medical imaging. In addition, sophisticated toxicological and pharmacological improvements are required to demonstrate the safety of nanoparticle formulations prior to clinical trials. We hope that this review will guide the future development of biomedical applications of Ln2O3 nanoparticles.

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