Multimodal nanoprobes are of great significance in clinical diagnosis, because they integrate the advantages of multiple imaging methods. The combination of multiple imaging modes provides more comprehensive and complex information than single-mode imaging, which can greatly improve clinical diagnoses. In this paper, Gd3+ and Tb3+ co-induced polyelectrolyte nanoaggregates (GTIPAs) are introduced as a novel dual-mode imaging probe. Containing gadolinium and terbium, GTIPAs are regular spherical nanoparticles, whose diameters are about 150 nm. As a fluorescent nanomaterial, GTIPAs have strong and stable luminescence intensity. At the same time, as an MRI contrast agent, GTIPAs exhibit a good contrast effect and a high longitudinal relaxation rate. In addition, the polyelectrolytes reduce the cytotoxicity of the complexes, confering excellent biocompatibility and water solubility. Therefore, GTIPAs are non-toxic luminescence/magnetic resonance dual-mode imaging probes.
© 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement
Molecular imaging technology provide many important methods of clinical diagnosis, including fluorescence imaging (FI), magnetic resonance imaging (MRI), ultrasound imaging (US), X-ray computed tomography (CT) and positron emission tomography (PET) [1–3]. While each imaging technology has advantages, using only a single imaging mode limits the amount of information that can be ascertained. For example, FL has single-cell sensitivity and sub-cellular resolution, but its spatial resolution and tissue penetration are poor [4–6]; although MRI has high three-dimensional spatial resolution and deep tissue penetration, it has poor sensitivity [7–9]. Therefore, multi-modal imaging technologies may combine the advantages of individual imaging techniques. Dual-mode probes can provide more comprehensive information and enable more accurate clinical diagnosis.
Lanthanides have unfilled 4f electron orbitals [10,11]. Lanthanide ions, including Tb3+ have a narrow emission band and long luminescence lifetime in the visible light region,due to the f-f electron transition [12,13]. Tb3+ exhibits sharp green luminescence emission in the visible light region, but due to the narrow absorption range of incident light, the luminescence intensity is weak . In order to enhance the luminescence intensity, organic conjugated ligands, such as acetyl acetone (acac) and 1,10-phenanthroline (phen), are complexed with Tb3+ [15,16]. These ligands act as “antennas,” which improve the absorption of light, thereby improving the luminescence emission. However, many lanthanide complexes with organic ligands have poor water solubility and are toxic to organisms. Polyelectrolytes with opposite charges, such as hyaluronan (HA) and chitosan (CHI), can be combined to form a stable nanoparticle complexes . Combining polyanions and polycations under favorable conditions can lead to formation of stable colloidal nanoparticles. These polyelectrolyte nanoparticles can be used as carriers for lanthanide complexes, reducing toxicity, preventing energy loss and further enhancing luminescence intensity [18,19]. The complexes have good biocompatibility and strong luminescence intensity, enabling biological luminescence imaging . In addition, co-doping Gd3+ and Tb3+ can not only further enhance the green luminescence intensity of Tb3+, but also provide magnetic resonance contrast for MRI [21–23].
Rare earth elements tend to have strong magnetism due to their unfilled 4f electron orbitals . There is one electron in each of the seven orbitals of the gadolinium element, which is the element with the largest number of unpaired electrons among the rare earth elements [25,26]. Because gadolinium has the largest magnetic moment of unpaired electrons, it has strong paramagnetism. Gd3+-based T1 weighted contrast agents have been most widely used in magnetic resonance imaging, as Gd3+ has seven unpaired electrons with a large magnetic moment [27,28]. However, Gd3+ ions are also highly toxic, because they inhibit calcium channels, induce changes in intracellular reactive oxygen species (ROS) levels, and cause cardiovascular and nervous system toxicity . To reduce the biological toxicity caused by Gd3+, one effective method is to embed Gd3+ in nanovesicles. Nanoparticle complexes formed by the combination of polyelectrolytes with opposite polarities can be prepared with by good water solubility and non-toxicity . These complexes can also be used to bind metal ions, including gadolinium. These complexes can preserve the MRI contrast properties and improve the biocompatibility of Gd3+.
In this article, Gd3+ and Tb3+-induced polyelectrolyte nano-aggregates (GTIPAs) are prepared, as shown in Fig. 1. Luminescence spectra confirmed that the GTIPAs have high green luminescence intensity. In addition, the addition of Gd3+ can enhance the luminescence intensity of Tb3+ at a certain concentration. Magnetic resonance imaging showed that the GTIPAs exhibited good contrast and a short relaxation time. The polyelectrolyte coating reduces the toxicity of the complex and also improves the water solubility of the complex. When used in in vivo MRI, GTIPAs exhibit good biocompatibility and clear contrast. In this work, we demonstrate a dual-modality detection probe that can provide both luminescence imaging and magnetic resonance imaging. This dual-modality imaging has broad prospects in clinical diagnosis.
2. Materials and methods
Gadolinium chloride hexahydrate and terbium chloride hexahydrate was purchased from Aladdin Company in Shanghai. Acetyl acetone (acac) and 1,10-phenanthroline (phen) were bought from Darui Company in Shanghai. Sodium hyaluronate (GlcuA >45%) was supplied by Beijing Solarbio Science & Technology Co., Ltd (Beijing, China). Chitosan (low viscosity, less than 200 mPa s, DD = 88%) was purchased from Aladdin Industrial Corporation (Shanghai, China). All water used was deionized. All chemicals mentioned above were of analytical grade.
2.2 Preparation of Gd3+and Tb3+-induced polyelectrolyte nano-aggregates (GTIPAs)
The Gd3+ and Tb3+-based complexes were prepared by the method according to our previous publication. Initially, GdCl3, TbCl3 and acac (Table 1) were mixed with different concentrations and stirred at room temperature for 30 minutes. After that, the pH of the mixture was adjusted to 7–8 by using NH3.H2O (1 mol/L) solution. Next phen were added to the solution in the amounts listed in Table 1, and the solution was constantly stirred for 1 h. Then the HA solution were added to the solutions and stirred for 1.5 h. Finally, the CHI solution was added to the solutions and stirred for 2 h to form nanoparticles. The HA solution (1 mg/mL) and the CHI solution (0.9 mg/mL) was obtained by dissolving the polyelectrolyte in an acetate buffer. The acetate buffer was 0.1 mol / L, pH = 5.0, formed from acetic acid and sodium acetate.
GTIPAs were characterized by transmission electronic microscopy (TEM) with a JEM-2100F (JEOL Ltd, Japan). The sample was ultrasonicated for 5–6 min before testing. The solution was dropped onto a copper grid, and the solvent was evaporated at room temperature for 1 or 2 s. The elemental composition was determined using scanning transmission electron microscopy with energy-dispersive X-ray spectroscopy (STEM-EDS) using a FEI Tecnai G2 F20 S-TWIN (FEI Inc., Hillsboro, OR, USA). The sizes and zeta potentials of GTIPAs were determined using Malvern laser particle size analyzer (Horiba SZ-100Z). X-ray photoelectron spectroscopy (XPS) was performed on a Thermo Fisher Scientific ESCALAB 250Xi. The XPS spectra was collected using a monochromatic AlKα X-ray source (incident energy = 1486.6 eV) and an electron emission angle of 90° to the surface at a power of 150 W, and a 500 µm beam spot. Binding energy was calibrated with C1s at 284.8 eV. The photoluminescence spectra were obtained at room temperature by using a Cary Eclipse luminescence spectrophotometer (Varian, USA) equipped with a 75 kW xenon lamp as the excitation source. The excitation slit width and emission slit width were both 5 nm (Edinburgh Instruments, FLS1000). Luminescence microscopy was performed with a microscope from Shanghai Optical Instrument Factory, XSP-63XD.
2.4 Luminescence lifetime and quantum yield
Luminescence lifetime and quantum yield of GTIPAs were evaluated by a photoluminescence spectrometer. For the study of luminescence decay of lowest excited state level of dopant ion, the data is fitted using monoexponential decay
Luminescence quantum yield (η) is related to number of photons absorbed (α) and number of photons emitted by the sample (ɛ) as
2.5 In vitro magnetic resonance imaging and relaxivity
The MR imaging and the T1 relaxivity of GTIPAs were obtained on 9.4T BioSpec MRI (Bruker, Germany). Samples with different Gd3+ concentrations were tested, and their respective MRI images and relaxation times were obtained. Relaxivity values of GTIPAs were obtained from the slope of the linear fitting of 1/T relaxation time (s−1) versus Gd3+ concentration (mM).
2.6 In vivo MR imaging
For in vivo MR imaging, GTIPAs were dispersed in PBS containing 0.9% NaCl and then injected into the tail vein of a Kunming mouse. According to previous research [31–33], GTIPAs is used at a dose of 0.02 mmol Gd kg−1. The in vivo MRI were obtained on BioSpec 94/20 (Bruker, Germany). T1-weighted MR imaging were acquired on the coronal surface of mice before and after injection (0.5 h) of GTIPAs.
3. Results and discussion
3.1 Structure of GTIPAs
GTIPAs are formed based on the coordination interaction between HA, CHI, and (Gd3+ and Tb3+)-acac-phen complexes in solution. A TEM image of GTIPAs in Fig. 2(a) and (b) shows the regular spherical nanoparticles, whose diameters are between 130–170 nm. Figure 2(e) shows that the size distribution of GTIPAs in solution, obtained by DLS, in which the peak is around 150 nm. This unique size distribution depends on the charge reaction between the polyanionic HA and the cationic (Gd3+&Tb3+)-acac-phen complexes, as well as between the polycation CHI and polyanion HA. The mutual attraction of the opposite charges causes the nano-sphere complexation. From Fig. 2(c) and (d), we can see that the dark-field scanning transmission electron microscopy (STEM) images and the elemental mapping of Tb (green) and Gd (orange). The detection of Gd and Tb confirmed the uniform presence of Gd and Tb in each nanoparticle. Figure 2(f) indicates that (Gd3+&Tb3+)-acac-phen complexes exhibit positive charge in the solution, which can complex with the polyanion, HA. The complexes with HA are negatively charged, indicating that HA encapsulates (Gd3+& Tb3+)-acac-phen complexes and can complex with polycationic CHI. GTIPAs are positively charged, indicating that CHI encapsulates complexes with HA to form the spherical nanoparticle. The reaction between the CHI, HA and the (Gd3+&Tb3+)-acac-phen complexes occurs through the charge interaction between the positive and negative charges. Thus, the GTIPA structures shown in Fig. 1 can be confirmed.
To further investigate the chemical structures of the (Gd3+&Tb3+)-acac-phen complexes, XPS spectra were acquired. As shown in Fig. 3(a), the complexes show Gd3d and Tb3d in the measured spectra respectively. In addition to the presence of C1s (near 285 eV), the presence of O1s (near 532 eV) and N1s (399 eV) are also apparent, confirming the chemistry of the acac and phen in the complexes. Before the complexation, we know that the binding energies of Gd3d are 1186.9 eV (Gd3d5) and 1219.6 eV (Gd3d3) (see Supplement 1), also the binding energies of Tb3d are 1242.1 eV (Tb3d5) and 1275.7 eV (Tb3d3) (see Supplement 1). As shown in Fig. 3(b), the Gd3d XPS spectrum indicates two peaks corresponding to the Gd3d5 (1187.82 eV) and Gd3d3 (1220.97 eV), the binding energies of Gd3d increased by 0.92 eV and 1.37 eV respectively. As shown in Fig. 3(c), the Tb3d XPS spectrum contains two peaks corresponding to the Tb3d5 (1242.92 eV) and Tb3d3 (1279.82 eV), the binding energies of Tb3d increased by 0.82 eV and 4.12 eV. The electron binding energy of Gd3d and Tb3d has changed, which shows that the Gd3+ and Tb3+ has undergone a complex reaction. Before the complexation, the binding energies of C-O and C = O are 533.0 eV and 532.0 eV . As shown in Fig. 3(d), the O1s XPS spectrum has two peaks corresponding to the C-O (531.77 eV) and C = O (531.07 eV) in the ligand acac, the binding energies of C-O and C = O reduced 1.23 eV and 0.93 eV respectively. From Fig. 3(e), we can see the peak of N1s (398.32 eV) in the ligand phen, comparing the binding energy of N1s (399.2 eV) before complexation (see Supplement 1), it reduced 0.88 eV. Similarly, through comparison, we can know that the binding energy of the O1s and N1s element in the ligands has changed, which indicates that the ligand has undergone a complex reaction. These results can confirm that the Gd3+ and Tb3+ have been complexed with the ligands, and the complex has been successfully synthesized.
3.2 Photophysical properties of GTIPAs
The complex of Tb3+ has sharp luminescence emission and long luminescence lifetime, and Gd3+ can significantly increase the luminescence intensity of the complex. The photophysical properties of GTIPAs were measured by luminescence spectrophotometry. From Fig. 4(a), we can see the TIPAs have a broad absorption band between 330 nm and 370 nm, with an absorption maximum at 350 nm. After adding Gd3+, the absorption band is slightly blue shifted, between 320 nm and 370 nm, and the absorption maximum is at 348 nm. The characteristic luminescence spectra of Tb3+ (λex = 348 nm) were obtained from GTIPAs, and the strong emissions are the result of 4f electron transmissions [5D4→7FJ (J=6 at 490 nm, 5 at 547 nm, 4 at 580 nm, and 3 at 620 nm) for Tb]. Comparing samples a, c, d and f in Table 1, Fig. 4(b) shows the luminescence intensity of GTIPAs with different concentration of Gd3+ at the same concentration of Tb3+. Based on Fig. 4(b), sample a with 5×10−5 mol Gd3+ shows the highest emission intensity. Therefore, this complex has the best luminescence intensity when the ratio of the concentration of Gd3+ to the concentration of Tb3+ is 5 to 1. Figure 4(c) is a fluorescence micrograph of GTIPAs. Under fluorescence microscopy, agglomerated green particles are visible. Luminescence lifetime is an important parameter for characterizing fluorescent nanoparticles. As shown in Fig. 4(d), the luminescence lifetime of GTIPAs is 640.73 µs. The quantum yield of GTIPAs is 21.7%. Thus, GTIPAs have the advantages of high luminescence intensity, narrow emission band, and very long luminescence lifetimes compared to organic fluorescent dyes.
It is worth noting that the emission intensity monitored in case of GTIPAs was observed to improve further in presence of Gd3+ ion in the complex. The Gd3+ ions are transparent to 348 nm radiation, because the lowest excited state of Gd3+ ion (∼32000cm−1) is much higher than the triplet states of acac/phen. Hence the Gd3+ ion does not take part directly in the energy transfer to the Tb3+ ion. It is believed that as both the rare earth ions (Gd3+and Tb3+) are in the same molecular system, Gd3+ ions could act as an energy bridge through which the unabsorbed energy of the acac/phen in Gd(acac)3phen complex is transferred to Tb3+ ions. Hence Gd(acac)3phen complex may act as energy harvesting center and improve the intramolecular energy transfer, which ultimately enhances the emission intensity of Tb3+ ions [35,36].
3.3 In vitro MR imaging
Based on the excellent magnetic properties of gadolinium, GTIPA has good MRI performance. As shown in Fig. 5(a), the intensity of the MR signal of GTIPAs increases with the increasing Gd3+ concentration (4.17 mM, 3.13 mM, 2.08 mM, 0.63 mM, 0.05 mM), demonstrating that the prepared GTIPAs could be applied as candidate for T1-weighted MR imaging. Particularly, the transverse relaxation rate (1/T1) exhibited a linear relation with the Gd3+ concentrations, where the slope was defined as T1 relaxivity. As shown in Fig. 5(b), the r1 value of GTIPAs was calculated to be 4.2 ± 0.2 mM−1s−1. For a chemical to be utilized as a highly sensitive T1-weighted MR imaging contrast agent, the r1 should be as large as possible. Therefore, GTIPAs have a short relaxation time and bright contrast effect, which can reflect the signal more quickly and clearly. So GTIPAS have good potential as an MRI contrast agent.
3.4 In vivo MR imaging
The presence of polyelectrolytes reduces toxicity and enhances biocompatibility (see Supplement 1), therefore, GTIPAs can be used for vivo MR imaging. In vivo imaging was conducted to investigate the potential of GTIPAs for MRI. The T1-weighted MR images were obtained before and after injection (0.5 h) of GTIPAs. As shown in Fig. 6(a) and (b), compared with the plain scanning images, upon injection of GTIPAs, after 0.5 h, a significant T1-weighted enhancement is visible in the heart and liver, owing to the high r1 relaxivity of the nanoprobes. Blood pool imaging is important in clinical MR imaging because it can detect myocardial infarction, renal failure, atherosclerotic plaque, thrombosis, and angiogenesis of tumor cells. Therefore, GTIPAs can be used for in vivo MR imaging, including blood pool imaging, and has a wide range of applications in clinical diagnosis.
We developed a new type of dual-mode imaging probe by complexing lanthanide ions (Gd3+ and Tb3+), organic ligands (acac and phen) and polyelectrolytes (HA and CHI). The complexing process of GTIPAs is simple and environmentally friendly, and the resulting product has a stable shape and uniform size. On the one hand, under the action of Tb3+, GTIPAs exhibit bright green luminescence, with high luminescence emission intensity and long luminescence lifetime. On the other hand, with the addition of Gd3+, GTIPAs have excellent magnetic properties, exhibit high longitudinal relaxation rate in in vitro magnetic resonance imaging and excellent contrast effects in vivo magnetic resonance imaging. At the same time, due to the sensitizing effect of gadolinium ions on terbium ions, the luminescence intensity of GTIPAs is further enhanced. Due to their non-toxicity and water solubility, GTIPAs can be used for biological testing. Therefore, the multiple advantages of GTIPAs can make this new type dual-mode imaging probes play an important role in clinical diagnosis.
National Natural Science Foundation of China (51473082); State Key Project of International Cooperation Research (2017YFE0108300, 2016YFE0110800); the High End Foreign Expert Project; Shandong Double-Hundred Project; the National Plan for Introducing Talents of Discipline to Universities; The 1st Class Discipline Program of Shandong Province of China.
This work was supported by (1) the Natural Scientific Foundation of China (Grant No. 51473082); (2) State Key Project of International Cooperation Research (2017YFE0108300, 2016YFE0110800); (3) the High End Foreign Expert Project (2020); (4) Shandong Double-Hundred Project (2018); (5) the National Plan for Introducing Talents of Discipline to Universities (“111” plan); (6) The 1st Class Discipline Program of Shandong Province of China.
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.
No data were generated or analyzed in the presented research.
See Supplement 1 for supporting content.
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