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Design and regulation of NaHoF4 and NaDyF4 nanoparticles for high-field magnetic resonance imaging Xinghua Zhang, Barbara Blasiak, Armando J. Marenco, Simon Trudel, Boguslaw Tomanek, and Frank C.J.M. van Veggel Chem. Mater., Just Accepted Manuscript • DOI: 10.1021/acs.chemmater.6b00264 • Publication Date (Web): 19 Apr 2016 Downloaded from http://pubs.acs.org on April 20, 2016

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Chemistry of Materials

35x15mm (300 x 300 DPI)

ACS Paragon Plus Environment


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Design and regulation of NaHoF4 and NaDyF4 nanoparticles for high-field magnetic resonance imaging Xinghua Zhang†‡*, Barbara Blasiak◊∆, Armando J. Marenco□, Simon Trudel□, BoguslawTomanek◊∆Π, and Frank C. J. M. van Veggel‡* †

School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300130, China

‡

Department of Chemistry, University of Victoria, Victoria, British Columbia V8W 3V6, Canada

◊

Experimental Imaging Center, University of Calgary, Calgary, Alberta T2N 4N1, Canada

∆ □

Department of Oncology, University of Alberta, Edmonton, Alberta T6G 2T4, Canada

Department of Chemistry and Institute for Quantum Science and Technology, University of Calgary,

Calgary, Alberta T2N 1N4, Canada Π

Institute of Nuclear Physics, Polish Academy of Sciences, Krakow, Poland

*Email: [email protected]; [email protected]

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ABSTRACT Lanthanide-based (Ln3+-based) nanoparticles have great potential for high-field magnetic resonance imaging (MRI) applications. Here, we report NaHoF4 and NaDyF4 nanoparticles with modulated sizes (9 − 40 nm) and shapes (spherical-like, hexagonal prism, rod-like), suitable for high- field MRI as shown through in vivo studies. We used X-ray diffraction, transmission electron microscope, dynamic light scattering, and MRI techniques to investigate the structure, morphology, hydrodynamic size and relaxivity of the prepared NaHoF4 and NaDyF4 nanoparticles, showing monodisperse nanoparticles of high crystallinity. In particular, we studied effects of the particle size, shape, surface coating and zeta-potential on transverse (spin-spin relaxivity, r2) and longitudinal (spin-lattice relaxivity, r1) relaxivity at 9.4 T. We found that the NaHoF4 and NaDyF4 nanoparticles have r2 relaxivities of (274.0 ± 6.9) × 104 and (4767.3 ± 160.9) × 104 mMNP-1s-1 per nanoparticle and high r2/r1 ratio of 781 and 410 at a high magnetic field of 9.4 T, respectively, making them attractive as MRI T2 contrast agents. The growth of the hexagonal structure of the NaHoF4 and NaDyF4 nanoparticles was mainly dominated by the growth competition along the [001] and [100] directions which could be modulated by the amount of oleic acid (OA), 1-octadecene (ODE), NaOH, and NH4F. Moreover, both the larger particle size and thin coating polymer layer of nanoparticles increased the transverse relaxivity. The effects of the parameters, such as rotation correlation time, diffusion, and electronic relation times on the dipolar and Curie components of the inner- and outer-sphere contribution, and thus directly on the relaxivity, are discussed. We found that these parameters can be modulated by the particle size and surface coating. Following the outer-sphere relaxation theory, we used computer simulations of r1 and r2 relaxivity as a function of the particle core size, hydrodynamic size, diffusion time and electronic relation time, which all show an impact on r1 and r2, albeit to very 2



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different extends, which has enhanced our understanding of the relaxivity mechanisms. According to the computer simulations, r1 can be controlled by the core size, hydrodynamic size at low magnetic fields of ~0.02 T corresponding to proton Larmor frequency of about 1 MHz. The r1 does not change significantly at the higher frequency and actually drops precipitously. However, based on theoretical simulations we expect r2 can be increased in a wide range of Larmor frequencies (0.1 − 1000 MHz) by increasing the core size, reducing thickness of the coating layer or increasing the magnetic field. The particle sizes, hydrodynamic sizes, and diffusion times and magnetic fields have larger contribution to the relaxivity than that of other parameters. Five animals were imaged and in vivo MRI showed that the rod-like NaDyF4 (25 nm × 35 nm) nanoparticles, without any targeting ligands, provided visible contrast between brain and breast tumors and normal tissues up to 24 hrs after injection. Contrast was observed in all animals after injection of nanoparticle solution which may be attributed to enhanced permeation and retention effects of the rod-shape nanoparticles in tumor. The experimental and simulation results suggest that the NaHoF4 and NaDyF4 nanoparticles are indeed good candidates for highfield (> 3 T) T2 imaging contrast agents.

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INTRODUCTION Magnetic resonance imaging (MRI) is one of most powerful diagnostic tools in modern clinical medicine. Compared with computed tomography (CT), single photon emission computed tomography (SPECT), and positron emission tomography (PET), MRI has advantages such as: lack of ionizing radiation, excellent soft tissue contrast and sub-millimeter spatial resolution of 2D and 3D images.1−3 The contrast in MR images is based on the differences in the proton density between tissues and the differences in their longitudinal (T1) and transverse (T2) relaxation times.4 In order to improve image contrast, different contrast agents are being used to shorten the proton relaxation times T1 (positive contrast) or T2 (negative contrast).5,6 Gadolinium-based chelates and iron-oxide nanoparticles are typically clinically used as T1 and T2 contrast agents, respectively.1,7 Among the lanthanide ions, gadolinium (Gd3+) is known as the most efficient longitudinal, spin lattice, relaxation (r1 = 1/T1) enhancer due to its symmetric seven-electron ground state which results in a longer electronic relaxation time compared with other lanthanide ions.8 Unfortunately, Gd3+-based complexes such as Gd-DTPA only offers one hydrate position since its other (eight) coordination sites are coordinated by the chelate.9 Moreover, the density of magnetic ions (Gd3+) within each repeating unit of gadolinium-based chelate is limited as compared to Ln3+-based nanoparticles.10 In order to increase relaxivity of Gd3+-based chelates, Gd3+-based nanoparticles11−14 such as Gd2O3, GdF3, and NaGdF4 have been synthesized and used as T1 contrast agents. The Gd3+-based nanoparticle whose surface Gd3+ offers all its seven unpaired electrons for water hydration results in larger values of r1 than that of gadolinium-based chelate,9 and the values of r1 (per mM Gd3+) increase with the reduced particle sizes due to the larger number of surface Gd3+ ions relative to the core ions.13,14 In addition, the surface suitable coating can also affect the value of r1. Cho et al.15 prepared Gd2O3 nanoplates 4



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using PAA-OA (oleic acid modified poly(acrylic acid)) as a coating layer to increase r1. It is known, that the value of r1 decreases with the increasing magnetic field,2 however, the inherent reasons affecting r1 and relative time constants, such as rotation, electronic relation and diffusion times of nanoparticles, that influence the longitudinal relaxivity have not yet been systematically investigated for Ln3+-based nanoparticles. While Gd3+-based compounds are used as T1 contrast agents, (superparamagnetic) iron oxide nanoparticles are typical (commercially available) T2 contrast agents. Iron oxides such as Fe3O4 are suitable for low field (< 3 T) MR imaging,16 as their transverse (spin-spin) relaxivity r2 (r2 = (1/T2) per mM ion) can be further increased from about one hundred to several hundreds of mM-1 s-1 by increasing their saturation magnetization by substituting Zn2+ or Mn2+ ions for Fe2+ in Fe3O417,18 and modulating its diameter and shape.19,20 Unfortunately, the magnetization of iron oxides saturates at low magnetic field (< 1 T) and the relaxivity r2 is thus not significantly improved with increasing magnetic fields from 0.5 T (147.2 mM-1s-1) to 9.4 T (167.6 mM-1s-1).21 Due to the need of higher MRI spatial resolution and shorter imaging acquisition,22 higher magnetic field MRI (> 3 T) has been applied, imposing the development of new contrast agents.23 Therefore, it is important to develop high-field contrast agents and to find the relevant parameters to optimise the relaxation rates for MRI at any magnetic field.24 Dysprosium (Dy3+) is an ion which may be suitable for high-field T2 contrast agent due to its short electronic relaxation time (~10-13 s) and large magnetic moment (~10.6 µB)8 without saturation of the magnetization even at high magnetic fields. Dy3+-based complexes for MRI have been systematically investigated via theoretical and experimental study.25,26 Compared with Dy3+-based complexes, further investigation of Dy3+-based nanoparticles for high-field MRI (> 3 T) is urgently needed. Up to now, there are only a few reports about NaDyF4 nanoparticles for 5


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high-field MRI application.27−29 To the best of our knowledge, there is no report on rod-like NaDyF4 nanoparticles smaller than 50 nm used as contrast agents for high-field MRI and in vivo imaging. Larger nanoparticles can act as a cross-linking agent to cluster receptors and induce uptake. Above 50 nm, nanoparticles bind such a large number of receptors that uptake is limited by the redistribution of receptors on the cell membrane via diffusion to compensate for local depletion.30 Yet these studies are urgently needed, particularly for pre-clinical small animal MRI that requires high resolution thus high magnetic field. The rod-like nanoparticles are of particular interest for tumor imaging due to their higher uptake into cells and longer blood half-life compared to other shaped (sphere, cylinders and cubes) nanoparticles.30−32 Beside Dy3+, holmium (Ho3+) is another potential candidate ion for T2 contrast agent due to its short electronic relaxation time (~10-13 s) and high effective magnetic moment (~10.6 µB),8 comparable to Dy3+. Xun et al.33 used a hydrothermal method to synthesize fairly large NaHoF4 particles with blocklike-shape and its average grain size of about 0.83 µm × 1.44 µm, while Liang et al.34 prepared NaHoF4 microtubes with tubular structures using the hydrothermal method. The nanoscale NaHoF4 nanoparticles with spherical-like shape (16 ± 1 nm) were reported by Cao et al.35 and non-aggregated colloidally stable suspension of nanoparticles in water was achieved by the PEGphosphonate ligands coating. Ho3+-doped NaYbF4 nanoparticles were first used for MR imaging at 3 T by Bu et al.36 Upconversion luminescence and CT imaging were simultaneously realized with NaYbF4: Ho3+ nanoparticles. In 2016, Ni et al.37 first reported NaHoF4 nanoparticles with DSPE-PEG5k coating and varied particle sizes (3 nm, 7 nm, 13 nm and 29 nm) which can be used as dual-modality contrast agents for high-field MRI and CT. They also investigated the in vivo toxicity, CT and T2-weighted MR images of 3 nm-NaHoF4 NPs. At present, the further

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theoretical and experimental investigation of particle size, shape, surface coating on relaxivities of NaHoF4 nanoparticles for high-field MRI is still urgently needed. Up to now, many theoretical and experimental studies have been carried out to improve the relaxivity rates r1 and r2 and to investigate the inherent reasons that influence the relaxivity of the lanthanide-based complexes. These studies aim at better understanding relaxivity mechanisms and providing strategies to improve relaxivity of complexes for MRI application.2,38−41 For the Ln3+-based complexes, relaxivity is mostly caused by the exchange of water molecules between the inner- and outer-coordination sphere of the paramagnetic metal ion to the bulk water.26,42 The inner-sphere relaxation is mainly determined by the two time constants TiM (TiM = 1/riM, i = 1, 2, r1M and r2M are the longitudinal and transverse relaxation rates of lanthanide ions coordinated water, respectively) and τM (residence time of coordinated water molecules before exchanging with bulk water). The inner-sphere relaxation occurs when water transiently binds to the lanthanide ions, therefore, the inner-sphere contribution to the relaxation for magnetic nanoparticles is minor and often can be neglected since the coating layer of nanoparticles impedes binding and exchange of water. The outer-sphere relaxation is mainly determined by the length of diffusion time (τD) and electronic relation times (τS or Tie, i = 1, 2). Up to date, there are no systematic reports on the influence of the key parameters such as core size, hydrodynamic size, magnetic field, diffusion time and electronic relation time on proton relaxivity caused by the Ln3+-based paramagnetic nanoparticles. The question as to which parameters have the larger contribution to the relaxivity remains unanswered. Therefore, it is important to investigate the factors that influence the relaxivity of Ln3+-based nanoparticles for high-field MRI applications and to find the effective methods to improve the relaxivities of Ln3+-based magnetic nanoparticles. 7


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In this article, we report NaDyF4 and NaHoF4 nanoparticles with different shapes (hexagonal prism, spherical- and rod-like) and sizes (9 − 40 nm) with high transverse relaxivity at high magnetic field (9.4 T). The growth rules of NaDyF4 and NaHoF4 nanoparticles were investigated and the modulation of shapes and sizes has been achieved. The relationship between particle size, surface coating, hydrodynamic size, zeta-potential and relaxivity were also studied systematically. High transverse relaxivity at high magnetic field (9.4 T) was obtained by optimizing these parameters. The maximum r2 of the rod-like NaDyF4 (25 nm× 35 nm) and spherical NaHoF4 nanoparticles were (4767.3 ± 160.9) × 104 mMNP-1s-1 (r2/r1 = 410 ± 30) and (274.0 ± 6.9) × 104 mMNP-1s-1 per nanoparticle (r2/r1 = 781 ± 111) at 9.4 T, respectively. In addition, the influence of relative parameters such as rotation correlation time, diffusion time, and electronic relation time on relaxivity was theoretically investigated according to the outersphere theory. We found that r1 and r2 can be modulated by controlling the relative time constants which are related to the particle core size, surface coating, hydrodynamic size and magnetic field. The optimal strategy for increasing relaxivity was developed based on computer simulations. At last, the non-targeted rod-like NaDyF4 nanoparticles (25 nm × 35 nm) were successfully produced and used for brain and breast tumor MR imaging at 9.4 T in a total of 5 live animals. The results show that both NaDyF4 and NaHoF4 nanoparticles are suitable contrast agents for high-field (9.4 T) MRI.

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EXPERIMENTAL SECTION Chemical materials. All the raw materials were used as received without further purifications. Dysprosium chloride hexahydrate (>99.99%), holmium chloride hexahydrate (>99.9%), oleic acid (technical grade, 90%), 1-octadecene (technical grad, 90%), ammonium fluoride (>99.99%), hexane (ACS reagent, ≥98.5%) were purchased from Sigma Aldrich. 1,2-distearoyl-sn-glycero3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-mPEG2000, >99%) was purchased from Avanti Polar Lipids. Sodium hydroxide (pellets, reagent ACS) was purchased from ACP Chemicals Inc. Methanol (ACS, VWR), ethanol, dimethyl sulfoxide (DMSO), and chloroform were of analytical reagent grade. Synthesis of NaHoF4 and NaDyF4 nanoparticle. A high-temperature synthesis has been used to prepare NaHoF4 nanoparticles in a mixture of oleic acid and octadecene following established protocols with minor modifications.43−45 In a typical synthesis of NaHoF4 nanoparticles, a mixture of 1 mmol HoCl3·6H2O, 2.5 mL oleic acid (OA) and 7.5 mL 1-octadecene (ODE) were added to a 50 mL three-neck flask. The mixture was heated to 135 °C while stirring under vacuum and kept at this temperature about 30 minutes to form a clear Ho3+-oleate solution. After the oleate solution was cooled down to room temperature, a clear methanol solution (7.5 mL) containing 2.5 mmol NaOH and 4 mmol NH4F was added dropwise into the flask and kept stirring for at least 2 hours under air condition. Then the solution was slowly heated to 70 °C to remove methanol. Under argon atmosphere, the solution was quickly heated from 70 to 305 °C (20 °C/min) and maintained at this temperature for 60 minutes and then cooled down to room temperature. Next, the NaHoF4 nanoparticles were precipitated with adding ethanol (~35 mL) and centrifuged for 5 minutes at 5000 rpm (g-force = 2683). The supernatant was poured away and the washing process was repeated three times. Finally, the nanoparticles were dispersed in 10 9


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mL of hexane for storing. We prepared NaHoF4 nanoparticles with different shapes (hexagonal prism, spherical- and rod-like) and sizes (9 − 40 nm) by modulating the volume of OA and ODE, heating temperature and time (as shown in Supporting Information). The synthesis of NaDyF4 nanoparticles was similar to that of NaHoF4 nanoparticles, the main difference was that the Dy3+-oleate solution was formed at 140 °C for 30 minutes under vacuum, and the mixed solution was heated at 306 °C for 90 minutes under argon atmosphere. The shape and size of NaDyF4 nanoparticles were modulated by changing contents of NaOH and NH4F with 1.5 mL OA and 7.5 mL ODE (as detailed in the Supporting Information). Surface coating with PMAO-PEG polymer (the amphiphilic PMAO-PEG (poly(maleic anhydride-alt-1-octadecene)-polyethylene glycol) polymer was prepared by ourselves27 according to the protocol developed by Yu et al.46). Typical example of NaDyF4 coating: Firstly, 10 mg of NaDyF4 nanoparticles was dispersed in 1 mL chloroform solution and about 10 mg PMAO-PEG polymer was dissolved in 1 mL chloroform, and then the mixed solution was added into a flask and shaken for about 30 minutes. Secondly, the chloroform was completely removed by a rotary evaporator for 30 minutes and a thin layer was left on the wall of the flask. Thirdly, about 15 mL of deionized water was added to the flask and sonicated for about 5 minutes to form a cloudy solution. Finally, the cloudy solution was filtered with a 0.45 µm filter and a clear water solution of NaDyF4 coated with PMAO-PEG was obtained. Surface coating with DSPE-mPEG2000 (1,2-distearoyl-sn-glycero-3-phosphoethanolamineN-[methoxy(polyethylene glycol)-2000] (ammonium salt)). The commercial DSPE-mPEG2000 was used to modify the surface of NaHoF4 nanoparticles according to a reported method with a slight modification.47 Typical example: To coat 10 mg of NaHoF4 nanoparticles, about 0.5 mL solution (20 mg/mL) was used and hexane was removed under argon flow and followed by 10



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adding 0.5 mL chloroform. About 10 mg DSPE-mPEG2000 was dissolved in 1.5 mL chloroform. The two chloroform solutions were mixed together and shaken for 15 minutes in a shaker. Then 4 mL of DMSO (dimethyl sulfoxide) was added slowly to the mixture and shaken in a shaker for 30 minutes. Chloroform was removed by vaporization under vacuum. After that, 15 mL deionized water was added slowly to the colloidal solution in DMSO. DMSO was substituted with deionized water by centrifuging in special centrifugal filter tubes (Vivaspin Turbo 15, 100 kD cutoff size) 3 times with water. NaHoF4 nanoparticles coated with DSPE-mPEG2000 were dissolved in 1 mL deionized water at last. Characterization. The phase of NaDyF4 and NaHoF4 nanoparticles was characterized by an X-ray diffractometer with a Cr source operating at 30 kV and 15 mA (XRD, λ = 2.2890 Å). Transmission electron microscope (TEM, JEOL JEM-1400) was used to analyze morphology and sizes of the prepared particles. The size distribution of the nanoparticles was obtained from more than 50 nanoparticles on average. The software of ImageJ was used to measure the diameter of nanoparticles by hand and the size distribution was obtained with Gauss function fitting. The concentration of Ho3+ and Dy3+ ions in the water solution was measured with an inductively-coupled plasma mass spectrometer (ICP-MS, Thermo X-Series II(X7)). The magnetization of NaDyF4 and NaHoF4 nanoparticles were measured by a super conducting quantum interference device magnetometer (SQUID, Quantum Design, MPMS-XL) from -7 to 7 T at 300 K. The hydrodynamic sizes and zeta-potentials of NaDyF4 and NaHoF4 nanoparticles coated with PMAO-PEG and DSPE-mPEG2000 were investigated using dynamic light scattering (DLS, Brookhaven Zeta PALS). To obtain hydrodynamic sizes of the coated individual nanoparticles (and thus as a way to investigate if any dynamic aggregation occurs at the storage concentrations), several times of dilution and sonication were applied for each sample solution 11


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before measuring DLS. The hydrodynamic sizes of the nanoparticles were obtained as the DLS results became stable even with further dilution. The magnetic resonance relaxivities of NaHoF4 and NaDyF4 nanoparticles were measured with a 9.4 T and 21 cm bore magnet, and a Bruker console (Bruker, Karlsruhe, Germany). For T1 measurements, TRUE FISP method was used with the following parameters: slice thickness 2 mm, field of view (FOV) 30 × 30 mm, matrix size 128 × 128, echo time (TE) 1.5 ms, repetition time (TR) 3 ms, number of averages 8. For T2 measurements, we used Multi Slice Multi Echo Sequence (MSME), with the following parameters: slice thickness 2 mm, FOV = 30 mm × 30 mm, matrix size 128 × 128, TR = 7500 ms, numbers of echoes = 64, TE = 4 ms, number of averages 1. The T2 relaxation time was calculated by a single exponential fitting of the echo train. The T1 and T2 relaxation times were converted into relaxivity r1 and r2 using 1/Ti (i=1, 2) divided by molar concentration of Ho3+ or Dy3+ ions. The r1 or r2 per NP was calculated according to the density of NaLnF4, the total Ln3+ content from the ICP-MS, and the number of Ln3+-ions per NP (as detailed in the Supporting Information). Contrast-enhanced MR imaging of the animals was performed using tail injection of the rod-like NaDyF4 nanoparticles (25 nm× 35 nm). Three mice labeled NANO-V-38, -39, and -40 were used for brain tumor MR imaging, and two mice labeled NANO-VB-01 and -02 were used for breast tumor MR imaging. The MR images were obtained before and at different times (12 min − 24 h) after injection of 0.25 mL NaDyF4 nanoparticles (25 nm× 35 nm) in water (~ 2 mg/mL).

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RESULTS AND DISCUSSION Shape and size control As the shape and size of NaLnF4 nanoparticles have large influence on their properties, investigation of the growth rules of the NaDyF4 and NaHoF4 nanoparticles and optimization of their shapes and dimensions are needed. Spherical NaDyF4 nanoparticles were obtained with OA = 1.5 mL, ODE = 7.5 mL, NaOH = 2.5 mmol and NH4F = 4 mmol. The shape of the NaLnF4 nanoparticles was modulated by changing both the contents of NaOH and NH4F and the ratio of OA to ODE. Figure 1 displays the TEM images of the rod-like NaDyF4 nanoparticles with different sizes and Table 1 provides the sizes and intensity ratio of the (002) to (100) facets for the NaDyF4 and NaHoF4 nanoparticles. TEM images confirmed rod-like NaDyF4 nanoparticles with low size dispersion were indeed synthesized. The rod-like NaDyF4 nanoparticles were produced by controlling the amount of NaOH or NH4F. With increasing amount of NaOH (3.0 to 3.5 mmol), the average particle sizes can be tuned from 15 nm× 20 nm (Figure 1(a)) to 25 nm×

Figure 1. TEM images of the NaDyF4 nanoparticles in hexane with average size of 15 nm× 20 nm (a), 16 nm× 19 nm (b), 19 nm× 25 nm (c), and 25 nm× 35 nm (d). 13


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35 nm (Figure 1(d)). The ratio of OA/NaOH decreases with increasing NaOH content, leading to less selective adsorption of organic molecules that may inhibit the growth of the (001) facet, enabling easier grow along the perpendicular [100] direction.48 The intensity of (002)/(100) also increases with the increased NaOH (Table 1) according to the XRD results (Figures S1-S3), which confirms the competitive growth along the [100] and [001] directions. In addition, the rodlike NaDyF4 nanoparticles can be synthesized with increasing or decreasing amount of NH4F. Because attachment of OA is preferential to the (001) surface of NaLnF4 nanocrystals, and the number of F− ions is reduced for decreasing content of NH4F, which leads to the growth prohibition of the nanocrystal along [001] direction and results in the formation of compressed spherical particles (Figure 1(b), 16 nm× 19 nm).47 With increasing amounts of NH4F, there are more F− ions capping on the nanocrystal surface and less OA capping, which induces faster growth of the nanocrystal along [001] direction and rod-like NaDyF4 nanoparticles are produced (Figure 1(c), 19 nm× 25 nm).29 Increasing NH4F results in the decreased intensity ratio of the (002) to (100) facets. Table 1. The size of NaDyF4 and NaHoF4 nanoparticles produced in different preparation conditions.

Sample

Size (nm)

OA (mL)

ODE (mL)

NaOH (mmol)

NH4F (mmol)

Temperature (°C) and time (min)

NaDyF4

13

1.5

7.5

2.5

4.0

NaDyF4

15 × 20

1.5

7.5

3.0

NaDyF4

25 × 35

1.5

7.5

NaDyF4

16 × 19

1.5

NaDyF4

19 × 25

NaHoF4

306 / 90

Size of (100) (nm) 12

Size of (002) (nm) 15

Intensity ratio of (002) to (100) 0.6

4.0

306 / 90

14

21

0.4

3.5

4.0

306 / 95

21

32

0.9

7.5

2.5

3.5

306 / 90

14

22

0.6

1.5

7.5

2.5

4.5

306 / 90

16

26

0.3

23 × 27

1.5

7.5

2.5

4.0

300 / 60

19

24

0.9

NaHoF4

27 × 34

1.5

8.5

2.5

4.0

300 / 60

24

28

1.3

NaHoF4

38 × 41

1.5

7.5

2.5

4.0

305 / 60

33

36

1.4

NaHoF4

18 × 28

6.0

7.5

2.5

4.0

305 / 60

15

27

0.4

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In addition, different shapes and sizes of the NaHoF4 nanoparticles were also prepared and typical TEM images are shown in Figure 2 and Figure S4. The shape of the NaHoF4 nanoparticles was also modulated by the volume of OA and ODE. For the lower amount of OA (< 2 mL), the concentration of ligand OA was low and it tended to coat the (001) surface first, which led to the faster growth of nanocrystals in the [100] than that in the [001] direction. As a result, plate-like nanoparticles were produced.49 It can be seen from Figure S4 and Table 1 that the intensity and crystalline size of the (100) facet was less than that of the (002) facet. The average diagonal length of the hexagonal nanoparticles increased from 27 nm to 42 nm with the increasing heating temperature from 300 to 305 °C. For larger amount of OA (> 4.5 mL), the ligand concentration was high and the growth of the nanocrystals along the [100] direction was faster than that of the [001] direction. The rod-like shaped nanoparticles were formed using higher amount of OA, and the average particle size in Figure S4(d) (OA = 6 mL) is about 18 nm× 28 nm. For a specific volume of OA (2.5 − 3.5 mL), spherical NaHoF4 nanoparticles (Figure 2) can be produced due to the comparable growth rate of the nanocrystal along the [100]

Figure 2. TEM images of NaHoF4 nanoparticles in hexane with average size of 9.2 ± 0.6 nm (a), 13.7 ± 0.7 nm (b), 16.1 ± 0.9 nm (c), and 18.9 ± 0.9 nm (d). 15


Page 17 of 40

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and [001] directions. The spherical NaHoF4 nanoparticles with different sizes (9.5 − 19.5 nm) were prepared by changing the ratio of OA/ODE, heating temperature and heating time. The produced spherical nanoparticles are very uniform and have a narrow size distribution (Inset of Figure 2). The XRD patterns (Figure S3) indicate that all prepared samples have the hexagonal phase (JCPDS standard card no. 49-1896). The average nanoparticle sizes measured by the TEM are in good agreement with these obtained from the Scherrer equation.50 In the preparation of NaHoF4 nanoparticles, oleic acid has a great influence on the growth rate of nanoparticles in different directions and results in visible modulation of the shape of nanoparticles. The prepared NaDyF4 and NaHoF4 nanoparticles are hydrophobic and thus not suitable for biomedical applications. To enable in vivo applications, we transferred the nanoparticles to aqueous media by PMAO-PEG polymer coating27,46 and DSPE-mPEG2000 coating.47 The nanoparticles, following the phase transfer, show good dispersion in aqueous solution. Figure S5 shows TEM images of the rod-like NaDyF4 nanopartices with PMAO-PEG coating in deionized water. They have good dispersion in water after surface coating. Figure S6 shows the TEM images of the spherical NaHoF4 nanoparticles (10.6 ± 0.4, 14.1 ± 1.1, 16.4 ± 1.1, and 19.5 ± 0.8 nm, respectively) coated with DSPE-mPEG2000 in deionized water. The size distribution of the NaHoF4 nanoparticles after coating was not significantly different than before the phase transfer, showing that coated nanoparticles exhibit good dispersion in water. Figure S7 displays the TEM images of the NaHoF4 nanoparticles in deionized water coated with PMAO-PEG. The average particle sizes of the prepared NaHoF4 nanoparticles in hexane were 9.2 ± 0.6, 13.7 ± 0.7, 16.1 ± 0.9 and 18.9 ± 0.9 nm, respectively. After coating with PMAO-PEG, the average particle core sizes of the NaHoF4 nanoparticles, as measured by TEM were 10.2 ± 0.4, 14.5 ± 0.7, 16.4 ± 1.0 and 19.8 ± 0.8 nm, respectively. The PMAO-PEG/DSPE-mPEG2000 polymer layer around the 16



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Page 18 of 40

surface of nanoparticles is difficult to observe directly from the TEM images since the coating layer is very thin and organic in nature thus providing very little contrast. However, DLS shows coated particle size in the solution because it measures the hydrodynamic size that includes the organic stabilizing layer. Therefore, we measured the hydrodynamic size by DLS of the NaDyF4 and NaHoF4 nanoparticles coated with PMAO-PEG and DSPE-mPEG2000 in water (Figures S8−S10 and Table 2). The hydrodynamic size of NaHoF4 with DSPE-mPEG2000 coating increased from 25.5 ± 2.8 to 42.4 ± 2.6 nm as the core size increased from 10.6 ± 0.4 to 16.4 ± 1.1 nm, while the hydrodynamic size with PMAO-PEG coating did not follow a clear trend with the increased core size, which might be caused by a different coating process between DSPEmPEG (dual solvent exchange method) and PMAO-PEG (ligand exchange method). The hydrodynamic size of the rod-like NaDyF4 nanoparticles in water was in the range of 45.5 ± 3.6 − 62.7 ± 6.5 nm. In addition, the zeta-potential of the nanoparticles with DSPE-mPEG2000 coating (< -5 mV) was less negative than that of larger nanoparticles with PMAO-PEG coating (4.8 to -28.7 mV), which we attribute to the numerous ionized carboxyl groups of PMAO-PEG, relative to the number of negatively charged moieties in solution. The nanoparticles with larger zeta-potential have better stability in water than that with smaller zeta-potential, but too large a zeta-potential is usually undesired51,52 because of non-specific binding to proteins and cell walls, thus a compromise has to be made for biological applications. The rate of uptake and retention in the cells is strongly correlated with nanoparticle’s surface charges, ligand chemistry and size. In addition, the toxicity of lanthanide-based nanoparticles coated with PEG or PMAO-PEG is very low according to the previous research[m], which is favourable for the biomedical application. MR Relaxivity of NaDyF4 and NaHoF4 nanoparticles

17


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The impact of the particle size, surface coating, shape, zeta-potential, and type of ions (Dy3+ and Ho3+) on the relaxivity of the NaHoF4 and NaDyF4 nanoparticles at high magnetic fields (9.4 T) is summarized in Table 2. The relaxivities were obtained by a linear fitting of the reciprocal of relaxation times with different ion concentrations. Figure 3 shows typical r1 and r2 relaxivities at 9.4 T as well as phantom MR images of the spherical NaHoF4 (~17 nm) and rod-like NaDyF4 (19 nm× 25 nm) nanoparticles coated with PMAO-PEG as a function of Ho3+ and Dy3+ concentration, Table 2. Core and hydrodynamic size, zeta-potential and relaxivity (9.4 T) of the NaHoF4 and NaDyF4 nanoparticles coated with DSPE-mPEG2000 and PMAO-PEG (SD-standard deviation, SE-standard error). L/a [SD]

a2/(1+ L/a) [SD]

r1 per ion (mM-1 s-1) [SE]

10.6 [0.4]

Hydrod ynamic size 2(L+a) (nm) [SD] 25.5 [2.8]

1.4 [0.4]

12.0 [2.0]

14.1 [1.1]

33.7 [5.8]

1.4 [0.6]

16.4 [1.1]

42.4 [2.6]

10.2 [0.4]

r2 per ion (mM-1 s-1) [SE]

0.18 [0.008]

r1 per NPs (mMNP -1 -1 s ) [SD] ×102 10.2 [0.5]

r2/r1 [SD]

Zetapotential (mV) [SD]

31.9 [4.7]

r2 per NPs (mMNP -1 -1 s ) [SD] ×104 18.1 [2.7]

179 [34]

-4.4 [0.2]

22.1 [5.5]

0.25 [0.025]

33.3 [3.3]

51.5 [5.5]

68.7 [7.3]

210 [43]

-4.4 [0.2]

1.6 [0.3]

26.2 [3.0]

0.22 [0.04]

46.2 [8.4]

70.4 [16.6]

147.7 [34.8]

347 [142]

-2.8 [0.2]

45.1 [6.6]

3.5 [0.8]

6.2 [1.6]

0.06 [0.005]

3.0 [0.3]

15.0 [0.6]

7.6 [0.3]

241 [28]

-12.7 [0.8]

14.5 [0.7]

40.7 [3.4]

1.8 [0.4]

19.2 [2.7]

0.15 [0.001]

21.8 [0.2]

61.0 [1.7]

88.5 [2.5]

407 [14]

-13.4 [2.2]

16.4 [1.0]

44.1 [3.6]

1.7 [0.4]

25.5 [3.8]

0.17 [0.02]

35.7 [4.2]

130.6 [3.3]

274.0 [6.9]

781 [111]

-24.5 [2.9]

16×19 deff=18. 5

45.5 [3.6]

1.5 [0.2]

34.4 [2.8]

0.24 [0.002]

108.2 [0.9]

75.0 [0.5]

338.0 [2.3]

313 [5]

-4.8 [0.9]

NaDyF4 coated with PMAO-PEG

15×20 deff=18. 9

48.2 [4.6]

1.6 [0.2]

34.5 [2.7]

0.16 [0.005]

76.9 [2.4]

65.2 [2.9]

313.3 [13.5]

408 [31]

-2.2 [0.4]


19×25 deff=23. 8

62.7 [6.5]

1.6 [0.3]

54.4 [5.6]

0.13 [0.006]

158.9 [7.3]

91.4 [4.6]

1117.2 [56.2]

706 [68]

-28.7 [2.1]


25×35 deff=32. 0

61.2 [3.1]

0.9 [0.1]

135.1 [7.1]

0.50 [0.02]

1166.2 [46.7]

204.4 [6.9]

4767.3 [160.9]

410 [30]

-24.1 [1.6]

Nanoparticle

Core size 2a (nm) [SD]

NaHoF4 coated with DSPE-mPEG NaHoF4 coated with DSPE-mPEG NaHoF4 coated with DSPE-mPEG NaHoF4 coated with PMAO-PEG NaHoF4 coated with PMAO-PEG NaHoF4 coated with PMAO-PEG NaDyF4 coated with PMAO-PEG

18



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Page 20 of 40

Figure 3. Relaxivity r1 (left) and r2 (right) and phantom images of water solutions of NaHoF4 (top, ~17 nm) and NaDyF4 (bottom, 19 nm× 25 nm) nanoparticles with PMAO-PEG coating and different concentrations.

respectively. Both r1 and r2 values increased with Ho3+ and Dy3+ concentration and the T2– weighted images became darker at higher concentrations. According to the slope of fitting curves, the r1 values of NaHoF4 and NaDyF4 were 0.17 ± 0.02 and 0.13 ± 0.01 mM-1s-1, and r2 values for NaHoF4 and NaDyF4 were 130.6 ± 3.3 mM-1s-1 and 91.4 ± 4.6 mM-1s-1, respectively. There are lots of lanthanide ions in one nanoparticle, which leads to the large increase of the transverse relaxivities. According to the density of NaLnF4, the size and volume of one nanoparticle, and the total Ln3+ contents from the ICP-MS results, the relaxivity per nanoparticle (mMNP-1s-1) can be obtained. The bigger nanoparticles have larger r1 and r2 values as the values of r1 and r2 per ion are fixed. The maximum of r2 for one NaHoF4 (~ 17 nm) and NaDyF4 (25 nm × 35 nm) can be up to (274.0 ± 6.9) × 104 (130.6 ± 3.3 mM-1s-1 per Ho3+ ion) and (4767.3 ± 160.9) × 104 mMNP-1s-1 (204.4 ± 6.9 mM-1s-1 per Dy3+ ion), respectively. In addition, the maximum ratio of r2 to r1 for NaHoF4 and NaDyF4 was 781 ± 111 and 706 ± 68, respectively, which indicates both 19


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NaHoF4 and NaDyF4 are suitable as T2 contrast agents for MRI at high magnetic fields. There are two contributions to the theory explaining the relaxivity, depending on whether the water protons merely diffuse past the magnetic particles (“outer sphere”) or temporarily bind to them (“inner sphere”).54,55 For lanthanide-based complexes, both inner- and outer-sphere contribution should be considered since water will bind to lanthanide ions. In this work, the surface coating of DSPE-mPEG and PMAO-PEG can be served as a hydrophobic barrier (so we assume it has very little water diffusion) of nanoparticles, which leads to that the relaxivity is mainly originated from the outer-sphere contribution since the inner-sphere contribution is expected to be negligible.19, 56 On the basis of the quantum mechanical outer-sphere theory, the T2 relaxivity is described by:19,54−56 V MS

T

V

D

L

N

(1) (2)

where γ is the proton gyromagnetic ratio, V*, MS, and a are the volume fraction, saturation magnetization (for Ln3+-based nanoparticles, MS should be substituted by MT which is the magnetization in a certain magnetic field (the same as T2 measuring field)), and the radius of nanoparticle core, respectively. N0 is Avogadro’s constant, M is molarity (mole/liter) of nanoparticles, D is the diffusivity of water molecules, and L is the thickness of an impermeable surface coating which corresponds to the hydrodynamic sizes of the NaHoF4 and NaDyF4 nanoparticles. From the equations (1) and (2), one can see that the r2 increases when L/a is decreasing and when a2/(1+L/a), V*, and MS are increasing. Therefore, the value of r2 can be optimized by controlling the particle size, shape, surface coating and magnetic moment. The r2 can thus be 20



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Page 22 of 40

increased with increased core size of the spherical and rod-like nanoparticles: the larger the particle size the larger V* and MT which causes increase of r2 values.57 The magnetic properties of the NaDyF4 and NaHoF4 nanoparticles were measured by SQUID magnetometry (Figure S11). As can be seen the nanoparticles are paramagnetic, and show no sign of saturating even at the highest field of 7 T. The magnetic moment for NaDyF4 was increased from 6.4 (16 nm × 19 nm) to 10.8 (25 nm × 35 nm) emu/g at 7 T. The magnetic moment of NaHoF4 was also increased from 6.7 (~15 nm) to 12.9 (~22 nm) emu/g with increasing particle size at 7 T. The relationship between the nanoparticle size and r2 is shown in Table 2. Moreover, surface coating is another effective parameter to improve r2 because it affects magnetization of nanoparticles. Decreasing the thickness L or L/a of the surface coating layer increases the r2 value. This effect is clearly seen in Table 2 that the r2 value for NaHoF4 nanoparticles coated with PMAO-PEG is increased from (7.6 ± 0.3) × 104 to (274.0 ± 6.9) × 104 mMNP-1s-1 per nanoparticle as L/a decreases from 3.5 ± 0.8 to 1.7 ± 0.4. The zeta-potential changes significantly for different surface coating which in turn impacts the stability of nanoparticles in aqueous solution. There is no obvious direct influence of the zeta-potential on relaxivity as seen in the data in Table 2. For Ln3+-based nanoparticles, Ho3+- and Dy3+-based nanoparticles have larger r2 values than other Ln3+-based nanoparticles because they have largest effective magnetic moment (~10.6 µB)8 which leads to larger magnetization at high magnetic field. In addition, high concentration of Ln3+ ions in one nanoparticle and larger M (higher concentration of Ln-based nanoparticles in a certain volume of solution), which will increase V* and thus results in the increased r2 values. Compared with typically reported T1 and T2 contrast agents as shown in Table 3, it can be seen that the Gd3+-based nanoparticles have higher relaxivity r1 than that of Gd3+-based complexes. The r1 value for Gd3+-based nanoparticles can be improved by decreasing the particle size and 21


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changing surface coating, which may be accomplished by the change of selected time-related parameters such as tumbling and diffusion time. Moreover, the value of r1 reduces with the increasing magnetic field, which is attributed to the varied contribution of dipolar and Curie Table 3. The reported relaxivity values of T1 and T2 contrast agents (SD-standard deviation). Samples

Size (nm)

Coating

Gd-DTPA

r1 per ion (mM-1s-1) [SD]

r1 per NP (mMNP-1 s-1) [SD] ×102

4.3

r2 per ion (mM-1s-1) [SD]

r2 per NP (mMNP-1 s-1) [SD] ×104

4.9

Field (T)

r2/r1 [SD]

Ref

1.41

1.1

59

Gd2O3

50

Silica

0.31

3314.8

4.7

60

Gd2O3

10

Silica

3.49

298.6

4.7

60

Gd2O3

4.6

DEG

4.4

36.6

GdF3

PAA

1.44

Gd2O3

30 ‒ 50 2

Oleic acid

8.0

5.5

24.1

0.2

1.41

3.0

15

Gd2O3

2

PAA-OA

47.2

32.3

82.4

0.6

1.41

1.7

15

Gd2O3

1.3

PEG

16.2

3.0

17.7

0.03

0.47

1.1

10

Gd2O3

1.3

PEG

10.4

2.0

17.2

0.03

11.7

1.7

10

NaGdF4

2.5

PVP

7.2

7.0

22.7

0.2

1.5

3.2

14

NaGdF4

8.0

PVP

3.0

95.6

28.9

2.4

7.0

6.6

9.4

61 62

1.5

14

18.8

9.4

63

36.0

11.75

64

Dy-DOTA(gly)2 Dy-DTPABC12pheA Dy2O3

70

dextran

190

85979.5

7

58

Dy2O3

70

dextran

675

305453.4

17.6

58

Dy2O3

2.9

40.3

1.3

3

252

41

Ho2O3

2.4

31.2

0.6

3

240

41

NaHoF4

12

36.0

29.6

3

307

36

NaDyF4: Tb3+

30 × 35

22.3

750.5

7

NaDyF4

20.3

D-glucuronic acid D-glucuronic acid DSPEPEG2000NH2 Cetyltrimeth ylammonium bromide (CTAB) PMAO-PEG

101

601.4

9.4

306

27

NaHoF4

17

PMAO-PEG

25 × 35

PMAO-PEG

274.0 [6.9] 4767.3 [160.9]

9.4

NaDyF4

130.6 [3.3] 204.4 [6.9]

781 [111] 410 [30]

This work This work

0.17 [0.02] 0.50 [0.02]

35.7 [4.2] 1166.2 [46.7]

22


9.4

14


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Page 24 of 40

component. In addition, the Dy3+-based complex (Dy-DOTA-(gly)2) has low r2 relaxivity (18.8 mM-1s-1) at the high field (9.4 T) because there is only one dysprosium ion in one molecular unit, which limits the enhancement of its relaxivity. The Dy3+-based nanoparticles have higher r2 relaxivity for larger particle size at the high field. Norek et al.58 tuned the particle size of Dy2O3 for optimal performance for very high-field MRI, and the particle size providing the maximum r2 relaxivity was found to vary between 70 nm at 7 T (r2 ≈ 190 mM-1s-1) and 60 nm at 17.6 T (r2 ≈ 675 mM-1s-1). In case of Dy3+-based fluoride nanoparticles, Zhang et al.28 synthesized NaDyF4: Tb3+ nanocrystals as multifunctional contrast agents for high-field magnetic resonance (r2 = 22.3 mM-1s-1 at 7 T with 30 nm × 35 nm) and optical imaging. We obtained spherical NaDyF4 nanoparticles (20.3 ± 1.7 nm) with high relaxivity r2 = 101 mM-1s-1 per ion (r2/r1 = 306) at 9.4 T and r2 = 15.8 mM-1s-1 (r2/r1 = 61) at 3.0 T.27 It can also be seen from Table 3 that the value of r2 for Ho2O3 and Dy2O3 nanoparticles with very small sizes (~ 3 nm) is about 30 − 40 mM-1s-1 at 3 T, but too small nanoparticles are quickly removed from blood system due to their short blood half-life and low EPR (enhanced permeability and retention) effect,31 which limits their application for (targeted) imaging. For the reported NaHoF4 and NaDyF4 nanoparticles, the value of r2 was 36.0 mM-1s-1 at 3 T and 101 mM-1s-1 at 9.4 T, respectively. The ratio of r2 to r1 was 307 and 306 for NaHoF4 and NaDyF4, respectively. In this work, the NaHoF4 and NaDyF4 nanoparticles showed large values of r2 ((274.0 ± 6.9) × 104 and (4767.3 ± 160.9) × 104 mMNP-1 s-1 per nanoparticle) at the high field (9.4 T), and the very high ratios of r2 to r1 have been achieved (781 ± 111 and 410 ± 30). These results make the nanoparticles suitable for T2weighted MR imaging at high magnetic field. Modeling of relaxivity To explore further the inherent reasons which influence the r1 and r2, we performed computer 23


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simulations of r1 and r2 using the outer-sphere theory. We investigated the impact of the particle size, hydrodynamic size, magnetic field, diffusion time and electronic relation time on r1 and r2. The outer-sphere relaxivities r1OS and r2OS can be calculated from the following equations: 40,65−68 16 135

3 1

1000 7

16 135 4

0,

1000 ,

13

/

2

/

/ ,

1

2

,

,

,

,

,

3

,

/

3 3

,

, 4

(3) , 0, (4)

where L(x) is Langevin function (x = µB0/kBT), B0 is the magnetic field, µ is the magnetic moment of a nanoparticle (µ = M0 ×B0 ×ρ × 4πa3/3), ρ is the density of nanoparticle, a is the core radius of nanoparticles and M0 is their magnetization (M0 is field dependent for paramagnetic nanoparticles and we fixed M0 = 1 emu/g/T in the simulation process.). NA is Avogadro number, [M] is the molar concentration of magnetized nanoparticles (in moles per liter) and [M] can be expressed as [M] = [Ln]Mn/(4πρNAa3/3), Mn is the molar mass of NaLnF4 and [Ln] is the mole concentration of lanthanide ions (fixed at 5 mM in the simulation process), r is the hydrodynamic radius of the nanoparticles and D is the water diffusion constant, τd is diffusion time (τd = r2/D), T1e and T2e are electronic relation times. ωI and ωS are the angular precession frequencies of proton and electron (ωS = 658ωI), respectively. The jD and jχ are spectral density functions for dipolar and Curie interactions, respectively (Supporting Information). According to the outer-sphere theory, dipolar and Curie interactions are the major contributors to the relaxivity (see also Supporting Information). The dipolar interaction is a spatial effect which originates from dipolar coupling between the spins of the unpaired electrons of the 24



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Page 26 of 40

lanthanide ions and nuclear spins. The dipolar contribution is described by a correlation time τCi (equation S(3)). When the magnetic field is low (< 0.1 T), dipolar correlation time τC1 is mainly dominated by T1e (10-12 − 10-5 s) because T1e is shorter than τd. However, the dipolar correlation time τC1 is determined by τd since T1e becomes longer and τd is shorter than other time constants with increasing magnetic field. For the dipolar correlation time τC2, the T2e is shorter (order of ps) and τC2 is dominated by T2e until it reaches ~10 ns and then τC2 is affected by τd, which indicates that τC2 is mainly dominated by T2e. Therefore, the dipolar contribution τCi can be modulated by both τd and Tie (Figure S16). The Curie component is caused by the dipolar interaction of the nuclei with the thermal average of electron spin polarization, which is described by the correlation time τCC (equation S(4)).39 The Curie contribution and correlation time τCC are mainly modulated by τR (for inner sphere) or τd (for outer sphere) since τM is usually significantly longer than τR or τd (Figure S17). In addition, the longer τM influences the solvent proton relaxation rate the lower the value of r1 relaxivity.40 From equation (3), we simulated r1OS as a function of the core size a (5, 10, 15 nm), hydrodynamic radius r (20 − 100 nm), magnetic field B0 (0.1 − 10 T), diffusion time τd (150 − 3800 ns) and electronic relation time τS (0.01 − 1000 ns). The simulation results are shown in Figure S20. According to the simulated results, the value of r1 is decreasing with increasing Larmor frequency, and it approaches zero for higher Larmor frequency (>1 MHz corresponding to 0.02 T) (Figure 4(a)). The modulation of r1 mainly occurs at the low Larmor frequency (below 1 MHz) and has the following behavior: (a) With the increasing particle size, the value of r1 increases about 30 folds as the core size increases about 3 times; (b) The value of r1 decreases rapidly with the increased hydrodynamic size of the nanoparticle; (c) The higher magnetic field 25


Page 27 of 40

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Figure 4. Computer simulation curves of the relaxivity r1 (left) and r2 (right) with different hydrodynamic radius r = 20 − 100 nm (τd = 152 − 3802 ns) and the fixed core size a = 10 nm, τS = 10 ns, and B0 = 10 T.

B0 the larger magnetic moment (µ) of the nanoparticle thus the increase of r1; (d) Faster diffusion decreases r1 value; (e) The value of r1 is not sensitive to electronic relation time as τS = 0.01 − 1000 ns. This behavior of r1 originates from the contribution of dipolar and Curie component. At the lower Larmor frequency (< 10 MHz), T1e is shorter than τd and the dipolar contribution is predominant. For the higher Larmor frequency (>10 MHz), T1e is increased and the Curie term modulated by τd becomes significant. In addition, the Curie interaction become dominant at the high magnetic field and Jχ departs from a flat curve (fixed constant smaller than 1) to a lower constant (close to 0) with increasing Larmor frequency. Therefore, the value of r1 is affected by τd only at the lower frequency, and r1 decreases with increasing Larmor frequency due to the change of Jχ. According to the simulation and experimental results, an effective correlation has been built between theory and experiments. The relaxivities (trends) can be estimated according to the simulation by modulating the particle sizes, surface coating, coating layer thickness and magnetic fields, which will make the optimization of the relaxivities less trial and error. In addition, we also simulated the r2 values using equation (4) with various core sizes (a = 5, 10, 15 nm), magnetic fields (B0 = 0.1 − 10 T), hydrodynamic radii (r = 20 − 100 nm), diffusion times (τd = 150 − 3800 ns), and electronic relation times (τS = 0.01−1000 ns). The simulation results are shown in Figure S21 and we conclude: (a) the particle core size also has large 26



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influence on r2, whose value can be increased thirty times as the core size increases three times (from 5 nm to 15 nm); (b) the transverse relaxation is low at the low magnetic fields (< 1 T) due to the smaller magnetization of nanoparticles. With the increasing magnetic field, µ increases and Curie contribution becomes predominant which leads to the increase of the r2 value; (c) the value of r2 increases 100 times when the magnetic field increases from 1 T to 10 T; (d) the hydrodynamic size or thickness of the coating layer decreases the value of r2 about 5 times as the hydrodynamic radius increases 5 times (from 20 to 100 nm) as shown in Figure 4(b). This process is likely caused by the reduction of magnetization of the nanoparticles due to the influence of the coating layer; (e) the value of r2 is not sensitive to electronic relation time as τS = 0.01 − 10 ns, but larger electronic relation time (> 100 ns) increases r2. The dipolar interaction contribution is predominant for r2 when electronic relation time is short, and the values of r2 decreases with the increasing Larmor frequency and becomes constant at higher frequency due to the change of T1e and T2e (Figure S15). For longer electronic relation times such as τS = 1000 ns, the diffusion time τd becomes predominant and the contribution of Curie interaction for r2 is thus enhanced. The simulated values of r2 is not far from the experimental results and the trends between simulation and experimental results are in agreement, which indicates the simulation can be used as design rules of Ln3+-based nanoparticles for MRI application. The values of relaxivity can be optimised by modulating the above key parameters and thus the dipolar and Curie contribution before experiments. In vivo imaging To demonstrate the potential of NaHoF4 or NaDyF4 nanoparticles in in vivo MRI, we imaged five animals before and after intravenous injection of 0.25 mL NaDyF4 (25 nm × 35 nm) solution (2 mg/mL) because it showed large values of r2 and r2/r1 and it probably has the largest EPR 27


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effect. We imaged three mice (NANO-V-37, 38, 39) with brain tumor (high-grade glioma) and two mice (NANO-VB-01, 02) with breast tumor (triple-negative) using T2-weighted MRI. The MR images and T2 relaxation times of the animals before and after injection are shown in Figures S22−S26 and Table S3−S7. Figure 5 shows an MR image of the brain (NANO-V-38) and breast tumor (NANO-VB-02) before and 12 min after injection. The contrast between tumor and the brain tissue is clearly visible in Figures 5(a) and 5(b). The increased contrast is caused by the magnetic action of the nanoparticles and their accumulation within the tumor due to its higher (leaky) vasculature7 than the normal tissue and the EPR effect. In brain-tumor imaging, before injection, the T2 of tumor was 51.9 ± 1.6 ms, and its value decreased to 48.4 ± 1.4 ms and 48.0 ± 1.4 ms 12 min 30 min after injection respectively and it increased to 50.4 ± 1.5 ms 2 h after injection and slightly decreased to 48.9 ± 1.5 ms 24 h after injection, which suggested competition of retention and removal of NaDyF4 nanoparticles from the tumor. The maximum

Figure 5. In vivo T2–weighted MR images of tumor bearing mice: brain tumor (top-NANO-V-38) and breast tumor (bottom-NANO-VB-02) before (left) and 12 min post injection (right) of the NaDyF4 nanoparticles.

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reduction of T2 was about 7.5% for brain tumor 30 min after injection in NANO-V-38 mouse. The maximum reduction of T2 in brain tumor in the NANO-V-39 mouse was just after injection and in the NANO-V-40 mouse 2 h after injection, it was 5.4% and 6.1%, respectively. The visible contrast and consistent results in the three mice indicate reproducibility and desired effect of the rod-like NaDyF4 nanoparticles on T2-weighted imaging of brain tumor in vivo. In T2-weighted MR imaging of the breast cancer model, T2 of breast tumor decreased from 87.9 ± 3.1 ms to 84.8 ± 2.9 ms after injection in the NANO-VB-01 mouse, and the maximum T2 reduction was about 3.5% just after injection. In addition, the T2 value of breast tumor in the NANO-VB-02 mouse changed from 53.2 ± 2.3 ms before injection to 46.0 ± 1.9 ms 12 min after injection (Figures 5(c) and 5(d)), and the maximum reduction of T2 was 13.5% just after injection. The large decrease of T2 of breast tumor indicated that the rod-like NaDyF4 nanoparticles are also suitable for breast-tumor MRI. These in vivo results suggest that the rodlike NaDyF4 nanoparticles can be used as high performance T2 contrast agents for brain- and breast-tumor imaging at 9.4 T. They are also good candidates for targeted contrast agents in molecular MR imaging68 as the conjugation with, for example, tumor specific antibodies, will make them even more efficient as contrast agents due to their selective targeting.

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CONCLUSION In summary, the rod-like NaDyF4 and NaHoF4 nanoparticles with hexagonal prism, sphericaland rod-like shape were prepared using a high temperature synthesis process. The structure and growth rules of the NaDyF4 and NaHoF4 nanoparticles were investigated and the effects of the particle size, surface coating and related time constants on relaxivity of the prepared nanoparticles were studied. In addition, we simulated the effects of particle sizes, magnetic fields, diffusion times and electronic relation times on r1 and r2 for the nanoparticles according to the outer-sphere theory. All the samples were of the hexagonal crystal structure, and the particle size was controlled by the volume of oleic acid and octadecence, heating time and temperature. The shapes were also controlled by changing the amount of NaOH and NH4F. The NaHoF4 and NaDyF4 became hydrophilic with DSPE-mPEG2000 and PMAO-PEG coating. The values of r2 for NaHoF4 (17 nm) and NaDyF4 (25 nm× 35 nm) nanoparticles with PMAO-PEG coating were and (274.0 ± 6.9) × 104 mM-1s-1 (r2/r1 = 781 ±111) and (4767.3 ± 160.9) × 104 mMNP-1s-1 per nanoparticle respectively (r2/r1 = 410 ± 30) at 9.4 T, and both the samples were found to be suitable as T2 contrast agents for MRI at 9.4 T. The simulation results indicate that r1 and r2 relaxivities could be increased about 30 times with the increase of the particle core size from 5 nm to 15 nm. The (theoretical) relaxivities increased about 100 times when the magnetic field is increased from 1 to 10 T. Both r1 and r2 values decreased about 5 times as the hydrodynamic size and diffusion times increased 5 and 25 times, respectively. In addition, the value of r1 can be controlled by the core size, hydrodynamic size, magnetic field and diffusion time mainly at proton Larmor frequencies below 1 MHz. The r1 does not strongly depend on electronic relation time, but longer electronic relation time increases r2. In vivo MR animal imaging showed that the rod-like NaDyF4 nanoparticles are suitable for tumor MR imaging since they have better EPR 30



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effects. Both NaDyF4 and NaHoF4 nanoparticles are good candidates for T2 contrast agents for high-field (9.4 T) MRI.

ASSOCIATED CONTENT Supporting Information Synthesis, surface coating and characterization of NaDyF4 and NaHoF4 nanoparticles in detail. XRD, TEM, DLS, magnetic measurements and relaxivity results for prepared nanoparticles. Tables of rotation and diffusion times for hydrodynamic sizes of nanoparticles. Simulation results of electronic relation times, dipolar and Curie correlation times, spectral density function, relaxivities of r1 and r2. In vivo imaging results of five mice with brain (three) and breast tumor (two) before and after injection of rod-like NaDyF4 nanoparticles. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] (Xinghua Zhang). *E-mail: [email protected] (Frank C. J. M. van Veggel). Author Contributions All authors contributed to writing the manuscript and approved the final version of the manuscript. Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS This work was supported by CSC (China Scholarship Council), NSERC (Natural Science and Engineering Council of Canada) and the Alberta Innovates Health Solutions programme, 31


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Collaborative Research and Innovation Opportunities (CRIO) with Grant Number 201200833. Thanks to Jody Spence for the measurements of ICP-MS.

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