Anchoring Ligand-Effect on Bright Contrast-Enhancing Property of

Jun 13, 2018 - Anchoring Ligand-Effect on Bright Contrast-Enhancing Property of Hollow Mn3O4 Nanoparticle in T1-Weighted Magnetic Resonance Imaging...
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Cite This: Chem. Mater. 2018, 30, 4056−4064

Anchoring Ligand-Effect on Bright Contrast-Enhancing Property of Hollow Mn3O4 Nanoparticle in T1‑Weighted Magnetic Resonance Imaging Jihwan Lee,† Nitee Kumari,† Soo Min Kim,† Seonock Kim,† Ki-Wan Jeon,† Geun Ho Im,‡ Moon-Sun Jang,‡ Won Jae Lee,‡ Jung Hee Lee,*,‡ and In Su Lee*,†

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National Creative Research Initiative Center for Nanospace-confined Chemical Reactions (NCCRs) and Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea ‡ Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine and Center for Molecular and Cellular Imaging, Samsung Biomedical Research Institute, Seoul 06351, Korea S Supporting Information *

ABSTRACT: Here, we describe and conceptualize the influence of surface engineering for hollow manganese oxide nanoparticles (HMONs)-based contrast agents for magnetic resonance imaging (MRI). A systematic study has been conducted for enhancing the relaxivities of HMONs by functionalizing their surface with various capping ligands having different anchoring groups (carboxylate, alcohol, thiol, and amine). Among all studied ligands, carboxylate-anchored ligands exhibit significant increase in magnetization value upon surface capping of HMON. Contrary to the previous hypotheses based on the surface-Mn2+ ions accessibility to water molecules, we proposed surface capping induced magnetization in HMON is responsible for the enhanced relaxivity (r1) value. Further, in vivo imaging efficacy of oleate-capped HMON (OA-HMON) has been demonstrated in mouse brain. This study provides an insightful understanding of contrast enhancement and modulation by surface ligands on manganese oxide-based T1-contrast agents.

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abundant and disease-specific biomarkers.3−7 Most efforts with NP-CAs so far have gone into developing superparamagnetic NPs, especially of iron oxide (IO), which cause signal loss in T2/T2* weighted MRI (T2-MRI), successfully demonstrating the high sensitivity imaging of small early stage tumors.8−11 However, these superparamagnetic iron oxide nanoparticle (SPIONs)-based CAs are laden with numerous drawbacks that restrain their extensive clinical applications: their intrinsic dark signals and lower contrast images in MRI, which are difficult to distinguish with other hypointense areas evolved from pathogenic conditions such as blood clots, calcification or metal deposition (endogenous iron); hence, resulting in less accurate diagnosis of patients.12−14 Furthermore, the susceptibility artifacts of SPIONs arising from the their high magnetic moment induces the magnetic field perturbation on the protons of neighboring normal tissue, and therefore results in the blurry MRI images.13 In addition, short blood circulation time and

INTRODUCTION The contrast agents (CAs) have become the essential and critical element for accurate and confident disease diagnosis with magnetic resonance imaging (MRI), which requires sensitive and spatially resolved contrast difference between normal and tumor tissues.1 In the current clinical MRI, molecular complexes of highly paramagnetic Gd3+, functioning by shortening the magnetic relaxation times of water protons through the dynamic exchange process and thereby enhancing the signal intensity in the T1-weighted MRI (T1-MRI), are used nearly exclusively as CAs.2 Short blood residual time allows the use of molecular Gd3+-CAs for the vascularity-based diagnosis by acquiring the dynamic T1-MRI in the early arterial phase. Recently, colloidal inorganic nanoparticles (NPs) have received significant attention as a new class of CAs, opening up the scope of MRI toward the molecular and cellular imaging, which could not be accessed with Gd3+-CAs. Because of their many superior properties, such as long blood circulation time, high payload of magnetic elements, easy and versatile conjugation of targeting molecules onto the surface, NP-CAs have been proved to be the most effective in the targeted imaging of low© 2018 American Chemical Society

Received: February 27, 2018 Revised: June 4, 2018 Published: June 13, 2018 4056

DOI: 10.1021/acs.chemmater.8b00854 Chem. Mater. 2018, 30, 4056−4064

Article

Chemistry of Materials

Chem., 99%), succinic acid (Samchun Chem., 99.3%), glycine (Samchun Chem., 99.8%), potassium hydroxide (Samchun Chem., 95%) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N[methoxy(polyethylene glycol)-2000] (Phospholipid, Avanti Polar Lipids, Inc.), dopamine-modified monomethoxypolyethylene glycol (Biochempeg, MW = 2000), bisphosphonate-modified monomethoxypolyethylene glycol (Surfactis Tech., MW = 2000), and Gd-DOTA complex (DOTAREM, Geurbet) were used as purchased without any purification. All used abbreviations are defined in Table 1.

rapid uptake of SPIONs by the liver Kupffer cells lead to their fast excretion from the body.15 For these aforementioned reasons, many SPION-CAs have been withdrawn from the market, and therefore considerable efforts have been devoted for the development of new positive and high-sensitivity-CAs for T1-MRI.16−20 Because manganese oxide NPs (MONs, e.g., MnO, Mn3O4) had first been evaluated as a positive CA for T1-MRI,21 several effective attempts were made recently to fabricate MON-CAs and to prove their effectiveness for the bright enhancement of target disease tissues in the in vivo T1-MRI.22−34 Most of the strategies for enhanced relaxivities so far have been devised based on the rationale to maximize surface area that expose paramagnetic Mn2+ ions, by maneuvering morphology to have large surface-to-volume ratio, 24−28 and to increase the accessibility of water molecules to their surface through optimizing its surface coating ligands (Table S1).29−34 For instance, in our previous work, hollow Mn3O4 NPs (HMON) was found to have a greatly enhanced relaxivity (r1 = 1.417 mM−1·s−1), compared with its solid-interior analogue (r1 = 0.209 mM−1·s−1), which is attributed to the increased wateraccessible surface area.27 However, for realizing a sufficiently high tumor/normal ratio in the T1-MRI, comparable to that with superparamagnetic NPs, an innovative strategy is needed to further improve the current state-of-the-art MON-CA, which must be preceded by the systematic study to find out the morphological and chemical factors determining the relaxivities. In this regard, our report suggests the very crucial role of surface anchoring ligands for enhancing MRI relaxation properties of MONs, which has not been comprehended so far in designing MRI-CAs. In the course of our effort to fabricate high-relaxivity MONCAs, whose surface is fully exposed to the water molecules, we found the relaxivity of the HMONs to be boosted up by the surface-capping having carboxylate-anchoring ligands. Although, there are few reports for tailoring the magnetic properties and relaxivity of iron oxide-based CAs as a function of the surface capping ligand,35−37 which has been explained theoretically by the enhanced surface spin disorder degree of NPs on coating with surface ligand, this report presents the first systematic investigation on the effects of the anchoring group of surface ligands on the relaxometric properties of MON-CAs. Herein, a series of ligand-capped HMONs and their magnetic properties to be influenced as a function of electronic effects originated from surface capping ligands, which, in turn, alters their MRI relaxometric properties, has been demonstrated. Finally, this study also revealed that the bright contrast enhancing performance of the HMON in in vivo T1-MRI is attributed to the magnetic susceptibility enhancement by the coordination of specific ligands, which suggests an unconventional interpretation about MON-CAs.

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Table 1. Description of Abbreviations in the Current Paper Abbreviation

Full Name

MON@SiO2 HMON@p-SiO2 HMON@h-SiO2 sf-HMON OA-PL-HMON OAmOHSHCC-PEG-HMON BP-PEG-HMON

Manganese Oxide Nanoparticle@Silica shell Hollow MON@Porous Silica shell Hollow MON@Hollow Silica shell Surfactant free-HMON Oleate-Phospholipid-HMON Oleyl AmineOleyl Alcohol1-HexadecanethiolDopamine-Polyethylene Glycol-HMON Bisphosphonate-Polyethylene Glycol-HMON

Characterization. Transmission electron microscopy (TEM) were conducted with JEOL JEM-2100. Magnetic properties of nanoparticles were measured using superconducting quantum interference device (SQUID) magnetometer (Quantum Design, MPMS XL-7), which was equipped with a 7 T superconducting magnet. X-ray diffraction patterns were obtained by using X-ray diffractometer (18 kW, Rigaku, Japan). Inductive coupling plasma optical emission spectroscopy was carried out with iCAP 7000 instrument (Thermo Scientific). FT-IR measurements were processed in a Cary 600 Series FT-IR spectrometer (Agilent Techonologies). The hydrodynamic size was measured using a Zetasizer (Nano S90, Malvern). Synthesis of HMON@p-SiO2. Manganese oxide nanoparticles (MON) and the silica coated HMON@p-SiO2 were synthesized by modification of a previously reported reverse microemulsion technique.38 Igepal CO-520 (0.6 mL) was dispersed in 20 mL of cyclohexane to generate a homogeneous reverse microemulsion suspension. A cyclohexane suspension of the oleic acid-coated MnO NPs (10 mg), which was prepared by the thermal decomposition method, was then added to the suspension with continuous stirring. After 15 min, when the suspension became transparent, a NH4OH solution (28−30%, 0.13 mL) was successively added. Finally, the mixture of TEOS (0.24 mL) and APTES (0.018 mL) was added and the resultant solution was stirred for 24 h, followed by addition of more TEOS (0.24 mL) and again stirred for 24 h, which led to the formation of the outer high-density silica shell. Then, MeOH (3.0 mL) was added to the reaction mixture and followed by centrifugation to isolate the solid MON@SiO2 NPs from the reaction suspension, which was washed with EtOH and distilled water. The resulting MON@SiO2 NPs possessed a 24.3 (±1.1) nm manganese oxide core and 23.7 (±1.7) nm-thick silica shell (Figure 1b), as observed in transmission electron microscopy (TEM) images. For further use, the purified MON@SiO2 NPs were redispersed in distilled water. To synthesize HMON@p-SiO2, MON@SiO2 (1 mg/mL) was treated with 0.5 M NH2OH solutions at room temperature for 16 h. The resulting HMON@p-SiO2 NPs were isolated from the reaction suspension by the centrifugation and purified by repeating the redispersion in water and the centrifugation, three times. Synthesis of HMON@h-SiO2. The suspension of HMON@pSiO2 was diluted with distilled water to 0.5 mg/mL and inner lowdensity silica shell was etched selectively with gentle stirring at 70 °C for 1.5 h. The resulting HMON@h-SiO2 was washed with water by repeating dispersion in distilled water and centrifugation three times. Synthesis of sf-HMON. The sf-HMON NPs were synthesised from HMON@h-SiO2 by annealing 100 mg of NPs under air at 500

EXPERIMENTAL SECTION

Chemicals. All chemical reagents, unless otherwise stated were purchased from Sigma and used without further purification but degassed before use: MnCl2·4H2O (Junsei, assay Mn 98%), sodium oleate (TCI, >98%), oleic acid (Tech. G., 90%), 1-octadecene (90%), cyclohexane (99%), NH4OH (Samchun Chem., 28−30%), polyoxyethylene-(5)-nonylphenylether (Igepal CO-520), tetraethyl orthosilicate (TEOS, Acros, 98%), 3-aminopropyl triethoxysilane (APTES, 99%), hydroxylamine (Wako, 50% solution), NaOH (Samchun Chem., 98%), 1,2-dichlorobenzene (99%), oleylamine (Acros, 80− 90%), oleyl alcohol (TCI, >60%), 1-hexadecanethiol (≥95%), guanidine hydrochloride (Samchun Chem., 98%), glycerol (Samchun 4057

DOI: 10.1021/acs.chemmater.8b00854 Chem. Mater. 2018, 30, 4056−4064

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Chemistry of Materials

Figure 1. (a) Schematic illustration of synthesis of sf-HMON; (b) TEM images of MON@SiO2 (i), HMON@p-SiO2 (ii), HMON@h-SiO2 (iii), and sf-HMON (iv); (c) over time change in hydrodynamic diameter of sf-HMON and HMON@p-SiO2; (d) XRD patterns of MON@SiO2, HMON@p-SiO2, HMON@h-SiO2, and sf-HMON compared with MnO (JCPDS Card No. 07-0230) and Mn3O4 (JCPDS Card No. 24-0734). °C for 5 h. The annealed solids were dispersed in a degassed NaOH solution (3.0 M, pH 14.0) and stirred at room temperature under the N2 atmosphere for 15 h to remove the silica shell. The resulting solids, sf-HMON, were collected by centrifugation and washed with water by repeating dispersion in an aqueous suspension and centrifugation three times. Synthesis of Ligand-PL-HMON. For recapping the surface of sfHMON with different ligands, 10 mg of sf-HMON powder and 5 mg of ligand (oleic acid, octadecylphosphonic acid, oleylamine, oleyl alcohol, 1-hexadecanethiol) were dispersed in 40 mL of 1,2dichlorobenzene. The mixture was refluxed at 150 °C for 24 h and solvent was evaporated in rotary evaporator. The waxy mixture was washed with cyclohexane by repeating dispersion in cyclohexane and centrifugation twice, and dispersed in chloroform for analysis and further treatment. To endow the water-dispersity, to a solution of ligand coated HMON (2 mL) in chloroform (10 mL) was added 10 mg of phospholipid in chloroform (1 mL). After the solvent was evaporated, the addition of 5 mL of distilled water resulted in a clear and dark-brown suspension. The excess phospholipid was removed by centrifugation and the purified ligand-PL-HMON was obtained by filtration with a 200 nm micropore filter. Synthesis of Ligand-PEG-HMON. For recapping the surface of sfHMON with functionalized PEG surfactant, 10 mg of sf-HMON powder and 30 mg of ligand (Dopamine-mPEG, BisphosphonatemPEG) were dispersed in 10 mL of chloroform. The mixture was stirred for 24 h and solvent was evaporated in rotary evaporator. The waxy mixture was dried in a vacuum oven at 80 °C for overnight. After the solvent was evaporated, the addition of 5 mL of distilled water resulted in a clear and dark-brown suspension. The excess ligand was removed by centrifugation and the purified Ligand-PEG-HMON was obtained by filtration with a 200 nm micropore filter. Measuring MRI Relaxation Properties. To determine the T1 and T2 relaxivity, the synthesized nanoparticles with different Mn ion concentrations (measured by ICP analysis) were dispersed in distilled water. For measuring the effect of small molecules, the particles were dispersed in aqueous solution of small molecules, which are adjusted

pH = 7 with KOH and HCl solution. T1 and T2 relaxation times of the nanoparticles that were prepared in Eppendorf safe-lock microcentrifuge tube of 2 mL capacity were measured on a 3.0 T clinical MRI scanner (Philips, Achieva ver. 1.2, Philips Medical Systems, Best, The Netherlands) equipped with 80 mT/m gradient amplitude and 200 ms/m slew rate. A Look-Locker sequence (TR/TE = 10/1 ms and flip angle = 5) was used to measure T1 by acquiring 17 gradient echo images at different inversion delay times using minimum inversion time of 87 ms with a phase interval of 264 ms with in-plane image resolution= 625 mm × 625 mm and slice thickness = 500 mm. The images were fitted into a 3-parameter function to calculate T1 values using Matlab program. T2 measurements were performed by using 10 different echo times in a multislice turbo spin echo sequence (TR/TE = 5000/20, 40, 60, 80, 100, 120, 140, 160, 180, 200 ms, in-plane resolution = 200 mm × 200 mm, slice thickness = 5.00 mm). The images were fitted into the Levenberg−Margardt method to calculate T2 values using the Matlap program. We calculated the specific relaxivities (r1 and r2) of the nanoparticles from the plot of 1/T1 and 1/T2 vs molar concentration of manganese atom measured by ICPAES. The signal intensities of each ROIs in the T1 map (60−80 pixels) and the T2 map (200−300 pixels) were measured for each concentration, which were then used for r1 and r2 calculations, respectively. As a control experiment we measured the relaxivities of Gd-DOTA complex (DOTAREM) (Figure S1). The obtained results accredited the method used for relaxivity measurement. Cytotoxicity Evaluation of OA/OP-PL-HMON. Cytotoxicity assay was performed on primay neuron cells of isolated embryo (E14) from mouse (Orient Bio). Cortex was isolated from E14 embryos and placed in HBSS by selectively removing the cerebellum, hippocampus and medulla from brain, which was digested in 0.25% trypsin and 100 μg/mL DNase for 30 min at 37 °C and finally rinsed twice using HBSS and pipetted 5−10 times. The neuron cells were resuspended in plating media and filtered with 40 um mesh filter. The filtered cells were counted and plated at density 3 × 104 cells with 100 μL/well into 96-well plates precoated with poly-L-lysine. These cells were cultured for 3−6 h in plating media at 37 °C in a humidified 4058

DOI: 10.1021/acs.chemmater.8b00854 Chem. Mater. 2018, 30, 4056−4064

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Chemistry of Materials atmosphere of 5% CO2 then, media was changed with Neurobasal media (Giobco) in which 1 mM L-glutamine was added and cultured again for 7−10 days. The cultured cortical neurons were incubated with OA/OP-PL-HMON for 4, 8, and 24 h. After treatment, the cells were washed and cell viability was assessed using Cell Counting Kit-8 (Dojindo) by measurement of the absorbance at 450 nm. Cell viability graphs were plotted vs Mn concentration. Mouse in Vivo MRI. BALB/C nude mice weighing 25−28 g were employed under the institutional guideline of Samsung Biomedical Research Institute for animal handling. For 2 mouse, 5 μL (3.24 μg of Mn measured by ICP-OES) of HMON and OA-PL-HMON was locally injected to the brain of a mouse using a streotaxic device employing a needle size of 31G. For in vivo MRI, the animals were anesthetized and set into an MR-compatible cradle. During MRI, the animals were anesthetized by breathing 1−2% isoflurane into oxygenenriched air with a facemask. The rectal temperature was carefully monitored and maintained at 36 ± 1 °C. To investigate the time course image of OA-PL-HMON and OAm-PL-HMON, the NPs were injected into each brain hemisphere of mice in the same time and MRI was performed 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 7.0, and 8.0 h after administration of 3 μL (1.98 μg of Mn measured by ICP-OES) of OA-PL-HMON and OAm-PL-HMON. All in vivo MRI were carried on a 7T/20 MRI System (Bruker-Biospin, Fallanden, Switzerland) equipped with a 20 cm gradient set capable of supplying up to 400 mT/m in 100 μs rise-time. A birdcage coil (72 mm i.d.) (BrukerBiospin, Fallanden, Switzerland) was used for excitation, and an actively decoupled phased array coil was used for receiving the signal. High-resolution, HMON contrast enhanced multislice MR images were obtained from each mouse brain using a fast spin−echo T1weighted MRI sequence (repetition time (TR)/echo time (TE) = 300/5.6 ms, number of experiment (NEX) = 16, echo train length = 2, 100 μm × 100 μm in plane resolution with a slice thickness of 700 μm and 12 slices), and a fast spin−echo T2-weighted MRI sequence (repetition time (TR)/echo time (TE) = 3000/60 ms, number of experiment (NEX) = 16, echo train length = 8, 100 μm × 100 μm in plane resolution with a slice thickness of 700 μm and 12 slices).

Figure 2. (a) Plots of 1/T1 vs [Mn] for MON@SiO2 (i), HMON@pSiO2 (ii), HMON@h-SiO2 (iii), and sf-HMON (iv), respectively. (Inset: comparison of r1 relaxivity values for i, ii, iii, and iv; (b) T1weighted MRI results obtained from aqueous suspensions at various Mn concentrations.

relaxivity value of HMON@p-SiO2 to be higher (r1 = 1.30 ± 0.13 mM−1·s−1), as compared to the precursor MON@SiO2 (r1 = 0.034 ± 0.02 mM−1·s−1), apparently because of the facile transport of water molecules through microporous silica shell toward HMON surface.29,32 When HMON@h-SiO2 with increased exposed surface of HMON were subsequently synthesized from HMON@p-SiO2, contrary to our expectations, the measured r1 value of HMON@h-SiO2 was found to be significantly lower (r1 = 0.32 ± 0.05 mM−1·s−1). Moreover, the r1 value of sf-HMON, isolated from HMON@h-SiO2, was measured to be negligible. Because the manganese ions present on the surface of nanoparticles are largely responsible for longitudinal water proton relaxation and the Mn3O4-phase is identical in all the studied particles in the manuscript, the effect of crystalline structures of various studied particles on relaxometric properties is not relevant. Further, to rule out the effect of colloidal instability of sf-HMON on r1 relaxivity, we synthesized phospholipid (PL)-modified HMON (PLHMON) having similar composition as sf-HMON but with enhanced water dispersibility. The DLS-based hydrodynamic size of PL-HMON was found to be in the range of 270−280 nm The measured r1 relaxivity of PL-HMON was also found to be negligible as in the case of sf-HMON (Figure S2). Also, the measured zeta potential (ζ) (Figure S3) of sf-HMON (−13.4 mV) is not much different than that of PL-HMON (−18.64 mV), in water. Moreover, as shown in Figure 1c, the hydrodynamic diameter of sf-HMONs starts increasing after 30 min, which is the sufficient time required to measure the relaxometric properties. These observed results steered us to that relaxometric properties of manganese oxide based CAs could be dependent on the surface ligands. Inspired by these results, we reinvestigated the MRI contrast enhancing properties of sf-HMON with almost identical morphology as of previously reported HMON with significantly high relaxivity (r1 = 1.4 mM −1 ·s −1).27 Based on the aforementioned observations, it was inferred that the presence of oleate ligands on the HMON surface, is distinct from the sfHMON and might be a crucial element for high MRI contrastenhancing effect. sf-HMON was synthesized from HMON@h-

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RESULTS AND DISCUSSION First, we began with our synthetic target HMON@h-SiO2 consisting of HMON-yolk in a rattle structure inside a colloidal hollow and porous silica shell, As illustrated in Figure 1a, synthetic route toward HMON@h-SiO2 commenced with the synthesis of MON@SiO2 by encapsulating MON with silica shell in a reverse microemulsion suspension.38 Treating the MON@SiO2 with NH2OH solution to selectively dissolve MnO phase and for partial hydrolysis of silica layer led to the formation of HMON@p-SiO2 that carries a HMON with thickness of 3.8 (±0.3) nm coated by a porous silica shell with thickness of 21 (±2.0) nm (Figure 1b). The X-ray diffraction (XRD) pattern revealed polycrystalline properties of the MON@SiO2 nanoparticles, consisting mainly of cubic MnOphase and small fraction of tetragonal Mn3O4-phase. The low intensity shoulder peaks at the angles 36.08 (211), and 59.9 (224) match with the Mn3O4 crystalline phase (Figure 1d). For confirmation, XRD spectrum of MON@SiO2 was also compared with our previously reported XRD data.38 Further, the crystallinity of the nanoparticles decreased after treatment with NH2OH to synthesize HMON@p-SiO2 and inner shell was found to be polycrystalline Mn3O4-phase. The Mn3O4phase was also found to be consistent in HMON@h-SiO2, synthesized by the selective removal of inner silica shell in HMON@p-SiO2 as confirmed by XRD. Similarly XRD pattern of the sf-HMON synthesized from HMON@h-SiO2 by complete removal of silica shell also reflected the polycrystalline Mn3O4-phase. The relaxometric analysis, carried out by using 3T human clinical MRI scanner (Figure 2), showed the 4059

DOI: 10.1021/acs.chemmater.8b00854 Chem. Mater. 2018, 30, 4056−4064

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Chemistry of Materials

Figure 3. (a) Schematic illustration of the capping on the sf-HMON surface with various ligand; (b) TEM image of OA-HMON; (c) FT-IR spectrum of oleic acid, OA-MnO, OA-HMON, and sf-HMON, respectively; (d) coordination mode of oleate on sf-HMON surface; (e) over time change in hydrodynamic diameter of OA-PL-HMON, OP-PL-HMON, CC-PEG-HMON, and OAm-PL-HMON.

SiO2 by air annealing at 500 °C for complete removal of organic surfactants, followed by silica etching in a basic aqueous solution and characterized by TEM, XRD, FT-IR, DLS, and EDS (Figure 1b, 1d, 3c, 1c, S4, respectively). Further, oleateHMON (OA-HMON) was synthesized by treating the sfHMON in oleic acid containing 1,2-dichlorobenzene solution (Figure 3a). Ligand bonding onto the surface of OA-HMON was probed by Fourier transformed infrared spectroscopy (FTIR); two new bands at at 1557 and 1426 cm−1 appeared for symmetric and asymmetric stretching of carboxylate (COO−), respectively. The calculated wavenumber separation, Δ (131 cm−1), of COO− corresponds to bridging binding mode with metal cation.39 However, we observed a hump peak at 1460 cm−1, which provides Δ (97 cm−1), corresponding to bidentate binding mode of COO−. These value strongly suggests that, in OA-HMON, COO− group is anchored to metal cation in a mixed (bridging and bidentate) coordination mode (Figure 3d). Further, functionalization of OA-HMON with hydrophilic phospholipids for good dispersity in water and to have the same surface environment as that of HMON provided the OA-PLHMON. The relaxivity measurement of aqueous suspension of OA-PL-HMON revealed a large relaxivity value (r1 = 1.10 ± 0.12 mM−1·s−1, r2 = 9.23 ± 0.20 mM−1·s−1) that was higly enhanced from that of sf-HMON and similar to previously reported value for HMON (r1 = 1.42 mM−1·s−1, r2 = 7.74 mM−1·s−1)27 (Figure 4, Figure S5). The relaxivity ratio r2/r1 of the OA-PL-HMON was compared with HMON and sfHMON in Table 2 and found to be significantly less than 10. To systematically investigate the effect of various anchoring groups on relaxometric properties of HMON, the surface of sfHMON was functionalized with dopamine-mPEG (CC-PEG), octadecyl-phosphonic acid (OP), bisphosphonate-mPEG (BPPEG), oleylamine (OAm), oleyl alcohol (OH), 1-hexadecanethiol (SH) ligands following the same method as in the case of OA-PL-HMON, resulting in water dispersible CC-PEGHMON, OP-PL-HMON, BP-PEG-HMON, OAm-PLHMON, OH-PL-HMON, and SH-PL-HMON, respectively. TEM, DLS, and FT-IR analyses confirmed that the different ligands were capped without any change in the structure of HMON and exhibited good colloidal properties in aqueous

Figure 4. (a) Plots of 1/T1 vs [Mn] for OA-PL-HMON, OP-PLHMON,CC-PEG-HMON, and OAm-PL-HMON (Inset: comparison of r1 relaxivity values for OA-PL-HMON, OP-PL-HMON, CC-PEGHMON, and OAm-PL-HMON); (b) T1-weighted MRI results obtained from aqueous suspensions at various Mn concentrations.

Table 2. Relaxivity Comparisons of sf-HMON, OA-PLHMON, and CC-PEG-HMON Sample

r1 (mM−1·s−1)

r2 (mM−1·s−1)

r2/r1

ref.

HMON sf-HMON OA-PL-HMON CC-PEG-HMON

1.42 ≈0 1.10 0.94

7.74 0.52 9.23 6.01

5.45

27 This work This work This work

8.39 6.39

suspension (Figure 3e, S6, S7). As shown in Figure 4, CCPEG-HMON, OP-PL-HMON, and BP-PEG-HMON showed significant enhanced value of relaxivity (r1 = 0.942, 0.835, and 0.696 mM−1·s−1, respectively), whereas unlike in the case of OA-PL-HMON ligands having −NH2, −OH, and −SH end groups were found to have a negligible effect on the r1 value of the HMON; the dispersed aqueous suspensions of each NPs 4060

DOI: 10.1021/acs.chemmater.8b00854 Chem. Mater. 2018, 30, 4056−4064

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Chemistry of Materials showed r1 ≈ 0 in both OAm-PL-HMON and OH-PL-HMON, and r1 = 0.17 ± 0.02 mM−1·s−1 for SH-PL-HMON, which are significantly lower than that of OA-PL-HMON. These results strongly suggest that high-relaxivity of HMON originates from chelating ligand capped surface. To substantiate our results on capping ligand effect, we analyzed the relaxivity of newly synthesized HMON@h-SiO2 (HMON@h-SiO2*) with larger silica shell [110 (±12.9) nm, Figure 5], in the solution of

Figure 6. M−H curves of sf-HMON (i), OA-HMON (ii), CC-PEGHMON (iii), OP-HMON (iv), OAm-HMON (v) measured at 300 K under a magnetic field from −30 to +30 kOe (lower-inset: schematic illustration of the magnetic moment change, upper-inset: magnified M−H curves from −1 to +1 kOe).

generated due unsaturated coordinated environment of Mn2+/3+ ions.40,41 Distinctively, OA-HMON and CC-PEG-HMON were found to have a much larger susceptibility and magnetization (2.213, 1.8 emu·g−1 respectively at 30 kOe) and exhibited a slight degree of sigmoidal curvature in −1 to +1 kOe (0.1 T) window, specifying the occurrence of weak superparamagnetic behavior (Figure 6 upper-inset). Similarly, OP-HMON and BP-PEG-HMON also exhibited the large susceptibility and magnetization (1.530, 1.21 emu·g−1 respectively at 30 kOe) with signature sigmoidal curve of superparamagnetic behavior in −1 to +1 kOe window. From these observations, we accomplished that the high magnetization of OA-HMON and CC-PEG-HMON are much enhanced by surface-capping with chelating ligands with bridging coordination mode with Mn2+/3+, which induces the ferromagnetic coupling between the surface spins possibly by providing a trail for their magnetic exchange.42 Further, because phosphate and bisphosphonate ligands have bridging/multidentate binding mode with metal and showed enhanced magnetization value, however, due to the high degree of electron delocalization, they exhibited less magnetization as compared to carboxylate and catechol ligands. In order to elucidate the observed higher relaxivity value in HMON@p-SiO2 compared with HMON@h-SiO2, we conducted SQUID measurements that showed similar saturation magnetization (Ms) values in both cases (Figure S10). The difference in r1 relaxivities of HMON@p-SiO2 and HMON@hSiO2 could be ascribed to the porous and hollow distributions of silica shells around HMONs, as the porous silica that is partially attached to HMON restricts the rotational motion of surface Mn-ions due to the close proximity with the polar hydroxyl groups of the silica shell and hence lead to their altered rotational motions.25,43 Furthermore, surface capping induced magnetization in OAHMON is crucial for manifesting the boosted relaxivity value by enhancing the outer sphere relaxation process of water proton-spins.44 Because, in the OA-PL-HMON system, water molecules have no direct contact with the paramagnetic centers, due to the inner hydrophobic layer of oleic acid, the innersphere contribution to the relaxation is negligible as compared to outersphere contribution. The outer sphere

Figure 5. TEM image of HMON@h-SiO2* (a) in water and (b) in succinate; (c) comparison of r1 value of HMON@h-SiO2* in the various soluions.

molecules (0.5 M), having various functional groups, which can pass through porous silica shell. For that purpose, we examined its relaxometric properties in the aqueous solution of molecules such as disodiumhydrogen phospahte (−PO4 group), glycerol (−OH groups), guanidine (−NH2 group), succinate (−COOH group) and glycine (−NH2 and −COOH groups). The morphology of the synthesized NPs was confirmed by TEM, which was identical regardless of the encapsulated molecules, and all the NPs retained the colloidal stability in the aqueous solutions (Figure S8). As shown in Figure 5, the r1 value of HMON@h-SiO2* dispersed in the glycine (r1 = 1.218 mM−1· s−1) or succinate (r1 = 0.527 mM−1·s−1) solution containing the carboxylate-group and in disodiumhydrogen phosphate (r1 = 0.537 mM−1·s−1) was found to be much higher than that of HMON@h-SiO2* dispersed in guanidine (r1 = 0.343 mM−1· s−1) and glycerol (r1 = 0.287 mM−1·s−1) solutions and a distilled water (r1 = 0.283 mM−1·s−1). These results were consistent with our previous observation that T1-shortening was prominent only in the case of OA-PL-HMON and OP-PLHMON, and indicate that carboxylate and phosphate group functionalized molecule binding to the HMON surface affects the MRI relaxation property. We further studied field-dependent magnetization sf-HMON coated with various capping ligands (L-HMON) by using SQUID equipment, in order to get an insight of the corresponding observe relaxometric properties. In Figure 6, with raising the external magnetic field at 300 K, M−H curves of sf-HMON and L-HMONs (L = OA, CC-PEG, OP, BPPEG, OAm, OH, SH), except for OA-HMON, CC-PEGHMON, OP-HMON, BP-PEG-HMON depict the linear increase of magnetization with almost the same susceptibility, reaching 0.504−0.776 emu·g−1 at 30 kOe (=3 T) that corresponds to the magnitude of field for clinical MRI scanner. This parmagnetic behavior observed for sf-HMON and LHMONs is in accordance with that of previously reported Mn3O4 NPs, explained by the contribution of the surface spins 4061

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HMON is able to exhibit contrast in the T2-weighted images, which diminishes with time rapidly; however, their positive contrast effect persists more prominently. As the promising T1based CAs, several reports also claim the use of manganese oxide NPs even with higher r2/r1 ratios.46,47 The ability of OAPL-HMON for contrast enhancement in the in vivo system corroborates the effect of chelating capping ligand on magnetic properties and relaxivity of HMON, which can be upheld in complex in vivo environment also.

relaxation is due to the movement of the water protons near the local magnetic field gradients generated by the magnetic surface, which is enhanced in the case of OA-PL-HMON; in this case, nearby H2O molecules (in outersphere) can experience the effect of additional magnetization causing the enhanced relaxation.45 The observed larger magnetization of OA-PL-HMON is due to the multidentate chelating ligand (carboxylate, catechol) bound to surface, which can induce the ferromagnetic coupling between the surface spin of HMON and this in turn lead to enhanced their ability for shortening the T1 relaxation time, for obtaining the brighter contrast images in MRI. Finally, the contrast enhancement feasibility of OA-PLHMON, in the in vivo system was demonstrated. The in vitro cytotoxicity was also evaluated on mouse primary cortical neurons using the CCK-8 kit. OA-PL-HMON had no significant cytotoxic effects up to a Mn concentration of 250 μM, even after 24 h (Figure S11). To evaluate the in vivo contrast, OA-PL-HMON and HMON were administered to each hemisphere of the mouse brain at 5 μL (3.24 μg of Mn measured by ICP-OES analysis). After 30 min of administration, the T1-weighted MR images of the brain revealed hyperintense bright regions at the two injected sites and the signal intensities were found similar for both the NPs (Figure 7a). Further, to validate the oleate-based contrast enhancing

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CONCLUSION In summary, for the first time we demonstrated the capping ligands-mediated modulation of contrast enhancing properties of HMON in MRI. The increased exposed surface and surfaceto-volume ratio of manganese ion in HMON NPs do not solely govern the relaxivities, though these are also dependent on the anchoring group of surface ligands. Among the various functional groups-based ligands, we found ligands with carboxylate group to be most effective in augmenting the r1 values of HMON. The enhanced value of relaxivities by carboxylate group and phosphate ligand is postulated to originate from their bridging chelation, which could induce ferromagnetic coupling between free surface spins of HMON and hence alter magnetic susceptibility. Further study on the in vivo system supported our proposition on the effect of carboxylate-ligands even in complex biological medium on contrast enhancement in MRI. We postulate that this systematic investigation on the alteration of r1 relaxivity of HMON by chelating ligands is highly significant for the MRI research field. This work may provide the basic understanding of the contrast enhancement effects in manganese NP-based systems and open up new venues to rationally design highperformance MRI contrast agents.

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ASSOCIATED CONTENT

S Supporting Information *

Figure 7. (a) T1-MRI of a mouse brain that was locally injected with HMON and OA-PL-HMON and compared with normal tissues. (b) Time course of T1-MRI of mouse brain injected with OAm-PLHMON (left) and OA-PL-HMON (right).

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.chemmater.8b00854. Additional details on the characterization by relaxometry, DLS, zeta potential, EDS, FT-IR, TEM, SQUID, cytotoxicity, in vivo MR images of the various nanoparticles and table on literature reports for MON-CAs (PDF)

effect, 3 uL of each (2.93 ug of Mn measured by ICP-OES analysis) OA-PL-HMON and OAm-PL-HMON were injected into each hemisphere of mouse brain and the time courses of the signal intensities in T1-weighted MR images were measured after 30 min of administration (Figure 7b). The OA-PLHMONs injected right brain showed bright contrast, where the suspension distributed. In contrast, the OAm-PL-HMON injected left brain exhibited very low contrast with surrounding tissues, except for a narrow region with highly concentrated NPs. As time elapsed, OAm-PL-HMONs were diffused, and the contrast difference with the surrounding tissues was reduced to such an extent that it was difficult to distinguish. In contrast, OA-PL-HMON enhanced contrast of the right hemisphere brain remained even after 8 h (Figure S12). Further, we performed in vivo study on mouse brain in order to assess their use as T2-weighted CAs in MRI; the timedependent contrast of OA-PL-HMON in mice brain hemisphere revealed that they generate negative contrast as well. However, with time, the negative contrast starts dwindling just after the 1.5 h, and after 3 h the image completely vanishes (Figure S13). With the same concentration range, OA-PL-

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AUTHOR INFORMATION

Corresponding Authors

*[email protected] (I.S.L.). *[email protected] (J.H.L.). ORCID

In Su Lee: 0000-0002-2588-1444 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by Samsung Research Funding Center of Samsung Electronics under Project Number SRFCMA1402-05. 4062

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