Article pubs.acs.org/Langmuir
Facile Preparation of Zwitterion-Stabilized Superparamagnetic Iron Oxide Nanoparticles (ZSPIONs) as an MR Contrast Agent for in Vivo Applications Dongkyu Kim,†,‡ Min Kyung Chae,† Hyun Jung Joo,† Il-ha Jeong,† Jee-Hyun Cho,† and Chulhyun Lee*,† †
Division of Magnetic Resonance Research, Korea Basic Science Institute (KBSI), Ochang, Chungbuk 363-883, Republic of Korea Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 2387 Dalgubeol-daero, Suseong-gu, Daegu 706-010, Republic of Korea
‡
S Supporting Information *
ABSTRACT: We describe a simple method for synthesizing superparamagnetic nanoparticles (SPIONs) as small, stable contrast agents for magnetic resonance imaging (MRI) based on sulfobetaine zwitterionic ligands. SPIONs synthesized by thermal decomposition were coated with zwitterions to impart water dispersibility and high in vivo stability through the nanoemulsion method. Zwitterion surfactant coating layers are formed easily on oleic acid-stabilized SPIONs via hydrophobic and van der Waals interactions. Our zwitterion-coated SPIONs (ZSPIONs) had ultrathin (∼5 nm) coating layers with mean sizes of 12.0 ± 2.5 nm, as measured by dynamic light scattering (DLS). Upon incubation in 1 M NaCl and 10% FBS, the ZSPIONs showed high colloidal stabilities without precipitating, as monitored by DLS. The T2 relaxivity coefficient of the ZSPIONs, obtained by measuring the relaxation rate on the basis of the iron concentration, was 261 mM−1 s−1. This value was much higher than that of the commercial T2 contrast agent because of the ultrathin coating layer. Furthermore, we confirmed that ZSPIONs can be used as MR contrast agents for in vivo applications such as tumor imaging and lymph node mapping.
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INTRODUCTION Superparamagnetic iron oxide nanoparticles (SPIONs) have been investigated intensively for in vivo medical imaging1−4 and drug delivery.5−7 Coprecipitation and thermal decomposition are the two major methods used to prepare SPIONs. In particular, thermal decomposition can be used to produce SPIONs with narrower size distributions and higher superparamagnetism than via coprecipitation. Despite the more favorable characteristics imparted by thermal decomposition, the nanoparticles synthesized by this method are not suitable for in vivo applications because they are stabilized by lipophilic molecules.8−10 For biological and in vivo applications, it is important that nanoparticles must be dispersed in an aqueous phase and be stable under physiological conditions. The introduction of poly(ethylene glycol) (PEG) onto a nanoparticle surface is one way to achieve this.10,11 However, PEGcoated nanoparticles can aggregate under high salt conditions.12 In addition, PEG increases the hydrodynamic size of nanoparticles, which prevents their renal excretion in vivo.12−14 Furthermore, the stability of PEG is compromised in the presence of oxygen and transition-metal ions because of oxidation.14,15 Zwitterions, which make up the majority of typical mammalian cell surface components, are antibiofouling materials that have been investigated to overcome the limitations of PEG.12,14,16−21 To our knowledge, zwitterion-stabilized SPIONs (ZSPIONs) have not been used as MR contrast agents for in vivo © 2012 American Chemical Society
applications. In this study, we report on a facile method whereby oleic acid-stabilized iron oxide nanoparticles were rendered water-dispersible and stable under physiological conditions using a zwitterion surfactant instead of PEG. Furthermore, the use of ZSPIONs as T2 contrast agents for in vivo imaging is examined.
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EXPERIMENTAL SECTION
Materials. Oleic acid, oleylamine, 1,2-hexadecanediol, and a zwitteion surfactant (ASB-14) were purchased from Sigma-Aldrich Chemical Co. (St. Louis, MO). Feridex I.V. was purchased from Advanced Magnetics Inc. (Cambridge, MA). Other organic chemicals were used as received. Synthesis of ZSPIONs. Oleic acid-stabilized SPIONs were synthesized using a method reported previously.8 Briefly, Fe3O4 nanoparticles were synthesized by a reductive thermal decomposition reaction. [Fe(acac)3] (1.42 g, 4.02 mmol), oleic acid (4 mL, 12.6 mmol), oleylamine (4 mL, 12.4 mmol), and 1,2-hexadecanediol (5.15 g, 20 mmol) were mixed vigorously at 120 °C for 2 h under partial vacuum to remove moisture and oxygen. In the presence of argon, the solution was heated to and maintained at 200 °C for 2 h. The solution temperature was then increased rapidly to 300 °C and maintained for 30 min, following which it turned dark brown. The solution was then cooled to room temperature and washed with ethanol. The nanoparticles were redispersed into hexanes, precipitated by adding Received: January 4, 2012 Revised: March 27, 2012 Published: May 18, 2012 9634
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Figure 1. (a) Schematic of ZSPION synthesis and chemical structure of zwitterion surfactant. (b) Photograph of dispersion behavior of oleic acidstabilized SPIONs before and after the zwitterion surfactant coating in hexane/distilled water. (c) Hydrodynamic size distribution along with TEM image of ZSPIONs. The scale bar in the TEM images denotes 20 nm. excess ethanol, and then purified by centrifugation. The final products were dispersed into hexanes and stored under an argon atmosphere. Next, oleic acid-stabilized SPIONs were coated with a zwitterion surfactant via nanoemulsion. The zwitterion surfactant was dissolved in distilled water (5 mL). Oleic acid-stabilized SPIONs(5 mg) in hexanes (200 μL) were added to the zwitterion solution, and the resulting two-phase suspension was sonicated vigorously using an ultrasonic processor (VC-750, Newtown, CT) at 300 W for 5 min. ZSPIONs were washed by using centrifugal filter units (Mw cutoff: 100 kDa, Millipore, Bedford, MA) three times with distilled water to remove the unbound zwitterion surfactant. Measurements. The hydrodynamic sizes of the ZSPIONs (n = 3, 50 times) in distilled water were measured using an ELS 8000 (Otsuka Electronics Korea, Seoul, South Korea). The core sizes and dispersity of the dried ZSPIONs were examined by transmission electron microscopy (TEM) using a Philips TECNAI F20 instrument (Philips Electronic Instruments Corp., Mahwah, NJ). An X-ray photoelectron spectroscopy (XPS) spectrum was obtained using an ESCALAB250 XPS system with a monochromatized Al Kα X-ray source. Thermal gravimetric analysis (TGA) was carried out using a TGA 2950 thermogravimetric analyzer (TA Instruments). The temperature of the sample gradually increased from 20 to 800 °C at a rate of 10 °C/min. The saturation magnetization (Ms) value was measured by a Quantum Design magnetic property measurement system (MPMS) at 300 K. The applied magnetic field was varied from 50 000 to −50 000 Oe. The Ms in emu/g was normalized with the weight percent of magnetite derived from TGA to obtain emu/g of iron. Relaxivity Measurements. T2 relaxivity coefficient r2 was measured by using the Carr−Purcell−Meiboom−Gill (CPMG)
sequence at room temperature (4.7-T Biospec MRI system (Bruker, Karlsruhe, Germany) with a 72 mm3 volume coil): TR = 10 000 ms TE = 7.45, 44.69, 81.94, 119.18, 156.43, 193.67, 230.92, 268.16, 305.41, 342.65, 379.9, 417.14, 454.39, 491.63, 528.88, 566.12, 603.37, 640.61, 677.86, 715.1, 752.35, 789.59, 826.84, 864.08, 901.33, 938.57, and 953.47 ms. For these measurements, FOV = 5 × 5 cm2, matrix = 128 × 128, and slice thickness = 2 mm. The relaxivities of the ZSPIONs and Feridex were determined by measuring the relaxation rates on the basis of the iron concentrations. Cell Culture and Preparation. The Lewis lung carcinoma (LLC) cell line (American Type Culture Collection, Manassas, VA) was maintained as an adherent culture. Cells were grown as monolayers in a humidified incubator (95% air, 5% CO2, both (v/v) at 37 °C in cell culture dishes (Nunc, Naperville, IL) containing DMEM (GIBCO, Grand Island, NY) supplemented with 10% (v/v) heat-inactivated fetal bovine serum (FBS; GIBCO), 100 IU mL−1 penicillin (GIBCO), and 100 IU mL−1 streptomycin (GIBCO)). In Vivo Imaging. Lymph Nodes. ZSPIONs (50 μg) in PBS (100 μL) were injected subcutaneously into the right hind paw of BALB/c mice that were purchased from Orient Bio Inc. (Gyeonggi-do, Korea). MR images were taken prior to injection and 24 h postinjection. Tumor Imaging. C57BL/6 mice were purchased from Orient Bio Inc. Allograft tumor models were developed by injecting them subcutaneously with LLC cells (1 × 106) into their midbacks. For all animals, MR images were taken prior to injection and at appropriate time points postinjection. ZSPIONs (10 mg/kg) in PBS (100 μL) were then injected through the tail vein of each mouse, and T2weighted MR images were taken at 0, 1, and 4 h postinjection. Mice that were used for lymph and tumor imaging were anesthetized using a general inhalation anesthetic (1.5% isoflurane in 9635
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Figure 2. Changes in the hydrodynamic size of ZSPIONs upon incubation in (a) 1 M NaCl and (b) 10% FBS with time. a 1:2 mixture of O2/N2). Magnetic resonance imaging (MRI) was performed using a 4.7-T Biospec MRI system (Bruker, Karlsruhe, Germany) with a 72 mm3 volume coil. The imaging parameters were as follows: repetition time/echo time = 3500/77, flip angle = 90°, field of view = 3 × 3, slice thickness = 1 mm, and matrix = 128 × 128. All MRI quantitative analyses were carried out by the same radiologist.
ultrathin coating layer had formed that was much thinner than the PEG coating on SPIONs when synthesized by using the same method.11 Because the stability of SPIONs under physiological conditions for use as MR contrast agents is important, we investigated the stability of ZSPIONs in 1 M NaCl and 10% FBS. Naked SPIONs usually become unstable and immediately aggregate under high salt conditions because their surface electronic layer is compressed significantly by the surrounding ionic environment.28 Upon incubation in 1 M NaCl, our ZSPIONs showed high colloidal stability under high salt conditions for 24 h without size changes, as monitored by DLS (Figure 2a). ZSPIONs in 1 M NaCl did not show any aggregation for at least 6 months (Figure S3 in the Supporting Information). To further evaluate the stability of ZSPIONs under physiological conditions, the size changes in ZSPIONs upon incubation in 10% serum were monitored. As shown in Figure 2b, the sizes of the ZSPIONs changed little after 24 h of incubation in 10% serum. Furthermore, ZSPIONs were well dispersed in the pH range of 4−7 and did not show any aggregation after 24 h (Figure S4 in the Supporting Information). No obvious size changes were observed for ZSPIONs under physiological conditions, indicating the excellent stability and antibiofouling properties of the nanoparticles. To examine whether the ZSPIONs could be used as MR contrast agents, the nanoparticles were dispersed at various concentrations in aqueous solution, and T2 relaxivity measurements were taken by using 4.7T MRI. The iron concentrations of the ZSPIONs were measured using an inductively coupled plasma atomic emission spectrophotometer (ICP-AES). As shown in Figure 3a, the T2-weighted phantom images showed that the dark signal was enhanced in proportion to the Fe concentration, indicating that the ZSPIONs behaved as a superparamagnetic substance. The T2 relaxivity coefficient (r2) of the ZSPIONs obtained by measuring the relaxation rate based on the Fe concentration was 261 mM−1 s−1. The r2 value of the ZSPIONs was therefore much higher than that of the commercial T2 contrast agent (Feridex: 217.6 mM−1 s−1; Figure 3b). This increased relaxivity may be attributed to the ultrathin coating layer. The coating thickness of SPIONs can significantly affect their relaxivity; as the coating thickness increases, the r2 relaxivity decreases dramatically.22 When the magnetic moment was measured as a function of the applied
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RESULTS AND DISCUSSION To use SPIONs synthesized by thermal decomposition for biomedical applications, ZSPIONs were prepared in two steps. First, oleic acid-stabilized SPIONs were synthesized using a well-known thermal decomposition method.8 Second, the oleic acid-stabilized SPIONs were coated with a zwitterion surfactant by creating a nanoemulsion. The method for synthesizing ZSPIONs and the structure of the zwitterion surfactant are shown in Figure 1a. The zwitterion part of the surfactant provided water dispersibility and biocompatibility. The hydrophobic alkyl chains allowed the zwitterion surfactant to coat the SPIONs in the organic solvent via hydrophobic and van der Waals interactions. Upon sonication, SPIONs migrated from the organic phase to the aqueous phase, which suggests that ZSPION formation occurred. After the phase transfer, unbound zwitterion surfactants were purified using a centrifugal filter (MWCO 100K). Figure 1b shows clear changes in the dispersibility of the ZSPIONs. The ZSPIONs showed no repopulation of the hexanes phase, indicating that the zwitterion part was probably exposed to the surrounding aqueous environment. Furthermore, we confirmed the presence of the zwitterion on the SPION by XPS and TGA analysis. XPS analysis showed that the intensity of the characteristic peak that corresponds to the N and S in the ZSPION (Figure S1 in the Supporting Information). TGA measurement revealed that the weight percentage of organic layers was 20% for oleic acid-coated SPION and 38% for ZSPION, respectively (Figure S2 in the Supporting Information). Figure 1c shows the hydrodynamic size of the ZSPIONs as measured by dynamic light scattering (DLS) as well as a TEM image of the same nanoparticles. As seen in the TEM image, the core size of the ZSPIONs was less than approximately 10 nm and had a narrow size distribution. DLS measurements revealed that the ZSPIONs had a relatively narrow size distribution with a mean size of 12.0 ± 2.5 nm. Particle size measurements by both TEM and DLS suggested that an 9636
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important therapeutic and prognostic significance in patients with newly diagnosed cancer.23 SLN is the first group of lymph nodes that receive metastatic cancer cells directly from lymphatic drainage from primary tumors. Therefore, SLN mapping is very important for precisely determining the extent of tumor metastasis.24,25 By precisely mapping the lymph nodes, unnecessary surgical dissection can be avoided. ZSPIONs have a hydrodynamic size of ∼15 nm, which is ideal for a lymph node imaging agent (5−50 nm).26−28 To image sentinel lymph nodes, ZSPIONs were injected subcutaneously into the hind paw pads of mice. Twenty-four hours following injection, the lymph nodes were examined by MR imaging. T2 signals dropped significantly in the right popliteal node, permitting clear SLN mapping of the mice (Figure 4b). Many patients who undergo a sentinel lymph node biopsy have a negative node following excision.29 Accurate lymph node imaging by ZSPION will help to reduce unnecessary surgery. Next, we examined the feasibility of using ZSPIONs as MR contrast agents for in vivo cancer detection. Tumor-bearing mice were prepared by injecting them subcutaneously with the LLC cell line into their midbacks. MR imaging of the mice was then performed at various time points after the tail vein injection of ZSPIONs in PBS. Tumors were observed as hyperintense areas in pre-enhanced T2-weighted MR images as indicated by the white arrow. At 1 h after the injection of the ZSPIONs, some darkening on the T2-weighted MR images was observed in the tumor area of a mouse with a T2 signal drop of 17% (Figure 4d). Additionally, we observed a significant T2 signal drop in the kidney for up to 4 h, indicating that the renal excretion of ZSPIONs had occurred (data not shown). Because NPs smaller than 20 nm are excreted through renal clearance,30 this characteristic of ultrasmall hydrodynamic size for ZSPIONs would be valuable for developing efficient MR contrast agents.
Figure 3. (a) T2-weighted MR images and (b) T2 relaxivity coefficients (r2 values) of ZSPIONs (black circles) and Feridex (white circles) as functions of increasing levels of Fe.
field at 300 K, ZSPION exhibited superparamagnetic behavior with an Ms of 76 emu/g Fe (Figure S5 in the Supporting Information). Encouraged by their high colloidal stability under physiological conditions, excellent dipersibility, ultrasmall size, and high r2 value, we examined the use of ZSPIONs as MR contrast agents for in vivo imaging. We first performed sentinel lymph node (SLN) imaging. Accurate lymph node imaging has
Figure 4. T2-weighted MR images of SLNs in a mouse (a) at 0 h (preinjection) and (b) 24 h after the injection of ZSPIONs (50 μg) into the right hind paw. The arrow indicates the popliteal node. T2-weighted MR images taken at (c) 0, (d) 1, and (e) 4 h after the injection of 10 mg/kg ZSPIONs. The arrowhead indicates allograft tumors. 9637
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(7) Veiseh, O.; Kievit, F. M.; Fang, C.; Mu, N.; Jana, S.; Leung, M. C.; Mok, H.; Ellenbogen, R. G.; Park, J. O.; Zhang, M. Chlorotoxin Bound Magnetic Nanovector Tailored for Cancer Cell Targeting, Imaging, and siRNA Delivery. Biomaterials 2010, 31, 8032−8042. (8) Park, J.; An, K.; Hwang, Y.; Park, J.-G.; Noh, H.-J.; Kim, J.-Y.; Park, J.-H.; Hwang, N.-M.; Hyeon, T. Ultra-Large-Scale Syntheses of Monodisperse Nanocrystals. Nat. Mater. 2004, 3, 891−895. (9) Jun, Y.-W.; Lee, J.-H.; Cheon, J. Chemical Design of Nanoparticle Probes for High-Performance Magnetic Resonance Imaging. Angew. Chem., Int. Ed. 2008, 47, 5122−5135. (10) Bae, K. H.; Kim, Y. B.; Lee, Y.; Hwang, J. Y.; Park, H.; Park, T. G. Bioinspired Synthesis and Characterization of Gadolinium-Labeled Magnetite Nanoparticles for Dual Contrast T1- and T2-Weighted Magnetic Resonance Imaging. Bioconjugate Chem. 2010, 21, 505−512. (11) Park, J.; Yu, M. K.; Jeong, Y. Y.; Kim, J. W.; Lee, K.; Phan, V. N.; Jon, S. Antibiofouling Amphiphilic Polymer-Coated Superparamagnetic Iron Oxide Nanoparticles: Synthesis, Characterization, and Use in Cancer Imaging in Vivo. J. Mater. Chem. 2009, 19, 6412−6417. (12) Muro, E.; Pons, T.; Lequeux, N.; Fragola, A.; Sanson, N.; Lenkei, Z.; Dubertret, B. Small and Stable Sulfobetaine Zwitterionic Quantum Dots for Functional Live-Cell Imaging. J. Am. Chem. Soc. 2010, 132, 4556−4557. (13) Choi, H. S.; Liu, W.; Misra, P.; Tanaka, E.; Zimmer, J. P.; Ipe, B. I.; Bawendi, M. G.; Frangioni, J. V. Renal Clearance of Quantum Dots. Nat. Biotechnol. 2007, 25, 1165−1170. (14) Estephan, Z. G.; Jaber, J. A.; Schlenoff, J. B. ZwitterionStabilized Silica Nanoparticles: Toward Nonstick Nano. Langmuir 2010, 26, 16884−16889. (15) Luk, Y. Y.; Kato, M.; Mrksich, M. Self-Assembled Monolayers of Alkanethiolates Presenting Mannitol Groups Are Inert to Protein Adsorption and Cell Attachment. Langmuir 2000, 16, 9604−9608. (16) Ladd, J.; Zhang, Z.; Chen, S.; Hower, J. C.; Jiang, S. Zwitterionic Polymers Exhibiting High Resistance to Nonspecific Protein Adsorption from Human Serum and Plasma. Biomacromolecules 2008, 9, 1357−1361. (17) Breus, V. V.; Heyes, C. D.; Tron, K.; Nienhaus, G. U. Zwitterionic Biocompatible Quantum Dots for Wide pH Stability and Weak Nonspecific Binding to Cells. ACS Nano 2009, 3, 2573−2580. (18) West, S. L.; Salvage, J. P.; Lobb, E. J.; Armes, S. P.; Billingham, N. C.; Lewis, A. L.; Hanlon, G. W.; Lloyd, A. W. The Biocompatibility of Crosslinkable Copolymer Coatings Containing Sulfobetaines and Phosphobetaines. Biomaterials 2004, 25, 1195−1204. (19) Li, L. Y.; Chen, S. F.; Zheng, J.; Ratner, B. D.; Jiang, S. Y. Protein Adsorption on Oligo(ethylene glycol)-Terminated Alkanethiolate Self-Assembled Monolayers: The Molecular Basis for Nonfouling Behavior. J. Phys. Chem. B 2005, 109, 2934−2941. (20) Zheng, J.; Li, L. Y.; Tsao, H. K.; Sheng, Y. J.; Chen, S. F.; Jiang, S. Y. Strong Repulsive Forces between Protein and Oligo(ethylene glycol) Self-Assembled Monolayers: A Molecular Simulation Study. Biophys. J. 2005, 89, 158−166. (21) Estephan, Z. G.; Schlenoff, P. S.; Schlenoff, J. B. Zwitteration as an Alternative to PEGylation. Langmuir 2011, 27, 6794−6800. (22) LaConte, L. E.; Nitin, N.; Zurkiya, O.; Caruntu, D.; O’Connor, C. J.; Hu, X.; Bao, G. Coating Thickness of Magnetic Iron Oxide Nanoparticles Affects r2 Relaxivity. J Magn. Reson. Imaging 2007, 26, 1634−1641. (23) Torabi, M.; Aquino, S. L.; Harisinghanni, M. G. Current Concepts in Lymph Node Imaging. J. Nucl. Med. 2004, 45, 1509− 1518. (24) Oh, M. H.; Lee, N.; Kim, H.; Park, S. P.; Piao, Y.; Lee, J.; Jun, S. W.; Moon, W. K.; Choi, S. H.; Hyeon, T. Large-Scale Synthesis of Bioinert Tantalum Oxide Nanoparticles for X-ray Computed Tomography Imaging and Bimodal Image-Guided Sentinel Lymph Node Mapping. J. Am. Chem. Soc. 2011, 133, 5508−5515. (25) Harisinghani, M. G.; Barentsz, J.; Hahn, P. F.; Deserno, W. M.; Tabatabaei, S.; van de Kaa, C. H.; de la Rosette, J.; Weissleder, R. Noninvasive Detection of Clinically Occult Lymph-Node Metastases in Prostate Cancer. N. Engl. J. Med. 2003, 348, 2491−2499.
CONCLUSIONS We developed a facile method for the ultrasmall size, high stability under physiological conditions, aqueous-phase dispersion of oleic acid-stabilized SPIONs synthesized by thermal decomposition. Furthermore, we examined the feasibility of ZSPIONs as MR contrast agents for in vivo imaging in SLN mapping and tumor imaging. A zwitterion surfactant coating using a nanoemulsion method allowed us easily to force an organic-to-aqueous phase transfer of oleic acid-stabilized SPIONs. The resulting ZSPIONs were less than 15 nm in diameter and showed high colloidal stability under physiological conditions. In addition, the nanoparticles had good superparamagnetic properties owing to their ultrathin coating layer. In vivo SLN mapping using ZSPIONs was also carried out successfully. Furthermore, the ZSPIONs could be used to diagnose cancer in vivo because they directly enter tumor tissues via an enhanced permeability and retention (EPR) effect. We anticipate that the ZSPIONs developed here will be clinically useful as imaging agents for biomedical diagnosis.
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ASSOCIATED CONTENT
S Supporting Information *
XPS, TGA, and magnetic moment measurement of ZSPION. Photograph of ZSPION dispersed in 1 M NaCl solution after several months. Photograph of ZSPION dispersed in distilled water at various pH values. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS This study was supported by a grant from the Korea Basic Science Institute (T31404). REFERENCES
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