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Multifunctional Theranostic Nanoparticles Based on Exceedingly Small Magnetic Iron Oxide Nanoparticles for T1‑Weighted Magnetic Resonance Imaging and Chemotherapy Zheyu Shen,†,‡,# Tianxiang Chen,†,# Xuehua Ma,† Wenzhi Ren,† Zijian Zhou,‡ Guizhi Zhu,‡ Ariel Zhang,‡ Yijing Liu,‡ Jibin Song,*,‡ Zihou Li,† Huimin Ruan,† Wenpei Fan,‡ Lisen Lin,‡ Jeeva Munasinghe,§ Xiaoyuan Chen,*,‡ and Aiguo Wu*,† †
CAS Key Laboratory of Magnetic Materials and Devices, Key Laboratory of Additive Manufacturing Materials of Zhejiang Province, and Division of Functional Materials and Nanodevices, Ningbo Institute of Materials Technology and Engineering, Chinese Academy of Sciences, 1219 Zhongguan West Road, Ningbo, Zhejiang 315201, China ‡ Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, United States § Mouse Imaging Facility, National Institute of Neurological Disorder and Stroke, National Institutes of Health, Bethesda, Maryland 20892, United States S Supporting Information *
ABSTRACT: The recently emerged exceedingly small magnetic iron oxide nanoparticles (ES-MIONs) (10 nm) are used as T2-weighted contrast agents because of their large transversal relaxivity (r2) and r2/r1 (r1 is longitudinal relaxivity).9 However, the development and production of MION-based T2-weighted contrast agents such as Feridex, Resovist, Combidex, Supravist, Clariscan, and Gastromark have largely ceased,10 presumably due to the fact that the dark images resulting from the T2weighted contrast agents are confused with those of some pathogenic conditions (e.g., hemorrhage, calcification, and metal deposits), and the large magnetic moments of the T2weighted contrast agents induce a susceptibility artifact that destroys the background around disease regions and generates unclear images.11,12 The recently emerged exceedingly small MIONs (ESMIONs) are promising to overcome the disadvantages of the Gd-chelate-based T1-weighted contrast agents and MIONbased T2-weighted contrast agents because they have good biocompatibility and can be utilized as T1-weighted contrast agents. Up to now, the ES-MIONs have been synthesized by the thermal decomposition method,10,13−17 solvothermal method,18 polyol method,19 reduction−precipitation method,20,21 and co-precipitation method.22,23 The ES-MIONs synthesized by these methods are all smaller than 5 nm, 10993
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Figure 2. MRI efficiencies of the ES-MIONs. (a) r1 value and r2/r1 ratio of ES-MIONs as a function of the particle size ( 0.05). The excellent therapeutic performance of DOX@ES-MION3@ RGD2 without PEG shedding was ascribed to the relatively small hydrodynamic particle size (∼10 nm), which allows effective tumor accumulation via the EPR effect.
Figure 8. Antitumor efficacies of DOX@ES-MION3@RGD2 and DOX@ES-MION3@RGD2@mPEG3 in U-87 MG tumor mice (mean ± SD, n = 5). PBS and free DOX were used as controls. (a) Tumor volume changes of mice treated with PBS, free DOX, DOX@ES-MION3@RGD 2 , or DOX@ES-MION3@RGD 2 @ mPEG3. (b) Mouse survival in the different treatment groups. (c) Body weight changes of mice in the different treatment groups.
Figure S19 shows photos of U-87 MG tumor-bearing nude mice on day 14 after the treatment, and Figure 8b shows the survival of treated mice. In addition, the relative body weights of the DOX@ES-MION3@RGD2@mPEG3 group and DOX@ ES-MION3@RGD2 group were much higher than those of the free DOX group (Figure 8c), which indicates that the side effect of DOX is significantly reduced via delivery by our nanoparticles. These results demonstrate that our nanoparticles are promising for the treatment of human glioblastoma. The good therapeutic performance of our nanoparticles may be ascribed to the high accumulation in the tumor region due to the EPR effect (Figure 7c−e), high uptake by U-87 MG cells with overexpression of integrin αvβ3 (Figure 4, Figure S16), and fast release of DOX in late endosome (pH ∼5.5) (Figure 1, Figure S13). In addition, although RGD peptides recognize not only tumor cells that express αvβ3 integrin but also inflamed/ angiogenic endothelium with an increased level of integrin receptors,54 the dimeric peptide RGD2 used in this study was hidden in the mPEG and would not be able to recognize integrin until the nanoparticles successfully extravasated and 11000
DOI: 10.1021/acsnano.7b04924 ACS Nano 2017, 11, 10992−11004
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and 4.0 mL of the ammonia solution were injected twice followed by a further 30 min of reaction to obtain ES-MION10. The obtained ES-MION8−10 solutions were cooled to room temperature and then dialyzed (Mw cutoff 12−14 kDa) for 5 days in ultrapure water that was changed every day. The dialyzed ESMION8−10 were then concentrated by centrifugal ultrafiltration (Millipore, molecular size cutoff of 10 kDa). The Fe concentrations of the ES-MION solutions were measured by ICP-OES. The recovery of the ES-MION8−10 was calculated from the molar ratio of Fe in the obtained ES-MIONs to that in the feeding materials. Synthesis of FITC-PEG-AC-CA. The FITC-PEG-OH (40 mg, 8 μmol) was dissolved in anhydrous tetrahydrofuran (THF, 2.0 mL) and then purged with nitrogen (≥50 min) to remove oxygen under an ice−water bath. After that, TEA (100 μL, 0.717 mmol) and acryloyl chloride (AC) (100 μL, 1.23 mmol) were added successively. The solution was then stirred at room temperature. After 16 h, 5.0 mL of CA dissolved in N,N-dimethylformamide (DMF) (30 mg/mL, 1.94 mmol) was added, and the mixture was stirred for 24 h at room temperature. The obtained polymers were washed three times using PBS (pH = 7.4) by centrifugal ultrafiltration (Millipore, molecular size cutoff of 3.0 kDa) and finally dissolved in 4.0 mL of PBS. The concentration of the obtained FITC-PEG-AC-CA solution was determined to be 7.8 mg/mL by fluorescence spectrophotometer (F-7000, HITACHI, Japan). The recovery of FITC-PEG-OH was calculated to be 78%. Synthesis of mPEG-AC-CA. mPEG (1.0 g, 0.20 mmol) was dissolved in THF (13 mL) and then purged with nitrogen (≥50 min) to remove oxygen under an ice−water bath. After that, TEA (460 μL, 3.3 mmol) and AC (200 μL, 2.46 mmol) were added successively. The solution was then stirred at room temperature. After 16 h, 10 mL of CA dissolved in DMF (30 mg/mL, 3.88 mmol) was added. The solution was then stirred for 24 h at room temperature. The obtained polymers were washed three times using PBS (pH = 7.4) by centrifugal ultrafiltration (Millipore, molecular size cutoff of 3.0 kDa) and finally dissolved in 100 mL of PBS. The concentration of the obtained mPEG-AC-CA solution could be considered as 7.8 mg/mL because the recovery of FITC-PEG-OH and mPEG should be very close due to the similar reaction conditions. Synthesis of ES-MION3@RGD2@FITC-PEG or ES-MION3@ RGD2@mPEG. The RGD2 and FITC-PEG-AC-CA (or mPEG-ACCA) were conjugated onto the surface of ES-MIONs via the reaction between −COOH and −NH2 in the presence of EDC. Typically, 10 μL of EDC (56.5 μmol) and 100 μL of RGD2 (5.0 mg/mL, 3.8 mM) were added into 8.0 mL of the ES-MION3 solution (Fe concentration of 5.0 mM, ice cold) under magnetic stirring. After 4 h, 1.00, 0.50, 0.25, or 0.10 mL of the obtained FITC-PEG-AC-CA or mPEG-AC-CA (7.8 mg/mL, 1.56 mM) plus 0, 0.50, 0.75, or 0.90 mL of H2O were added into the mixtures. The reaction was kept at room temperature for 16 h under magnetic stirring. The obtained ES-MION3@RGD2@ FITC-PEG1−4 or ES-MION3@RGD2@mPEG1−4 were washed three times using PBS by centrifugal ultrafiltration (Millipore, molecular size cutoff of 10 kDa) to remove unreacted EDC, RGD2, and FITC-PEG-AC-CA (or mPEG-AC-CA) and finally dissolved in 8.0 mL of PBS (pH 7.4) or saline. In the obtained ES-MION3@ RGD2@mPEG1−4 solutions, the Fe concentrations were measured by ICP-OES. In addition, the conjugation contents of FITC-PEG, which were considered as equal to those of mPEG due to the same reaction conditions, were determined by fluorescence spectrophotometer. Hydrolysis of the Acid-Labile β-Thiopropionate Linker. The hydrolysis of acid-labile β-thiopropionate linker (i.e., shedding of FITC-PEG from the surface of ES-MION3@RGD2@FITC-PEG3) was monitored at pH 5.5, 6.0, 6.5, and 7.4 via fluorescence determination of FITC-PEG. Typically, 2.0 mL of ES-MION3@ RGD2@FITC-PEG3 in saline (CFe = 4.6 mM, CFITC‑PEG = 331 μg/mL) was added in 10 mL of PBS with a pH value of 5.5, 6.0, 6.5, or 7.4. The solutions with various pH values were kept in a shaking incubator (Excella E24, New Brunswick Scientific) at 37 °C. At predetermined time intervals, 1.0 mL amounts of the solutions with different pH values were taken and subjected to centrifugal ultrafiltration (Millipore, molecular size cutoff of 10 kDa). The supernatants were
diffused in the slightly acidic tumor interstitium, where the PEG was cleaved and RGD2 was exposed to bind integrin-expressing tumor cells.
CONCLUSIONS In this study, we developed a co-precipitation synthesis method with precise size control of ES-MIONs below 5 nm, clarified the relationship between the r1 (or r2/r1) and the particle size, and drew a conclusion that 3.6 nm is the best particle size for ES-MIONs to be utilized as T1-weighted MRI contrast agent. The results of MRI, UV−vis, FT-IR, TEM, HR-TEM, EDS, DLS, XRD, XPS, and magnetization curves verified the compositions, structures, and physicochemical properties of ES-MIONs. Furthermore, to lower the nonspecific uptake of nanoparticles by normal healthy cells, we constructed a drug delivery system of DOX@ES-MION@RGD2@mPEG for T1weighted MR imaging and chemotherapy of integrin-expressing tumors. The hydrolysis of the acid-labile β-thiopropionate linker leads to PEG polymer shedding at the tumor site and exposure of the ligand RGD2 to realize integrin-specific binding. Treatment of integrin-positive U87MG tumor bearing mice with DOX@ES-MION3@RGD2@mPEG3 led to partial or even complete regression of tumors due to combined passive and active tumor targeting and pH-responsive release of doxorubicin molecules. EXPERIMENTAL METHODS Materials and Reagents. Poly(acrylic acid) (PAA, Mw = 1800), iron(III) chloride (FeCl3, ≥97%), gadolinium(III) nitrate hexahydrate (Gd(NO3)3·6H2O, 99.9%), triethylamine (TEA, ≥99%), cysteamine (CA, ≥98%), N-(3-(dimethylamino)propyl)-N′-ethylcarbodiimide (EDC, ≥97%), acryloyl chloride (AC, ≥97%), poly(ethylene glycol) methyl ether (mPEG, Mw 5000), doxorubicin hydrochloride (DOX), phalloidin-FITC, and Hoechst 33258 were purchased from SigmaAldrich (USA). Iron(II) sulfate heptahydrate (FeSO4·7H2O) was purchased from Acros Organics. FITC PEG hydroxyl (FITC-PEGOH, Mw 5000) was purchased from Nanocs Inc. (Boston, MA, USA). Glu-{Cyclo[Arg-Gly-Asp-(D-Phe)-Lys]}2 (i.e., RGD dimer, or RGD2, 97.92%, Mw = 1318.51) was purchased from C S Bio Co. (CA, USA). Synthesis of ES-MIONs Smaller than 4 nm. A 20 mL amount of PAA (Mw = 1800) solution (0.4−5.0 mg/mL) was first purged with nitrogen (≥50 min) for removal of oxygen. The polymer solution was then heated to reflux (100 °C). After that, 0.4 mL of iron precursor solution (50−500 mM FeCl3 plus 25−500 mM FeSO4) was quickly injected into the heated polymer solution, followed by addition of 6.0 mL of ammonia solution (2.8−28%). The reaction was kept at 100 °C under magnetic stirring. After 1.0 h, the solutions were cooled to room temperature. The obtained ES-MION1−7 were dialyzed (Mw cutoff 6−8 kDa) for 5 days in ultrapure water, which was changed every day. The dialyzed ES-MION1−7 were then concentrated by centrifugal ultrafiltration (Millipore, molecular size cutoff of 10 kDa). The Fe concentrations of the ES-MION1−7 solutions were determined by ICP-OES (Agilent 5100). The recovery of the ES-MION1−7 was calculated from the molar ratio of Fe in the obtained ES-MIONs to that in the feeding materials. Synthesis of ES-MIONs Larger than 4 nm. A 20 mL amount of PAA (Mw = 1800) solution (4 mg/mL) was first purged with nitrogen (≥50 min) for removal of oxygen. The polymer solution was then heated to reflux (100 °C) under magnetic stirring. After that, 0.4 mL of iron precursor solution (1.0 M FeCl3 plus 0.5 M FeSO4) was quickly injected into the heated polymer solution, followed by addition of 9.0 mL of ammonia solution (28%). The reaction was continued 1.0 h to obtain ES-MION8, or after 15 min of reaction, 0.6 mL of the iron precursor solution and 4.0 mL of the ammonia solution were injected followed by a further 45 min of reaction to obtain ES-MION9, or after both 15 and 30 min of reaction, 0.6 mL of the iron precursor solution 11001
DOI: 10.1021/acsnano.7b04924 ACS Nano 2017, 11, 10992−11004
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ACS Nano then determined by fluorescence spectrophotometer, and the fluorescence intensity (Ex = 495 nm, Em = 520 nm) was converted into the CFITC‑PEG via a calibration curve constructed with standard FITC-PEG solutions. The hydrolysis behavior of the acid-labile βthiopropionate linker at different pH values was monitored via a plot of the shed FITC-PEG content (i.e., the mass percentage of the shed FITC-PEG to the total amount of FITC-PEG on the surface of nanoparticles) as a function of incubation time. Synthesis of DOX@ES-MION3@RGD2@mPEG. The DOX was loaded onto the surface of ES-MION3@RGD2@mPEG1−4 via an ionic bond, hydrogen bond, and coordination bond as shown in Figure S1. Typically, 4.0 mL of ES-MION3@RGD2@mPEG1−4 (CFe = 4.0 mM) in PBS (pH 7.4) was mixed with 2.0 mL of DOX (2.0 mM, 1.16 mg/mL) under magnetic stirring at room temperature. After 24 h, the obtained DOX@ES-MION3@RGD2@mPEG1−4 solutions were washed using saline by centrifugal ultrafiltration (Millipore, molecular size cutoff of 10 kDa) to remove unloaded DOX. The finally obtained DOX@ES-MION3@RGD2@mPEG1−4 were dissolved in 4.0 mL of PBS (pH 7.4). The unloaded DOX in the supernatants was measured by UV−vis spectrophotometer, and the absorbance at 233 nm was converted to the CDOX via a calibration curve constructed with standard solutions of DOX. The DOX loading content was calculated from the mass percentage of the loaded DOX to the nanoparticle DOX@ES-MION3@RGD2@mPEG. Release Behavior of DOX from DOX@ES-MION3@RGD2@ mPEG3. The release behavior of DOX from DOX@ES-MION3@ RGD2@mPEG3 was determined by UV−vis spectrophotometer at pH 5.5, 6.0, 6.5, or 7.4. The same experiments on ES-MION3@RGD2@ mPEG3 were used as the control. Typically, 2.0 mL of DOX@ESMION3@RGD2@mPEG3 (CFe = 4.6 mM, CDOX = 321 μg/mL) or ES-MION3@RGD2@mPEG3 (CFe = 4.6 mM) was added in 10 mL of PBS (pH = 5.5, 6.0, 6.5, or 7.4) without BSA, or PBS (pH = 7.4) with 10 mg/mL of BSA. The solutions with various pH values were kept in a shaking incubator (Excella E24, New Brunswick Scientific) at 37 °C. At predetermined time intervals, 1.0 mL of the solutions with different pH values was taken and subjected to centrifugal ultrafiltration (Millipore, molecular size cutoff of 10 kDa). The supernatants were then measured by UV−vis spectrophotometer, and the absorbance at 233 nm was converted to the CDOX via a calibration curve constructed with standard solutions of DOX. The DOX release behavior at various pH values was monitored by plotting the cumulatively released DOX content as a function of incubation time.
ORCID
Jibin Song: 0000-0003-4771-5006 Xiaoyuan Chen: 0000-0002-9622-0870 Aiguo Wu: 0000-0001-7200-8923 Author Contributions #
Z. Shen and T. Chen contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS This work is supported in part by Youth Innovation Promotion Association of Chinese Academy of Sciences (2016269) (Z.S.), the Intramural Research Program (IRP), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) (Grant No. ZIA EB000073), the Public Welfare Technology Application Research Project of Zhejiang Province (2017C33129), the National Key Research & Development Program (2016YFC1400600), National Natural Science Foundation of China (Grant Nos. 51761145021, 61571278, U1501501, and 21305148), Bureau of Science and Technology of Ningbo Municipality City (Grant No. 2015B11002), and NSFC-Guangdong Province Joint Project on National Supercomputer Centre in Guangzhou (NSCC-GZ) (A.W.). REFERENCES (1) Shen, Z.; Wu, A.; Chen, X. Iron Oxide Nanoparticle Based Contrast Agents for Magnetic Resonance Imaging. Mol. Pharmaceutics 2017, 14, 1352−1364. (2) Jia, Z.; Song, L.; Zang, F.; Song, J.; Zhang, W.; Yan, C.; Xie, J.; Ma, Z.; Ma, M.; Teng, G.; Gu, N.; Zhang, Y. Active-Target T1Weighted MR Imaging of Tiny Hepatic Tumor Via RGD Modified Ultra-Small Fe3O4 Nanoprobes. Theranostics 2016, 6, 1780−1791. (3) Wang, Y.; Chen, J.; Yang, B.; Qiao, H.; Gao, L.; Su, T.; Ma, S.; Zhang, X.; Li, X.; Liu, G.; Cao, J.; Chen, X.; Chen, Y.; Cao, F. In vivo MR and Fluorescence Dual-Modality Imaging of Atherosclerosis Characteristics in Mice Using Profilin-1 Targeted Magnetic Nanoparticles. Theranostics 2016, 6, 272−286. (4) Gao, Z.; Ma, T.; Zhao, E.; Docter, D.; Yang, W.; Stauber, R. H.; Gao, M. Small is Smarter: Nano MRI Contrast Agents − Advantages and Recent Achievements. Small 2016, 12, 556−576. (5) Yan, G. P.; Robinson, L.; Hogg, P. Magnetic Resonance Imaging Contrast Agents: Overview and Perspectives. Radiography 2007, 13, e5−e19. (6) McCarthy, J. R.; Weissleder, R. Multifunctional Magnetic Nanoparticles for Targeted Imaging and Therapy. Adv. Drug Delivery Rev. 2008, 60, 1241−1251. (7) Laurent, S.; Forge, D.; Port, M.; Roch, A.; Robic, C.; Elst, L. V.; Muller, R. N. Magnetic Iron Oxide Nanoparticles: Synthesis, Stabilization, Vectorization, Physicochemical Characterizations, and Biological Applications. Chem. Rev. 2008, 108, 2064−2110. (8) Mertens, M. E.; Frese, J.; Bolukbas, D. A.; Hrdlicka, L.; Golombek, S.; Koch, S.; Mela, P.; Jockenhovel, S.; Kiessling, F.; Lammers, T. FMN-Coated Fluorescent USPIO for Cell Labeling and Non-Invasive MR Imaging in Tissue Engineering. Theranostics 2014, 4, 1002−1013. (9) Yang, K.; Hu, L.; Ma, X.; Ye, S.; Cheng, L.; Shi, X.; Li, C.; Li, Y.; Liu, Z. Multimodal Imaging Guided Photothermal Therapy using Functionalized Graphene Nanosheets Anchored with Magnetic Nanoparticles. Adv. Mater. 2012, 24, 1868−1872. (10) Wei, H.; Bruns, O. T.; Kaul, M. G.; Hansen, E. C.; Barch, M.; Wisniowska, A.; Chen, O.; Chen, Y.; Li, N.; Okada, S.; Cordero, J. M.; Heine, M.; Farrar, C. T.; Montana, D. M.; Adam, G.; Ittrich, H.; Jasanoff, A.; Nielsen, P.; Bawendi, M. G. Exceedingly Small Iron Oxide Nanoparticles as Positive MRI Contrast Agents. Proc. Natl. Acad. Sci. U. S. A. 2017, 114, 2325−2330.
ASSOCIATED CONTENT S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsnano.7b04924. Experimental protocols; tables of synthesis conditions and characterization results; schematic representation for the chemical reactions and synthesis process; TEM images and size distributions; r1 or r2 measurements; UV−vis and FT-IR spectra, HR-TEM image, EDS, XRD, and XPS spectra; hydrolysis behavior of the acid-labile βthiopropionate linker; zeta potential changes of DOX@ ES-MION3@RGD2@mPEG3; release behaviors of DOX; LSCM images; flow cytometry analysis; MR imaging of cells; T1-weighted MR images of U-87 MG tumor-bearing nude mice; photos of tumor-bearing nude mice (PDF)
AUTHOR INFORMATION Corresponding Authors
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Nanophores for Therapy and Treatment Monitoring Via Molecular MRI Quenching. Nat. Commun. 2014, 5, 3384. (28) Mikhaylov, G.; Mikac, U.; Magaeva, A. A.; Itin, V. I.; Naiden, E. P.; Psakhye, I.; Babes, L.; Reinheckel, T.; Peters, C.; Zeiser, R.; Bogyo, M.; Turk, V.; Psakhye, S. G.; Turk, B.; Vasiljeva, O. Ferri-Liposomes As an MRI-Visible Drug-Delivery System for Targeting Tumours and Their Microenvironment. Nat. Nanotechnol. 2011, 6, 594−602. (29) Kislukhin, A. A.; Xu, H.; Adams, S. R.; Narsinh, K. H.; Tsien, R. Y.; Ahrens, E. T. Paramagnetic Fluorinated Nanoemulsions for Sensitive Cellular Fluorine-19 Magnetic Resonance Imaging. Nat. Mater. 2016, 15, 662−668. (30) Zhou, Z.; Zhao, Z.; Zhang, H.; Wang, Z.; Chen, X.; Wang, R.; Chen, Z.; Gao, J. Interplay between Longitudinal and Transverse Contrasts in Fe3O4 Nanoplates with (111) Exposed Surfaces. ACS Nano 2014, 8, 7976−7985. (31) De Leon-Rodriguez, L. M.; Martins, A. F.; Pinho, M. C.; Rofsky, N. M.; Sherry, A. D. Basic MR Relaxation Mechanisms and Contrast Agent Design. J. Magn. Reson. Imaging 2015, 42, 545−565. (32) Zhou, Z.; Wu, C.; Liu, H.; Zhu, X.; Zhao, Z.; Wang, L.; Xu, Y.; Ai, H.; Gao, J. Surface and Interfacial Engineering of Iron Oxide Nanoplates for Highly Efficient Magnetic Resonance Angiography. ACS Nano 2015, 9, 3012−3022. (33) Na, H. B.; Song, I. C.; Hyeon, T. Inorganic Nanoparticles for MRI Contrast Agents. Adv. Mater. 2009, 21, 2133−2148. (34) Sheng Eng, A. Y.; Sofer, Z.; Sedmidubsky, D.; Pumera, M. Synthesis of Carboxylated-Graphenes by the Kolbe-Schmitt Process. ACS Nano 2017, 11, 1789−1797. (35) Kang, T. W.; Jeon, S. J.; Kim, H. I.; Park, J. H.; Yim, D. B.; Lee, H. R.; Ju, J. M.; Kim, M. J.; Kim, J. H. Optical Detection of Enzymatic Activity and Inhibitors on Non-Covalently Functionalized Fluorescent Graphene Oxide. ACS Nano 2016, 10, 5346−5353. (36) Cheong, S.; Ferguson, P.; Feindel, K. W.; Hermans, I. F.; Callaghan, P. T.; Meyer, C.; Slocombe, A.; Su, C. H.; Cheng, F. Y.; Yeh, C. S.; Ingham, B.; Toney, M. F.; Tilley, R. D. Simple Synthesis and Functionalization of Iron Nanoparticles for Magnetic Resonance Imaging. Angew. Chem., Int. Ed. 2011, 50, 4206−4209. (37) Liu, J.; Sun, Z.; Deng, Y.; Zou, Y.; Li, C.; Guo, X.; Xiong, L.; Gao, Y.; Li, F.; Zhao, D. Highly Water-Dispersible Biocompatible Magnetite Particles with Low Cytotoxicity Stabilized by Citrate Groups. Angew. Chem., Int. Ed. 2009, 48, 5875−5879. (38) Bunge, H. J. Influence of Texture on Powder Diffraction. Textures Microstruct. 1997, 29, 1−26. (39) Pinho, S. L. C.; Pereira, G. A.; Voisin, P.; Kassem, J.; Bouchaud, V.; Etienne, L.; Peters, J. A.; Carlos, L.; Mornet, S.; Geraldes, C. F. G. C.; Rocha, J.; Delville, M. H. Fine Tuning of the Relaxometry of γFe2O3@SiO2 Nanoparticles by Tweaking the Silica Coating Thickness. ACS Nano 2010, 4, 5339−5349. (40) Prado, Y.; Daffe, N.; Michel, A.; Georgelin, T.; Yaacoub, N.; Greneche, J. M.; Choueikani, F.; Otero, E.; Ohresser, P.; Arrio, M. A.; Cartier-dit-Moulin, C.; Sainctavit, P.; Fleury, B.; Dupuis, V.; Lisnard, L.; Fresnais, J. Enhancing the Magnetic Anisotropy of Maghemite Nanoparticles Via the Surface Coordination of Molecular Complexes. Nat. Commun. 2015, 6, 10139. (41) Phan, V. N.; Lim, E. K.; Kim, T.; Kim, M.; Choi, Y.; Kim, B.; Lee, M.; Oh, A.; Jin, J.; Chae, Y.; Baik, H.; Suh, J. S.; Haam, S.; Huh, Y. M.; Lee, K. A Highly Crystalline Manganese-Doped Iron Oxide Nanocontainer with Predesigned Void Volume and Shape for Theranostic Applications. Adv. Mater. 2013, 25, 3202−3208. (42) Wang, Y.; Gu, H. Core-Shell-Type Magnetic Mesoporous Silica Nanocomposites for Bioimaging and Therapeutic Agent Delivery. Adv. Mater. 2015, 27, 576−585. (43) Liu, F.; He, X.; Chen, H.; Zhang, J.; Zhang, H.; Wang, Z. GramScale Synthesis of Coordination Polymer Nanodots with Renal Clearance Properties for Cancer Theranostic Applications. Nat. Commun. 2015, 6, 8003. (44) Unni, M.; Uhl, A. M.; Savliwala, S.; Savitzky, B. H.; Dhavalikar, R.; Garraud, N.; Arnold, D. P.; Kourkoutis, L. F.; Andrew, J. S.; Rinaldi, C. Thermal Decomposition Synthesis of Iron Oxide
(11) Na, H. B.; Song, I. C.; Hyeon, T. Inorganic Nanoparticles for MRI Contrast Agents. Adv. Mater. 2009, 21, 2133−2148. (12) Gu, L.; Fang, R. H.; Sailor, M. J.; Park, J. H. In vivo Clearance and Toxicity of Monodisperse Iron Oxide Nanocrystals. ACS Nano 2012, 6, 4947−4954. (13) Kim, B. H.; Lee, N.; Kim, H.; An, K.; Park, Y.; Choi, Y.; Shin, K.; Lee, Y.; Kwon, S. G.; Na, H. B.; Park, J. G.; Ahn, T. Y.; Kim, Y. W.; Moon, W. K.; Choi, S. H.; Hyeon, T. Large-Scale Synthesis of Uniform and Extremely Small-Sized Iron Oxide Nanoparticles for HighResolution T1 Magnetic Resonance Imaging Contrast Agents. J. Am. Chem. Soc. 2011, 133, 12624−12631. (14) Tromsdorf, U. I.; Bruns, O. T.; Salmen, S. C.; Beisiegel, U.; Weller, H. A Highly Effective, Nontoxic T1 MR Contrast Agent Based on Ultrasmall PEGylated Iron Oxide Nanoparticles. Nano Lett. 2009, 9, 4434−4440. (15) Huang, J.; Wang, L.; Zhong, X.; Li, Y.; Yang, L.; Mao, H. Facile Non-Hydrothermal Synthesis of Oligosaccharide Coated Sub-5 nm Magnetic Iron Oxide Nanoparticles with Dual MRI Contrast Enhancement Effects. J. Mater. Chem. B 2014, 2, 5344−5351. (16) Zhang, H.; Li, L.; Liu, X. L.; Jiao, J.; Ng, C. T.; Yi, J. B.; Luo, Y. E.; Bay, B. H.; Zhao, L. Y.; Peng, M. L.; Gu, N.; Fan, H. M. Ultrasmall Ferrite Nanoparticles Synthesized via Dynamic Simultaneous Thermal Decomposition for High-Performance and Multifunctional T 1 Magnetic Resonance Imaging Contrast Agent. ACS Nano 2017, 11, 3614−3631. (17) Sherwood, J.; Lovas, K.; Rich, M.; Yin, Q.; Lackey, K.; Bolding, M. S.; Bao, Y. Shape-Dependent Cellular Behaviors and Relaxivity of Iron Oxide-Based T1 MRI Contrast Agents. Nanoscale 2016, 8, 17506−17515. (18) Luo, Y.; Yang, J.; Yan, Y.; Li, J.; Shen, M.; Zhang, G.; Mignani, S.; Shi, X. RGD-Functionalized Ultrasmall Iron Oxide Nanoparticles for Targeted T1-Weighted MR Imaging of Gliomas. Nanoscale 2015, 7, 14538−14546. (19) Park, J. Y.; Daksha, P.; Lee, G. H.; Woo, S.; Chang, Y. Highly Water-Dispersible PEG Surface Modified Ultra Small Superparamagnetic Iron Oxide Nanoparticles Useful for Target-Specific Biomedical Applications. Nanotechnology 2008, 19, 365603. (20) Peng, Y. K.; Liu, C. L.; Chen, H. C.; Chou, S. W.; Tseng, W. H.; Tseng, Y. J.; Kang, C. C.; Hsiao, J. K.; Chou, P. T. Antiferromagnetic Iron Nanocolloids: A New Generation In vivo T1 MRI Contrast Agent. J. Am. Chem. Soc. 2013, 135, 18621−18628. (21) Liu, C. L.; Peng, Y. K.; Chou, S. W.; Tseng, W. H.; Tseng, Y. J.; Chen, H. C.; Hsiao, J. K.; Chou, P. T. One-step, Room-Temperature Synthesis of Glutathione-Capped Iron-Oxide Nanoparticles and Their Application in In Vivo T1-Weighted Magnetic Resonance Imaging. Small 2014, 10, 3962−3969. (22) Li, Z.; Yi, P. W.; Sun, Q.; Lei, H.; Zhao, H. L.; Zhu, Z. H.; Smith, S. C.; Lan, M. B.; Lu, G. Q. Ultrasmall Water-Soluble and Biocompatible Magnetic Iron Oxide Nanoparticles as Positive and Negative Dual Contrast Agents. Adv. Funct. Mater. 2012, 22, 2387− 2393. (23) Li, Z.; Tan, B.; Allix, M.; Cooper, A. I.; Rosseinsky, M. J. Direct Coprecipitation Route to Monodisperse Dual-Functionalized Magnetic Iron Oxide Nanocrystals Without Size Selection. Small 2008, 4, 231−239. (24) Huang, G.; Li, H.; Chen, J.; Zhao, Z.; Yang, L.; Chi, X.; Chen, Z.; Wang, X.; Gao, J. Tunable T1 and T2 Contrast Abilities of Manganese-Engineered Iron Oxide Nanoparticles Through Size Control. Nanoscale 2014, 6, 10404−10412. (25) Kucheryavy, P.; He, J.; John, V. T.; Maharjan, P.; Spinu, L.; Goloverda, G. Z.; Kolesnichenko, V. L. Superparamagnetic Iron Oxide Nanoparticles with Variable Size and an Iron Oxidation State as Prospective Imaging Agents. Langmuir 2013, 29, 710−716. (26) Peer, D.; Karp, J. M.; Hong, S.; Farokhzad, O. C.; Margalit, R.; Langer, R. Nanocarriers As an Emerging Platform for Cancer Therapy. Nat. Nanotechnol. 2007, 2, 751−760. (27) Kaittanis, C.; Shaffer, T. M.; Ogirala, A.; Santra, S.; Perez, J. M.; Chiosis, G.; Li, Y.; Josephson, L.; Grimm, J. Environment-Responsive 11003
DOI: 10.1021/acsnano.7b04924 ACS Nano 2017, 11, 10992−11004
Article
ACS Nano Nanoparticles with Diminished Magnetic Dead Layer by Controlled Addition of Oxygen. ACS Nano 2017, 11, 2284−2303. (45) Shen, Z.; Wu, H.; Yang, S.; Ma, X.; Li, Z.; Tan, M.; Wu, A. A Novel Trojan-Horse Targeting Strategy to Reduce the Non-Specific Uptake of Nanocarriers by Noncancerous Cells. Biomaterials 2015, 70, 1−11. (46) Dan, K.; Pan, R.; Ghosh, S. Aggregation and pH Responsive Disassembly of a New Acid-Labile Surfactant Synthesized by ThiolAcrylate Michael Addition Reaction. Langmuir 2011, 27, 612−617. (47) Tamura, A.; Yui, N. A Supramolecular Endosomal Escape Approach for Enhancing Gene Silencing of siRNA Using Acid Degradable Cationic Polyrotaxanes. J. Mater. Chem. B 2013, 1, 3535− 3544. (48) Park, S. H.; Zheng, J. H.; Nguyen, V. H.; Jiang, S. N.; Kim, D. Y.; Szardenings, M.; Min, J. H.; Hong, Y.; Choy, H. E.; Min, J. J. RGD Peptide Cell-Surface Display Enhances the Targeting and Therapeutic Efficacy of Attenuated Salmonella-Mediated Cancer Therapy. Theranostics 2016, 6, 1672−1682. (49) Chen, H.; Niu, G.; Wu, H.; Chen, X. Clinical Application of Radiolabeled RGD Peptides for PET Imaging of Integrin αvβ3. Theranostics 2016, 6, 78−92. (50) Melemenidis, S.; Jefferson, A.; Ruparelia, N.; Akhtar, A. M.; Xie, J.; Allen, D.; Hamilton, A.; Larkin, J. R.; Perez-Balderas, F.; Smart, S. C.; Muschel, R. J.; Chen, X.; Sibson, N. R.; Choudhury, R. P. Molecular Magnetic Resonance Imaging of Angiogenesis In Vivo Using Polyvalent Cyclic RGD-Iron Oxide Microparticle Conjugates. Theranostics 2015, 5, 515−529. (51) Xia, Y.; Wu, X.; Zhao, J.; Zhao, J.; Li, Z.; Ren, W.; Tian, Y.; Li, A.; Shen, Z.; Wu, A. Three Dimensional Plasmonic Assemblies of AuNPs with Overall Size of Sub-200 nm for Chemo-Photothermal Synergistic Therapy of Breast Cancer. Nanoscale 2016, 8, 18682− 18692. (52) Ren, W.; Zeng, L.; Shen, Z.; Xiang, L.; Gong, A.; Zhang, J.; Mao, C.; Li, A.; Paunesku, T.; Woloschak, G. E.; Hosmane, N. S.; Wu, A. Enhanced Doxorubicin Transport to Multidrug Resistant Breast Cancer Cells via TiO2 Nanocarriers. RSC Adv. 2013, 3, 20855−20861. (53) Zhou, Z.; Wang, L.; Chi, X.; Bao, J.; Yang, L.; Zhao, W.; Chen, Z.; Wang, X.; Chen, X.; Gao, J. Engineered Iron-Oxide-Based Nanoparticles as Enhanced T1 Contrast Agents for Efficient Tumor Imaging. ACS Nano 2013, 7, 3287−3296. (54) Koning, G. A.; Schiffelers, R. M.; Wauben, M. H. M.; Kok, R. J.; Mastrobattista, E.; Molema, G.; Hagen, T. L. M.; Storm, G. Targeting of Angiogenic Endothelial Cells at Sites of Inflammation by Dexamethasone Phosphate-Containing RGD Peptide Liposomes Inhibits Experimental Arthritis. Arthritis Rheum. 2006, 54, 1198−1208.
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DOI: 10.1021/acsnano.7b04924 ACS Nano 2017, 11, 10992−11004
