Gadolinium Complexes Functionalized Persistent Luminescent

Apr 4, 2014 - ... available by participants in Crossref's Cited-by Linking service. .... Teri W. Odom ( Executive Editor ) , Robert M. Dickson ( Senio...
17 downloads 0 Views 4MB Size
Download PDF
Editors' Highlight pubs.acs.org/ac

Gadolinium Complexes Functionalized Persistent Luminescent Nanoparticles as a Multimodal Probe for Near-Infrared Luminescence and Magnetic Resonance Imaging in Vivo Abdukader Abdukayum,†,§ Cheng-Xiong Yang,† Qiang Zhao,‡ Jia-Tong Chen,‡ Lu-Xi Dong,† and Xiu-Ping Yan*,† †

State Key Laboratory of Medicinal Chemical Biology (Nankai University), Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), and Research Center for Analytical Sciences, College of Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, China ‡ College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China S Supporting Information *

ABSTRACT: The development of multimodal nanoprobes that combined properties of near-infrared (NIR) fluorescence and magnetic resonance imaging (MRI) within a single probe is very important for medical diagnosis. The NIR-emitting persistent luminescent nanoparticles (PLNPs) are ideal for optical imaging owing to no need for in situ excitation, the absence of background noise, and deep tissue penetration. However, no PLNP based multimodal nanoprobes have been reported so far. Here, we report a novel multimodal nanoprobe based on the gadolinium complexes functionalized PLNPs (Gd(III)-PLNPs) for in vivo MRI and NIR luminescence imaging. The Gd(III)-PLNPs not only exhibit a relatively higher longitudinal relaxivity over the commercial Gd(III)-diethylenetriamine pentaacetic acid complexes but also keep the superlong persistent luminescence. The prepared Gd(III)-PLNPs multimodal nanoprobe offers great potential for MRI/optical imaging in vivo.

M

advantages such as no need for in situ excitation, no interference from tissue autofluorescence and light scattering, and no phototoxicity originating from the excitation source. R e c en t l y , s e ve r a l N I R - e m i t t in g P LN P s s u c h a s Ca0.2Zn0.9Mg0.9Si2O6:Eu2+,Mn2+,Dy3+, CaMgSi2O6:Eu2+,Mn2+,Pr3+, LiGa5O8:Cr3+, and Zn2.94Ga1.96Ge2O10:Cr3+,Pr3+ have been reported for in vivo small animal imaging with high SNR and no background noise.23−26Among them, the Cr3+-doped gallate based NIRemitting PLNPs have demonstrated a bright and superlong persistent luminescence property in long-term bioimaging.25,26 Multimodal imaging has drawn much attention in biomedical applications because it provides more accurate, complete, and reliable information on diagnosis.27,28 Each imaging modality has its own advantages and disadvantages in sensitivity, spatial/ temporal resolution, and penetration depth. The NIR fluorescence imaging has advantages of high sensitivity but hardly offers high-resolution tomographical images. In contrast, MRI has advantages of excellent spatial resolution and unlimited depth penetration but remains at an inherently low sensitivity.29,30 Furthermore, both imaging techniques are free from ionizing radiation. The nanoparticles integrating multimodal imaging properties into a single probe have great

olecular imaging becomes increasingly important in the medical diagnosis, the therapy of various diseases, and the basic biological research.1,2 Various imaging technologies including positron emission tomography, single-photon emission computed tomography, contrast-enhanced computed tomography, magnetic resonance imaging (MRI), optical imaging, ultrasound imaging, and photoacoustic tomography have been utilized to visualize targeted cells or molecules in living organisms.3−9 Fluorescence optical imaging has received particular attention in recent years owing to high sensitivity, no radiation risk, cost- and time-effectiveness, good portability, and suitability for image-guided surgery.10−13 With the rapid growth of nanotechnology, the emergence of nanoparticles offers new prospects for the imaging and therapy of disease14,15 and provides vast opportunities to engineer a large number of fluorescent nanoparticles as imaging probes for in vivo biomedical imaging in the past decade.16−18 In particular, the near-infrared (NIR) fluorescent nanoparticles have become increasingly popular due to low tissue autofluorescence and absorption in the NIR region of the “biological window”.19,20 The NIR-emitting persistent luminescent nanoparticles (PLNPs) are one of the promising classes of imaging probes for in vivo imaging with high signal-noise ratio (SNR) and deeptissue penetration (here, persistent luminescence means the emission after removing the excitation source, also called afterglow emission).21,22 Compared to the conventional fluorescent nanoparticles, this type of nanoparticle has unique © 2014 American Chemical Society

Received: February 16, 2014 Accepted: April 4, 2014 Published: April 4, 2014 4096

dx.doi.org/10.1021/ac500644x | Anal. Chem. 2014, 86, 4096−4101

Analytical Chemistry

Editors' Highlight

obtained on a JEOL-100CX II microscope (JEOL, Japan). The samples for transmission electronic microscopy (TEM) were obtained by drying sample droplets from water dispersion onto a 300-mesh Cu grid coated with a carbon film, which was then allowed to dry prior to imaging. Photoluminescence spectra were recorded on an F-4500 Spectrofluorometer (Hitachi, Japan). Fourier transform infrared (FT-IR) spectra (4000−400 cm−1) in KBr were recorded on a Magna-560 spectrometer (Nicolet, Madison, WI). The hydrodynamic size and Zeta potential (at neutral pH) of samples were measured on a Zetasizer Nano-ZS with a 633 nm He−Ne laser (Malvern, UK). The content of Gd in the Gd(III)-PLNPs was measured by an X series inductively coupled plasma mass spectrometer (ICPMS, Thermo Elemental, UK). The NIR afterglow decay images were acquired on a Berthold NightOWL LB 983 Imaging System (Bad Wildbad, Germany) equipped with a cooled CCD camera. In Vivo Luminescence Imaging. The adult athymic BALB/c mice (13−15 g) and Kunming mice (17−21 g) were obtained from Beijing HFK bioscience Co., Ltd. (Beijing, China). All animal experiments were carried out according to the guidelines of the Animal Experimentation Ethics Committee of Nankai University. In vivo experiments were performed on anesthetized mice with chloral hydrate (200 μL, 4%). The Gd(III)-PLNPs (300 μL, 1 mg mL−1) dispersed in 10 mM PBS solution were injected through the tail vein into normal nude mice. The Gd(III)-PLNPs were excited 10 min with a 254 nm UV lamp (6 W) before injection, and luminescence images were immediately acquired after injection. In vivo luminescence images of the mice were acquired on a Berthold NightOWL LB 983 Imaging System without excitation sources. The emission filter was set as 700 nm, and the exposure time was set as 120 s. In Vitro and In Vivo MRI. In vitro T1-weighted MR images were obtained on a 1.2 T MRI system (Huantong Corporation, Shanghai, China). The parameters adopted were as follows: TR/TE = 100.0/8.8 ms, slice thickness = 1 mm, 30.0 °C. Gd(III)-PLNPs samples were dispersed in water at various Gd concentrations. The relaxation time values (T1) were also measured on the same MRI system (1.2 T) by the inversion recovery sequence. The r1 relaxivity values were determined through the curve fitting of 1/T1 relaxation time (s−1) versus the Gd concentration (mM). In vivo MRI of Kunming mice (17−21 g) was performed on a 1.2 T MRI system (Huantong Corporation, Shanghai, China). Typically, the Gd(III)-PLNPs solution (300 μL, 1 mg mL−1) was injected via tail vein into the anesthetized Kunming mice with 4% chloral hydrate (250 μL). Images were obtained using a small animal coil, before and at 15 min following injection. The MRI parameters were as follows: spin-echo T1-weighted MRI sequence, TR/TE = 100.0/8.8 ms, FOV = 100 × 50 mm2, matrix = 256 × 256, slice thickness = 1 mm, 30.0 °C.

potential to overcome current limitations in one single imaging modality.31 To date, quite a few nanoparticle based multimodal probes which combine MRI and fluorescence imaging modalities have been applied to MRI/optical imaging.32,33 The combination of NIR-emitting PLNPs and MRI contrast agent into one nanoparticle platform will offer attractive synergistic advantages in biomedical imaging with high sensitivity, good spatial resolution, high SNR, and no ionizing radiation. Nevertheless, to the best of our knowledge, no PLNP based multimodal probes have been reported for in vivo multimodal imaging so far. Herein, we report a novel class of multimodal imaging probe based on the marriage of PLNPs with the gadolinium complexes for in vivo T1-weighted MRI and NIR luminescence imaging. The new conception of this combination not only keeps the excellent NIR persistent luminescence but also makes the paramagnetic property superior to that of the commercial Gd(III)-diethylenetriamine pentaacetic acid complexes for MRI.

■

EXPERIMENTAL SECTION Materials. All reagents were used as received without further purification. GdCl3·6H2O (99.9%), diethylenetriamine pentaacetic acid (DTPA, 99%), 3-amino propyltriethoxysilane (APTES, 99%), 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (EDC·HCl), and N-hydroxysuccinimide (NHS) were purchased from Aladdin (Shanghai, China). The gadopentetic acid dimeglumine salt injection (0.5 M Gd-DTPA, Magnevist) was purchased from Bayer Schering Pharma AG (Berlin, Germany). Ultrapure water (Hangzhou Wahaha Group Co. Ltd., Hangzhou, China) was used throughout. Synthesis of Gd(III)-PLNPs. The synthesis of NIR-emitting PLNPs (Zn2.94Ga1.96Ge2O10:Cr3+,Pr3+) and size selection of PLNPs were performed according to our previous method.26 The dry PLNPs (5 mg) were dispersed in dimethylformamide (2 mL) by sonication, and APTES (50 μL) was added. The mixture was vigorously stirred at 80 °C for 8 h, so that the surface of PLNPs was modified with APTES. The APTESmodified PLNPs were collected by centrifugation and washed with dimethylformamide to remove unreacted APTES. The precipitate was dried under vacuum, and then, the dry sample was dispersed in 10 mM phosphate buffered saline (PBS, pH 7.4) under sonication. The dry DTPA (10 mg) was dissolved in dilute NaOH solution, and the pH of solution was adjusted to 6 with NaOH solution. EDC (4 mg) and NHS (6 mg) were added into the above DTPA solution, and the mixture was gently stirred in the dark at room temperature for 2 h. Following activation, the colloidal solution of APTES-modified PLNPs was added. The pH of mixture solution was adjusted to 8 with NaOH solution and stirred in the dark at room temperature for 8 h. The unreacted DTPA was removed by centrifugation, and the resulting DTPA-PLNPs were washed with PBS three times. The products were redispersed in 10 mL of water by sonication, and then, 5 mL of GdCl3 (0.025 mM) aqueous solution was dropwise added. The pH of the final mixture was maintained at ∼7 with NaOH solution and stirred at room temperature overnight. The excess Gd3+ was removed by centrifugation, and the resulting Gd(III)-PLNPs were washed with ultrapure water five times. Characterization. X-ray diffraction (XRD) patterns were recorded on a D/max-2500 diffractometer (Rigaku, Japan) using Cu Kα radiation (λ = 1.5418 Å). TEM images were

■

RESULTS AND DISCUSSION The synthesis procedures of the multimodal imaging probe based on PLNPs are illustrated in Figure 1a. First, we synthesized the NIR-emitting PLNPs with a nominal composition of Zn2.94Ga1.96Ge2O10:Cr3+,Pr3+ according to our previous method (Supporting Information).26 Then, APTES was coated on the surface of PLNPs to introduce the amino functional group on the surface of the PLNPs. DTPA was covalently bonded to the amino-group on the PLNPs via the 4097

dx.doi.org/10.1021/ac500644x | Anal. Chem. 2014, 86, 4096−4101

Analytical Chemistry

Editors' Highlight

Figure 1. (a) Schematic illustration for the preparation of a multimodal imaging probe based on PLNPs. (b) XRD patterns of PLNPs and Gd(III)-PLNPs. (c) TEM image of the Gd(III)-PLNPs.

EDC and NHS coupling reaction, and there was the subsequent chelation of Gd3+ ion to obtain the Gd(III)-PLNPs. The XRD patterns indicate that both the synthesized PLNPs and Gd(III)-PLNPs have a pure spinel phase structure, and the crystal structure of PLNPs was not changed after the surface modification with the gadolinium complexes (Figure 1b). Figure 1c shows a TEM image of the as-prepared Gd(III)PLNPs nanostructure with irregular shapes. Dynamic light scattering analysis results reveal that the hydrodynamic diameter of PLNPs increased from 70.5 to 109.1 nm after the surface functionalization with the gadolinium complexes (Figure S1, Supporting Information). Surface modification of the PLNPs with APTES, DTPA, and Gd3+ was further confirmed by FT-IR spectrometry and Zeta potential analysis (Figures S2 and S3, Supporting Information). ICPMS determination found that the content of Gd in the Gd(III)PLNPs nanostructure was 0.31 ± 0.01 μM mg−1. The aqueous solution of the as-synthesized Gd(III)-PLNPs exhibits excellent NIR persistent luminescence properties. Under 254 nm excitation, the aqueous dispersion of Gd(III)PLNPs gave a red emission band in the range of 630−830 nm with a maximum emission at 700 nm due to the 2E → 4A2 transition of Cr3+ in the octahedral site of a spinel structure (Figure 2a).34,35 The large Stokes shift of the Gd(III)-PLNPs (∼450 nm) resulted from a nonradiative energy transfer between the emission of zinc gallogermanate host and the absorption of Cr3+.26 The NIR afterglow decay curves of PLNPs and Gd(III)-PLNPs (1 mg mL −1) in water, which were monitored at 700 nm after 5 min of UV irradiation, are shown in Figure 2b. Although the persistent luminescence intensity of PLNPs slightly decreased after the surface modification with the gadolinium complexes, the Gd(III)-PLNPs still gave a longlasting NIR persistent luminescence. We also investigated the NIR afterglow decay of the aqueous dispersion of Gd(III)PLNPs (1 mg mL−1) using a CCD camera in a dark room and captured a NIR persistent luminescence (SNR = 5.2) 24 h after stopping excitation (Figure 2c). A non-negligible NIR luminescence signal (SNR = 3.1) was still detected even 30 h after removing the UV lamp, indicating the as-synthesized Gd(III)-PLNPs still have the excellent NIR persistent luminescence property after surface modification with the gadolinium complexes.

Figure 2. (a) Excitation (blue curve, emission at 700 nm) and emission (red curve, excitation at 254 nm) spectra of the aqueous dispersion of Gd(III)-PLNPs (1 mg mL −1). The inset shows the digital photo of the aqueous dispersion of Gd(III)-PLNPs under the 254 nm UV excitation. (b) NIR afterglow decay curves of aqueous dispersion of PLNPs and Gd(III)-PLNPs (1 mg mL −1) after 5 min of irradiation with a 254 nm UV lamp; persistent luminescence intensity was monitored at 700 nm. The inset shows the persistent luminescence spectrum of the aqueous dispersion of Gd(III)-PLNPs at 20 s after stopping excitation. (c) NIR afterglow decay images of the aqueous dispersion of Gd(III)-PLNPs (1 mg mL −1) obtained by a CCD camera at different times after 5 min of irradiation with a 254 nm UV lamp.

To evaluate the capability of the as-prepared Gd(III)-PLNPs multimodal probe for MRI application, longitudinal proton relaxation times (T1) of the Gd(III)-PLNPs and Gd-DTPA were determined as a function of Gd3+ concentration. T1weighted MR images of the Gd(III)-PLNPs show that the MR signal was enhanced as Gd3+ concentration increased (Figure 3a). The longitudinal relaxivity (r1) of Gd(III)-PLNPs was determined to be 6.72 mM−1 s−1 in the 1.2 T MRI system, which is much higher than that of the commercial Gd-DTPA (r1 = 4.07 mM−1 s−1 at 1.2 T) due to the reduction of the 4098

dx.doi.org/10.1021/ac500644x | Anal. Chem. 2014, 86, 4096−4101

Analytical Chemistry

Editors' Highlight

was hardly seen in the image of the preinjection mouse, but it could be visualized and distinguished from the stomach after 15 min postinjection of Gd(III)-PLNPs (Figure 5). Like in vivo

Figure 3. (a) T1-weighted MR images of Gd(III)-PLNPs and GdDTPA with different concentrations of Gd. (b) T1-relaxation rate as a function of Gd concentration of Gd(III)-PLNPs and Gd-DTPA.

molecular tumbling rate after the gadolinium complexes bind to nanoparticles (Figure 3b).36,37 The experimental results demonstrate the potential of Gd(III)-PLNPs as an effective contrast agent for T1-weighted MRI. We performed in vivo NIR luminescence imaging of a small animal after intravenous injection of Gd(III)-PLNPs solution (300 μL) in PBS. The Gd(III)-PLNPs solution (1 mg mL−1) was excited using a 254 nm UV lamp for 10 min before injection. The persistent luminescence images of nude mice were collected without in situ excitation for more than 6 h (Figure 4). The major signal of persistent luminescence was

Figure 5. In vivo T1-weighted MR images of the mouse before and after intravenous injection of Gd(III)-PLNPs (0.3 mg); the yellow arrow indicates the liver.

NIR luminescence imaging (Figure 4), the T1-weighted MRI also shows enhanced signal in the liver site of the mouse but with higher spatial resolution. The above results indicate that the as-prepared Gd(III)-PLNPs have the complementary advantages of MRI and NIR persistent luminescence imaging. After the gadolinium complexes were immobilized onto PLNPs, the nanoparticulate MRI contrast agent gave higher MRI sensitivity (increase of the longitudinal relaxivity per Gd3+) than the commercial gadolinium complexes, thereby reducing the contrast agent dose desirable for biomedical application. We also evaluated in vitro and in vivo toxicity of the Gd(III)PLNPs. The viability of 3T3 normal cells and MCF-7 cancer cells was still higher than 75% after the incubation of the cell lines with the Gd(III)-PLNPs even at a concentration as high as 1000 μg mL−1 for 24 h (Figure 6a). We performed the histological examination of the heart, liver, spleen, lung, and kidney collected from the mice at 7 day after intravenous administration of Gd(III)-PLNPs (0.3 mg) (Supporting Information). The results show that no injury or inflammation was found in the five organs of the mice injected with Gd(III)PLNPs, and their morphological structures were still normal (Figure 6b). We also noticed that the amount of granules or vacuoles in the liver and spleen of the Gd(III)-PLNP treated groups is more than that in the control groups, which may be attributed to the phagocytosis of the macrophages in mononuclear phagocyte system-related organs for the invasion of foreign particles.38 The long-term in vivo toxicity of Gd(III)PLNPs was tested via monitoring weights of mice (Figure 6c). After 30 days of Gd(III)-PLNPs injection, there was no significant difference between the body weights of the control and treated mice. The above preliminary experimental results indicate the low toxicity of the Gd(III)-PLNPs, but further investigation of the chronic toxicity of the Gd(III)-PLNPs is still required before clinical application.

Figure 4. In vivo NIR luminescence images of a normal mouse after intravenous injection of Gd(III)-PLNPs (0.3 mg, 10 min irradiation with a 254 nm UV lamp before injection but without irradiation during imaging).

observed in the liver sites of the mouse. Although NIR persistent luminescence of the Gd(III)-PLNPs gradually decayed with time, the persistent luminescence signal with a SNR of 5 was still obtained at 6 h postinjection (Figure 4). The results demonstrate that the Gd(III)-PLNPs are capable of long-term in vivo imaging without in situ excitation. We further performed the in vivo T1-weighted MRI of Kunming mice before and after intravenous injection of Gd(III)-PLNPs solution (300 μL, 1 mg mL−1) on a 1.2 T MRI system (Supporting Information). The liver of the mouse 4099

dx.doi.org/10.1021/ac500644x | Anal. Chem. 2014, 86, 4096−4101

Analytical Chemistry

Editors' Highlight

Figure 6. (a) In vitro cell viability of 3T3 cells and MCF-7 cells incubated with Gd(III)-PLNPs at different concentrations for 24 h. (b) Representative hematoxylin and eosin stained images of major organs including heart, liver, lung, spleen, and kidney collected from Gd(III)-PLNPs (0.3 mL, 1.0 mg mL−1) injected mice (n = 3) and the control mice (n = 4, injected with PBS) at 7 day after administration. The scale bars is 50 μm for all images. (c) Body weight changes of the mice (n = 3) injected with Gd(III)-PLNPs (0.3 mL, 1.0 mg mL−1) and the control mice (n = 3) injected with PBS. The error bars represent standard deviation.

■

(2) Jokerst, J. V.; Gambhir, S. S. Acc. Chem. Res. 2011, 44, 1050− 1060. (3) Wadas, T. J.; Wong, E. H.; Weisman, G. R.; Anderson, C. J. Chem. Rev. 2010, 110, 2858−2902. (4) Mariani, G.; Bruselli, L.; Kuwert, T.; Kim, E. E.; Flotats, A.; Israel, O.; Dondi, M.; Watanabe, N. Eur. J. Nucl. Med. Mol. Imaging 2010, 37, 1959−1985. (5) Lusic, H.; Grinstaff, M. W. Chem. Rev. 2013, 113, 1641−1666. (6) Mahmoudi, M.; Hosseinkhani, H.; Hosseinkhani, M.; Boutry, S.; Simchi, A.; Journeay, W. S.; Subramani, K.; Laurent, S. Chem. Rev. 2011, 111, 253−280. (7) Hellebust, A.; Richards-Kortum, R. Nanomedicine 2012, 7, 429− 445. (8) Kiessling, F.; Huppert, J.; Palmowski, M. Curr. Med. Chem. 2009, 16, 627−642. (9) Kim, C.; Favazza, C.; Wang, L. H. V. Chem. Rev. 2010, 110, 2756−2782. (10) Kobayashi, H.; Ogawa, M.; Alford, R.; Choyke, P. L.; Urano, Y. Chem. Rev. 2010, 110, 2620−2640. (11) He, X.; Wang, K.; Cheng, Z. Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol. 2010, 2, 349−366. (12) Keereweer, S.; Van Driel, P. B. A. A.; Snoeks, T. J. A.; Kerrebijn, J. D. F.; Baatenburg de Jong, R. J.; Vahrmeijer, A. L.; Sterenborg, H. J. C. M.; Lowik, C. W. G. M. Clin. Cancer Res. 2013, 19, 3745−3754. (13) Kunjachan, S.; Gremse, F.; Theek, B.; Koczera, P.; Pola, R.; Pechar, M.; Etrych, T.; Ulbrich, K.; Storm, G.; Kiessling, F.; Lammers, T. ACS Nano 2013, 7, 252−262. (14) Goesmann, H.; Feldmann, C. Angew. Chem., Int. Ed. 2010, 49, 1362−1395. (15) Barreto, J. A.; O’Malley, W.; Kubeil, M.; Graham, B.; Stephan, H.; Spiccia, L. Adv. Mater. 2011, 23, H18−H40. (16) Michalet, X.; Pinaud, F. F.; Bentolila, L. A.; Tsay, J. M.; Doose, S.; Li, J. J.; Sundaresan, G.; Wu, A. M.; Gambhir, S. S.; Weiss, S. Science 2005, 307, 538−544. (17) Dreaden, E. C.; Alkilany, A. M.; Huang, X.; Murphy, C. J.; ElSayed, M. A. Chem. Soc. Rev. 2012, 41, 2740−2779. (18) Haase, M.; Schafer, H. Angew. Chem., Int. Ed. 2011, 50, 5808− 5829.

CONCLUSIONS In conclusion, we have reported the first example of PLNP based multimodal nanoprobe for NIR persistent luminescence and T1-weighted MRI. The novel combination of PLNPs with the gadolinium complexes not only preserves the excellent NIR persistent luminescence property of PLNPs but also has the paramagnetic property of higher longitudinal relaxivity than commercial Gd-DTPA. The present combination provides new opportunities for in vivo biomedical imaging with high sensitivity, good spatial resolution, and high SNR.

■

ASSOCIATED CONTENT

S Supporting Information *

Cytotoxicity assay, histopathology, calculation of SNR, dynamic light scattering spectra, FT-IR spectra, and Zeta potential. This material is available free of charge via the Internet at http:// pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].. Tel/Fax: (86)22-23506075. Present Address §

A.A.: Department of Chemistry and Environmental Sciences, Kashgar Teachers College, Kashgar, 844008, China. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported by the National Basic Research Program of China (No. 2011CB707703) and the National Natural Science Foundation of China (No. 21275079).

■

REFERENCES

(1) Weissleder, R.; Pittet, M. J. Nature 2008, 452, 580−589. 4100

dx.doi.org/10.1021/ac500644x | Anal. Chem. 2014, 86, 4096−4101

Analytical Chemistry

Editors' Highlight

(19) Altinoglu, E. I.; Adair, J. H. Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol. 2010, 2, 461−477. (20) Pansare, V. J.; Hejazi, S.; Faenza, W. J.; Prud’homme, R. K. Chem. Mater. 2012, 24, 812−827. (21) Maldiney, T.; Viana, B.; Bessière, A.; Gourier, D.; Bessodes, M.; Scherman, D.; Richard, C. Opt. Mater. 2013, 35, 1852−1858. (22) Yao, C.; Tong, Y. TrAC, Trends Anal. Chem. 2012, 39, 60−71. (23) le Masne de Chermont, Q.; Chaneac, C.; Seguin, J.; Pelle, F.; Maitrejean, S.; Jolivet, J. P.; Gourier, D.; Bessodes, M.; Scherman, D. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 9266−9271. (24) Maldiney, T.; Lecointre, A. l.; Viana, B.; Bessière, A. l.; Bessodes, M.; Gourier, D.; Richard, C.; Scherman, D. J. Am. Chem. Soc. 2011, 133, 11810−11815. (25) Liu, F.; Yan, W.; Chuang, Y.-J.; Zhen, Z.; Xie, J.; Pan, Z. Sci. Rep. 2013, 3, 1554−1563. (26) Abdukayum, A.; Chen, J.-T.; Zhao, Q.; Yan, X.-P. J. Am. Chem. Soc. 2013, 135, 14125−14133. (27) Lee, D.-E.; Koo, H.; Sun, I.-C.; Ryu, J. H.; Kim, K.; Kwon, I. C. Chem. Soc. Rev. 2012, 41, 2656−2672. (28) Kim, J.; Piao, Y.; Hyeon, T. Chem. Soc. Rev. 2009, 38, 372−390. (29) Reddy, L. H.; Arias, J. L.; Nicolas, J.; Couvreur, P. Chem. Rev. 2012, 112, 5818−5878. (30) Colombo, M.; Carregal-Romero, S.; Casula, M. F.; Gutierrez, L.; Morales, M. P.; Bohm, I. B.; Heverhagen, J. T.; Prosperi, D.; Parak, W. J. Chem. Soc. Rev. 2012, 41, 4306−4334. (31) Louie, A. Y. Chem. Rev. 2010, 110, 3146−3195. (32) Mulder, W. J. M.; Griffioen, A. W.; Strijkers, G. J.; Cormode, D. P.; Nicolay, K.; Fayad, Z. A. Nanomedicine 2007, 2, 307−324. (33) Janczewski, D.; Zhang, Y.; Das, G. K.; Yi, D. K.; Padmanabhan, P.; Bhakoo, K. K.; Tan, T. T. Y.; Selvan, S. T. Microsc. Res. Tech. 2011, 74, 563−576. (34) Kim, J. S.; Kim, J. S.; Park, H. L. Solid State Commun. 2004, 131, 735−738. (35) Pan, Z.; Lu, Y.-Y.; Liu, F. Nat. Mater. 2012, 11, 58−63. (36) Terreno, E.; Castelli, D. D.; Viale, A.; Aime, S. Chem. Rev. 2010, 110, 3019−3042. (37) Duncan, A. K.; Klemm, P. J.; Raymond, K. N.; Landry, C. C. J. Am. Chem. Soc. 2012, 134, 8046−8049. (38) Mueller, R. H.; Gohla, S.; Keck, C. M. Eur. J. Pharm. Biopharm. 2011, 78, 1−9.

4101

dx.doi.org/10.1021/ac500644x | Anal. Chem. 2014, 86, 4096−4101