Advanced Drug Delivery Reviews 65 (2013) 1951–1963

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Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr

Carbon nanotubes for biomedical imaging: The recent advances☆ Hua Gong, Rui Peng ⁎, Zhuang Liu ⁎ Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China

a r t i c l e

i n f o

a b s t r a c t

Article history: Accepted 16 October 2013 Available online 30 October 2013

This article reviews the latest progresses regarding the applications of carbon nanotubes (CNTs), including singlewalled carbon nanotubes (SWNTs) and multi-walled carbon nanotubes (MWNTs), as multifunctional nanoprobes for biomedical imaging. Utilizing the intrinsic band-gap fluorescence of semi-conducting single-walled carbon nanotubes (SWNTs), fluorescence imaging in the near infrared II (NIR-II) region with enhanced tissue penetration and spatial resolution has shown great promise in recent years. Raman imaging based on the resonance Raman scattering of SWNTs has also been explored by a number of groups for in vitro and in vivo imaging of biological samples. The strong absorbance of CNTs in the NIR region can be used for photoacoustic imaging, and their photoacoustic signals can be dramatically enhanced by adding organic dyes, or coating with gold shells. Taking advantages of metal nanoparticle impurities attached to nanotubes, CNTs can also serve as a T2-contrast agent in magnetic resonance (MR) imaging. In addition, when labeled with radioactive isotopes, many groups have developed nuclear imaging with functionalized CNTs. Therefore CNTs are unique imaging probes with great potential in biomedical multimodal imaging. © 2013 Elsevier B.V. All rights reserved.

Keywords: Carbon nanotubes Biomedical imaging NIR-II fluorescence Raman scattering Photoacoustic Magnetic resonance Nuclear imaging

Contents 1. Introduction . . . . . . . . 2. Fluorescence imaging . . . . 3. Raman imaging . . . . . . 4. Photoacoustic imaging . . . 5. Magnetic resonance imaging 6. Nuclear imaging . . . . . . 7. Prospects and challenges . . Acknowledgments . . . . . . . References . . . . . . . . . . .

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1. Introduction

Abbreviations: CNTs, carbon nanotubes; SWNTs, single-walled carbon nanotubes; NIR, near infrared; MR, magnetic resonance; 1D, one dimensional; PA, photoacoustic; PET, positron emission tomography; SPECT, single photon emission computed tomography; SERS, surface enhanced Raman scattering; QDs, quantum dots; DOS, density of states; VHSs, van Hoff singularities; PEG, polyethylene glycol; QY, quantum yield; PL–PEG, phospholipid–PEG; PCA, principle component analysis; C18PMH-PEG, poly(maleic anhydride-alt-1-octadecene)polyethylene glycol; EPR, enhanced permeability and retention; RBM, radical breathing mode; PAH, poly(allylamine hydrochloride); GNTs, golden nanotubes; CTCs, circulating tumor cells; ICG, indocyanine green; US-tubes, ultra-short SWNTs; MSC, mesenchymal stem cells; hMSCs, human MSCs; DOTA, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. ☆ This review is part of the Advanced Drug Delivery Reviews theme issue on “Carbon nanotubes in medicine and biology — Therapy and diagnostics”. ⁎ Corresponding authors. E-mail addresses: [email protected] (R. Peng), [email protected] (Z. Liu). 0169-409X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.addr.2013.10.002

Carbon nanotubes (CNTs), including single-walled carbon nanotubes (SWNTs) and multi-walled carbon nanotubes (MWNTs), have become star materials since its first discovery in 1990 [1–3]. Various applications related to CNTs, such as composite materials [4], nanoelectronics [5], field effect emitters [6], as well as in the area of energy research [7], have been extensively explored due to the unique physical and chemical properties of this type of one-dimensional nanomaterials. In the area of biomedicine, CNTs have also received tremendous attentions. A large variety of CNT-based bio-sensors with different sensing mechanisms have been reported by numerous groups for detections of different biological molecules [8,9]. Drug delivery and cancer therapy with CNTs are another intensively explored field attracting great interests [10–18]. In the direction of bio-imaging, CNT-based imaging probes have also been widely investigated [19–24].

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The unique physical properties of CNTs, particularly SWNTs, make them extremely attractive in the area of biomedical imaging. The quasi one-dimensional (1D) semi-conducting SWNTs exhibit a narrow band gap of about 1 eV [25], which allows fluorescence emission in the near infrared (NIR) regions, including the classical NIR-I region (700–900 nm) and the newly defined NIR-II region (1100–1400 nm) [26–28]. SWNTs possess strong resonance Raman scattering with extremely large scattering cross-section, and are thus great Raman probes useful in biological sensing and imaging [22,29]. CNTs as one of the darkest materials exhibit strong absorbance in the NIR region, and therefore can be used as photoacoustic (PA) imaging contrast agents [30,31]. The impurities of metal nanoparticles contained in the CNT samples can be utilized in magnetic resonance (MR) imaging, offering strong T2-weighted imaging contrast [32]. Besides adopting the intrinsic characteristics of CNTs, radionuclides, can also be conjugated or even inserted to CNTs to render more modalities of imaging, including positron emission tomography (PET) [33] and single photon emission computed tomography (SPECT) [34]. In the past several years, several review papers have summarized the progresses of using SWNTs in the area of biomedicine. Wu et al. summarized different surface modification strategies to obtain functionalized SWNTs for biomedical use [35]. Kostarelos et al. discussed the advantages and challenges of using CNTs in biomedicine in their progress article in 2009 [36]. In the same year, Liu et al. published a comprehensive review which covers the surface modification, potential toxicity, as well as both in vitro and in vivo applications of CNTs [31]. In 2010, we wrote another specific review paper about the applications of SWNTs in biomedical imaging [37]. However, considering tremendous progresses made in the very recent few years to explore CNTbased biomedical imaging, an up-to-date review article is therefore needed to summarize the latest exciting results in this area. In this current review article, we will summarize the very recent progresses on the applications of CNTs as multimodal contrast agents for biomedical imaging. For example, in the past several years, the in vivo fluorescence imaging of SWNTs in the NIR-II region has made remarkable progresses, making it an encouraging imaging tool with great potential in biomedical research [26,38–47]. By growing noble metal nanoparticles on SWNTs, their Raman scattering signals can be dramatically enhanced by surface enhanced Raman scattering (SERS), allowing Raman imaging of biological samples with much faster speeds [48]. By loading different dyes with NIR absorbance at varied wavelengths, multiplexed photoacoustic imaging in vivo has been demonstrated [49]. Moreover, SWNTs with appropriate surface functionalization have also been used for stem cell labeling and in vivo multimodal tracking based on Raman imaging, magnetic resonance imaging, and photoacoustic imaging [32]. It is hoped that this review article could offer a timely update regarding the use of CNTs in biomedical imaging. 2. Fluorescence imaging Fluorescence imaging plays a pivotal role in the scientific research and medical diagnosis. However, the limited penetration depth of light becomes the major hurdle for the further application of fluorescence imaging [50]. To overcome this problem, researchers have been focusing on developing and implementing fluorescent probes with excitation and emission wavelengths falling into the biological transparent NIR window [51]. The classical NIR window, or NIR I window, is defined to be from ~700 nm to ~900 nm, within which neither hemoglobin nor water exhibits significant light absorbance. Currently, various probes, including organic dyes [52–54], as well as semiconducting quantum dots (QDs) [55] lie within this region. Recently, it has been uncovered that light with even longer wavelength in the range of 1100– 1400 nm, although would be slightly absorbed by water, shows further reduced tissue absorbance, and more importantly, remarkably reduced scattering by biological tissues, allowing in vitro assay [56] and in vivo

fluorescence imaging with improved tissue penetration and much better spatial resolutions [26,43,57–59]. SWNTs are quasi one dimensional quantum wires with energy levels become split as a result of quantum confinement effect. The density of states (DOS) are characterized by the so called van Hoff singularities (VHSs), which define narrow energy ranges where the DOS intensity is very high [60,61]. The band-gap between each semiconducting SWNTs is in the order of 1 eV, which allows for the fluorescence in the NIR-II region under the excitation in the NIR-I region [61]. (Fig. 1a&c) Furthermore, the large Stoke-shift between the excitation at 550– 850 nm and emission at 900–1600 nm (Fig. 1c) would dramatically lower the autofluorescence of biological tissues during imaging, offering enhanced in vivo imaging sensitivity. (Fig. 1d–g) [28]. Despite the encouraging results for the use of SWNTs in NIR fluorescence imaging, the low quantum yield (QY) of SWNTs at that time was the major limitation for the further applications of SWNTs for in vivo imaging. Covalent functionalization would disrupt the structure of SWNTs and lead to complete elimination of their NIR fluorescence. SWNTs suspended by small surfactant molecules such as sodium cholate showed relatively high QY, however appeared to be toxic in biological systems. Non-covalent PEGylation of SWNTs, although can offer nanotubes great water-solubility and enhanced biocompatibility, usually would also drastically decrease of QY of SWNTs. In 2009, an interesting coating exchange method was developed by Dai and co-workers to obtain biocompatible SWNTs with high QY. In their method, SWNTs were debundled and solubilized in a solution of sodium cholate, which was then displaced by phospholipid–PEG (PL–PEG). Compared with the traditional modification strategy in which SWNTs were directly sonicated in PL–PEG solutions over a long period (N 15 min), this relative gentle coating exchange method prevents the loss of QY for SWNTs. Using PEGylated SWNTs with high QY prepared by this method, in vivo whole body NIR-II fluorescence imaging of mice with intravenously (i.v.) injected SWNTs was realized for the first time. Moreover, high-resolution in vivo intravital microscopy imaging was also realized upon injection of SWNTs, visualizing small tumor vessels beneath the thick skin [20]. In a later work by the same group, Welsher et al. used SWNTs as NIRII contrast agent to perform the high frame rate fluorescent video imaging of mice i.v. injected with SWNTs, and investigated the path of SWNTs through mouse anatomy [26]. As shown in Fig. 2a, they observed in real time that SWNTs first reached the lungs several seconds after injection, and then the spleen and the liver at later time points. By means of principle component analysis (PCA), the anatomic resolution of organs was dramatically enhanced. Even the pancreas, which could not be resolved from real time raw images, could be discriminated after PCA analysis of NIR-II fluorescence images of mice with SWNTinjection. (Fig. 2b) Therefore, this work demonstrated that the NIR-II fluorescence imaging, together with PCA, could provide powerful tools for a wide range of potential applications from biomedical research to disease diagnosis. Subsequently, by making use of a new type of PEGylated amphiphilic polymer, poly(maleic anhydride-alt-1-octadecene)-polyethylene glycol (C18PMH-PEG), to solubilize SWNTs, Robinson et al. prepared a well functionalized SWNTs formulation with long blood circulation (half-life of 30 h) in vivo to achieve ultrahigh accumulation of ~30% inject dose (%ID/g) in 4T1 murine breast cancer bearing Balb/c mice [43]. For the first time, high fluorescent video rate imaging and PCA were adopted to monitor the fluorescent signals in tumors and other organs. They found obvious fluorescent signals in the tumor only 20 s after injection, and the fluorescent signal remained there for up to 72 h. Furthermore, the 3D reconstruction of NIR-II fluorescence signals inside tumors revealed the co-localization of tumor vasculatures and SWNTs, indicating that the enhanced permeability and retention (EPR) effect may serve as important role in mediating the tumor accumulation of nanotubes. Besides tumor imaging, high fluorescent video rate imaging and PCA analysis were also adopted for vessel imaging in vivo. In a recent work

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Fig. 1. Comparison of NIR-I and NIR-II fluorescence imaging. IRDye800 conjugated SWNTs emit with both NIR-I (from IRDye 800) and NIR-II (from SWNTs) fluorescence were used in this experiment. (a) A schematic showing that upon excitation by a 785 nm laser, the SWNTs-IRDye-800 conjugate emits at the 800 nm NIR-I region from IRDye-800 dye and the 1100– 1400 nm NIR-II region from SWNTs. (b) A schematic of the imaging setup for simultaneous detection of both NIR-I and NIR-II photons using silicon and InGaAs cameras.(c) Absorption spectrum of the SWNTs–IRDye-800 conjugate (black dashed line) together with emission spectra of IRDye-800 (green line) and SWNTs (red line).(d–g) NIR-II (d) and NIR-I (f) fluorescent images and the corresponding cross-section fluorescent intensity profiles (e & g) along red-dashed bars of a mouse injected with SWNTs–IRDye-800. Copyright 2012 Nature Publishing Group [28].

by Hong et al., arterial and venous vessels were unambiguously differentiated using a dynamic contrast-enhanced NIR-II imaging technique on basis of their distinct hemodynamics. In Fig. 3a–d, the NIR-II image showed greater numbers of small vessels in the distal hind limp of mouse compared to micro-CT at the same location. The smallest vessel by NIR-II had a Gaussian-fit diameter of only 35.4 μm (Fig. 3g), where micro-CT could not discern any vessels smaller than 100 μm (Fig. 3h). Furthermore, the blood velocity inside the vessels could also be measured in both ischemic and normal limbs, even at very low blood velocities, which are beyond the capabilities of ultrasonography. Therefore, their results suggested that the NIR-II fluorescence imaging of vasculatures using SWNTs as nano-probes showed several advantages when compared with Micro-CT and ultrasound imaging techniques [28]. As-synthesized SWNTs currently in use all contain various chiralities, and each chirality corresponds to a different set of excitation and emission wavelengths. Therefore, in previous NIR-II fluorescence imaging experiments, only a small portion of SWNTs are excited by the laser to give fluorescence, while the major portion is not in the resonance with the excitation laser wavelength would be ‘dark’ during imaging. Therefore, if chirality-purified SWNTs are used for NIR-II fluorescence imaging, the amount of nanotubes injected into animals would be remarkably reduced. Various strategies have been developed in order to obtain SWNTs with pure chiralities, including dielectrophoresis, density gradient centrifugation [62], DNA wrapping chromatography [63], and gel filtration [64–66]. In a recent work, Diao et al. developed a simple gel separation method to enrich semiconducting (12,1) and (11,3) SWNTs with identical resonance absorption at 808 nm and emission at 1200 nm. The chirality sorted SWNTs exhibited 5 folds higher fluorescent intensity under the resonant excitation at 808 nm than unsorted SWNTs on a per mass basis, dramatically lowering the injection dosage of SWNTs (~ 6 folds) needed for in vivo imaging [42].

In a short summary, NIR-II fluorescent imaging with SWNTs has shown great potential in biomedical imaging, demonstrating several unique advantages over other existing imaging techniques. Further development in this direction requires better SWNT samples with high QY and purified chiralities to provide even ‘brighter’ fluorescence. Moreover, different SWNTs with purified single chiralities would show separated excitation and emission wavelengths, potentially useful for multicolor NIR-II fluorescence imaging, which remains to be demonstrated in future studies. Other fluorescence enhancement techniques, such as gold substrate based surface resonance enhancement of SWNT fluorescence [47], may also be integrated for further improved imaging and detection sensitivity. 3. Raman imaging Unlike fluorescence, Raman scattering also involves emission of photons with shifted wavelengths under light excitation, is a photon scattering process rather than photoluminescence. The inherent Raman scattering signals of molecules without involving enhancement mechanism such as SERS are usually rather weak. However, the scattering efficiency gets larger when the laser energy matches the energy needed for the electron transition from the valence to the conduction bands, and this enhancement of Raman signals is also named resonance Raman scattering [67]. Typically, SWNTs have multiple Raman peaks, including the radical breathing mode (RBM, 100 cm−1–300 cm−1) and tangential G band (~1580 cm−1), which correspond to the vibration of carbon atoms in the radical direction and in the tangential direction, respectively. The resonance Raman scattering for SWNTs is determined by the DOS available for the optical transition (e.g. E11 and E22 transition), which is heavily determined by their diameters and chirality indices [68]. When the Raman spectrum of SWNTs is taken,

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Fig. 2. Video-rate NIR-II imaging of SWNTs in a live mouse. (a–h) Frames from video imaging of a mouse injected with PEGylated SWNTs taken at different time points post injection. (i). Dynamic contrast-enhanced imaging of the mouse injected with SWNTs through PCA. PCA images taken over the first 130 s following injection were performed by taking every 150 evenly spaced frames out of the 2000-frame dataset. Major features observed belong to the lungs, liver, kidney, spleen and even the pancreas. Copyright 2011 National Academy of Sciences [26].

those SWNTs with Eii in resonance would offer strong resonance Raman scattering useful for biological sensing and imaging. The intrinsic Raman properties of SWNTs were first adopted by Heller et al. for live cell imaging in 2005 [27]. In their work, SWNTs wrapped by DNA oligonucleotide were used as markers for live cell tracking. Without adding any extra fluorescent labels, the RBM peak of SWNTs was recorded inside live 3T3 cells under the excitation of a 785-nm laser. Compared with organic dyes and quantum dots which could be gradually quenched or photo-bleached over time, SWNTs showed rather robust Raman scattering signals without any significant quenching or photobleaching, allowing them to be used for long-term tracking in biological samples over months [69]. Taking advantages of the inherent Raman G band of carbon nanotubes, Lamprecht et al. were able to map and track the intracellular distribution of carbon nanotubes after targeted delivery to carcinoma cells [70]. In another recent study, Kang et al. used high-speed confocal Raman imaging to study the cellular uptake of SWNTs. In their work, movies of two cell-intrinsic and nine nanotube-derived Raman signals in RAW 264.7 macrophage were taken to resolve SWNTs with different indices and aggregation states, as well as their positions inside the cells. This work highlighted the advantages of Raman spectroscopy for molecular imaging of live cells [71]. In vivo Raman imaging of tumors on mice has also been demonstrated by using targeting ligandconjugated SWNTs [72,73]. Raman scattering usually exhibits rather sharp peaks with varied locations for different molecules, and thus is ideal for multiplexed sensing and imaging [74–76]. The frequency of carbon–carbon bond vibration in the G band Raman peak of SWNTs is determined by the carbon atom mass. By changing the carbon isotope from 12C to 13C, the G band peaks of SWNTs could be altered accordingly [77]. The first multiplexed Raman imaging of live cells was identified by Liu et al. [22]. In this paper, three types SWNTs with varied 13C doping ratio and thus different Raman G-band peaks were conjugated with different targeting ligands

to recognize the corresponding cell lines. By means of spectrum unmixing, multiplexed Raman imaging was realized simultaneously. A later work by the same group went a further step to realize the fivecolor Raman imaging of cells by conjugating SWNTs with different targeting molecules, for both multiplexed in vitro cell imaging and ex vivo tissue slice staining [78]. Although SWNTs are likely to exhibit the strongest inherent Raman signals among all single molecules, for biological samples labeled with SWNTs, the acquisition time to get a appropriate Raman image is still long (hours for a image with 100×100 pixels). Since the acquisition time in Raman imaging is highly determined by the Raman signals of Raman tags, the best way to shorten the imaging time is to enhance the Raman signals of those tags. Surface enhanced Raman scattering (SERS) may serve as possible way to enhance Raman signals of SWNTs by coating noble metal nanoparticles on the nanotube surface [48,79–81]. Although the on-substrate deposition of noble metal nanoparticles on SWNTs to achieve the SERS effect has been widely reported by many different groups [81–83], and there has been different methods to attach gold nanoparticles to covalently functionalized SWNTs which usually showed rather low Raman signals due to the damage of nanotube structure during functionalization (e.g. by oxidization) [84,85], the development of noble metal coated pristine SWNTs with noncovalent functionalization as a SERS nano-probe for Raman imaging of biological samples was not reported until a recent work by our group [48]. In this article, single strand DNA was used to functionalize pristine SWNTs with retained strong Raman scattering. After coating with positively charged poly(allylamine hydrochloride) (PAH), those nanotubes were then attached with negatively charged gold nano-seeds, which induced the growth of gold or silver nano-shells on the surface of SWNTs. (Fig. 4a–d) The noble metal coated SWNTs gained excellent SERS effects, with the maximal enhancement factor of over 20 (Fig. 4e–g) in the solution phase. Owing to the markedly enhanced Raman scattering,

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Fig. 3. The comparison of SWNT-based NIR-II fluorescence imaging and micro-CT imaging. (a) A NIR-II SWNT fluorescence image of a mouse thigh. (b) A micro-CT image showing the same area of the thigh as that in (a). (c) A cross-sectional fluorescence intensity profile measured along the green dashed line in (a) with its two peaks fitted to Gaussian functions. (d) A crosssectional intensity profile measured along the green dashed line in (b) with its two peaks fitted to Gaussian functions. (e) A NIR-II image at the level of the gastrocnemius. (f) A micro-CT image showing the same area of the limb as in e. (g) A cross-sectional fluorescence intensity profile measured along the green dashed line in e with its peak fitted to a Gaussian function. (h) A cross-sectional intensity profile measured along the green dashed line in (f) with its peak fitted to a Gaussian function. All scale bars indicate 2 mm. Copyright 2012 Nature Publishing Group [28].

gold-coated SWNTs were then conjugated with folic acid for specific cell labeling and Raman imaging, whose imaging time was shortened by one order of magnitude to enable fast mapping of biological samples (Fig. 4h).

SWNTs as a novel Raman tag exhibit several advantages over other organic Raman dyes. Firstly, the Raman peaks of SWNTs are simple, narrow, and intense, with a full width at half-maximum less than 2 nm, which is very easy to be distinguished from the

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Fig. 4. Noble metal enhanced SERS of SWNTs. (a) Schematic illustration of the synthetic procedure of SWNT–Au (or SWNT–Ag) nanocomposite. (b) A SEM image of SWNT–Au–PEG nanocomposite. (c,d) TEM images of SWNT–Au–PEG nanocomposite. (e) A photo of SWNT–Au–PEG solutions prepared by adding different concentrations of growth solution. (f) Raman spectra of SWNT–Au–PEG with different concentrations of growth solutions added during sample preparation. The spectra were taken under 785 nm laser excitation. (g) Enhanced factors of SWNT–Au–PEG as a function of added gold growth solution concentrations under the 633-nm and 785-nm excitations. (h) High-resolution Raman image of a SWNT–Au–PEG–FA labeled KB cell. The inset was a bright field image of this cell. Copyright 2012 American Chemical Society [48].

autofluorescent background. Secondly, the Raman signals of SWNTs are rather robust, without quenching or bleaching, enabling longterm tracking and imaging. Thirdly, the Raman shifts can be modulated by changing the isotope composition within SWNTs to achieve

multiple ‘colors’, allowing multiplexed Raman imaging. Lastly, the resonance Raman signals of SWNTs can be combined with the SERS technique, which further increases the detection sensitivity and reduces the imaging time.

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4. Photoacoustic imaging Photoacoustic (PA) imaging is a recently developed imaging modality, which has been widely used in the biological field [86–88]. The principle of PA imaging is as follows: the laser pulses can be absorbed by light-absorbing molecules, either endogenous molecules or contrast agents, in the biological sample to generate heat, inducing transient thermoelastic expansion and thus leading to wideband ultrasonic emission, which can be detected by an ultrasound microphone to construct 2D or 3D images. Compared with traditional optical imaging, PA imaging detects sound instead of light, and thus shows a number of obvious advantages such as greatly improved tissue penetration and enhanced spatial resolutions, by avoiding absorbance and scattering of the emission light in fluorescence imaging, respectively. Various nanomaterials which have strong absorbance in the NIR region are useful contrast agents in PA imaging [89–91]. Both MWNTs and SWNTs have been adopted as a photothermal agent due to its strong NIR absorbance [92–94]. On the other hand, its strong NIR absorbance also makes nanotubes ideal contrast agents for photoacoustic imaging. For cell imaging, Avti et al. [95]. adopted photoacoustic microscopy to detect, map and quantify the trace amount (nanograms to micrograms) of SWNTs in a variety of histological tissue specimens. The results showed that the noise-equivalent detection sensitivity was as low as about 7 picogram, which allowed further application in tissue analysis. For in vivo PA imaging, Gambhir et al. for the first time adopted RGD conjugated SWNTs as PA contrast agent. In their study, strong PA signals could be observed from the tumor in SWNT– RGD injected group, while only weak signals were observed in the plain SWNTs injected group [19].

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In order to further enhance the sensitivity of photoacoustic signal of SWNTs, a gold layer or some organic molecules with NIR absorbance were coupled with SWNTs to increase their absorbance in the NIR region. Zharov and coworkers developed ‘golden nanotubes’ (GNTs) by coating CNTs with gold to enhance the intrinsic PA signals of SWNTs [21]. In their work, the thin layer of gold encapsulated on the surface of SWNTs enhanced their optical density at the NIR region, and then the GNTs were conjugated with antibodies to specifically recognize the endothelium of murine lymphatic vessels (Fig. 5a). The obtained GNTs offered enhanced NIR PA imaging contrast (~102 fold) for targeting lymphatic vessels in mice using extremely low laser fluency level at a few mJ/cm−2. Furthermore, antibody conjugated GNTs were used to map the lymphatic endothelia receptor. As can be seen from Fig. 5, both the photoacoustic signal and photothermal signal in the antibody conjugated group (Fig. 5c&g) exceeded that of endogenous background and were preferentially located in the wall of lymphatic vessels, while for the GNTs without conjugation with antibodies (Fig. 5d,e,h&i), only random signals were seen and no signals could be found in the lymphatic wall of vessels. A later work by the same group further extended the application of GNTs to detect circulating tumor cells (CTCs) under PA imaging. Taking advantage of the strong PA signals of GNTs, folate conjugated GNTs were used as the PA contrast agent to image CTCs in vivo after being captured by an external magnetic field [96]. For the dye enhanced PA imaging with SWNTs, Gambhir et al. [49] loaded indocyanine green (ICG) molecules on PEGylated SWNTs through pi–pi stacking, which increased the optical density of the nano-probe by ~20 fold at 780 nm. Compared to the sensitivity of PA imaging obtained by plain SWNTs (~50 nM), SWNT–ICG exhibited sub-nanomolar detection sensitivity in PA imaging. Based on the same

Fig. 5. In vivo molecular targeting of murine lymphatics with GNTs guided by an integrated photoacoustic (PA)/photothermal (PT) technique. (a) Schematics of GNTs synthesis and its delivery to the target. (b–i) PT (b–e) and PA (f–i) two-dimensional lymphatic mapping in selected mesenteric areas taken before GNTs administration (b,f), at 60 min after administration of antibody — GNTs (c,g), and at 15 min (d,h) and 60 min (e,i) after administration of GNTs alone. Dashed white lines in (b–i) indicated the lymphatic wall and valve. Copyright 2009 Nature Publishing Group [21].

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Fig. 6. Multiplexed photoacoustic imaging. (a) Optical absorbance spectra of SWNT–QSY (red), and SWNT–ICG (green). The QSY and ICG dye-enhanced SWNTs showed 17- and 20-times higher optical absorption than plain SWNTs at their peak absorption wavelengths, 710 and 780 nm, respectively.(b) Optical absorbance spectra of plain SWNTs (black), SWNT-melanin (purple), SWNT-Cy5.5 (brown), and SWNT-MB (blue). (c) PA imaging of mice subcutaneously injected with SWNT–QSY or SNWT–ICG at concentrations between 0.5 and 122 nM. PA images were acquired at λ = 710 nm (red) and 780 (green) excitation, for SWNT–QSY and SWNT–ICG, respectively. The skin and inclusion region were visualized in the ultrasound images (black/white). (d) The in vivo PA signals from SWNT–ICG and SWNT–QSY at different SWNT concentrations. The error bars represented standard error (n = 3 mice). Linear regression (R2 = 0.97 for both particles) of the two PA signal curves estimated that a concentration of 450 pM for SWNT–QSY or 170 pM for SWNT–ICG produced the equivalent background signal of tissues. Copyright 2012 American Chemical Society [97].

concept, they further developed multiplexed PA imaging probes by loading five types of NIR dyes with shifted absorbance peaks on PEGylated SWNTs (Fig. 6a&b) [97] In particular, SWNTs loaded with QSY21 (SWNT–QSY) or indocyanine green (SWNT–ICG) exhibited strong and separated absorbance spectra, and could be used for multicolor PA imaging in vivo with great sensitivity (Fig. 6c&d). Therefore, CNTs with strong NIR absorbance are promising contrast agents in photoacoustic imaging. In addition to the use of their intrinsic optical absorbance, CNTs could also serve as a versatile nano-platform by coupling them with other light-absorbing nano-structures or molecules for enhanced or multiplexed photoacoustic imaging. Although most of currently reported CNT-based photoacoustic imaging probes are based on SWNTs, MWNTs should also be useful for this type of imaging modality. 5. Magnetic resonance imaging Magnetic resonance (MR) imaging is one of the most powerful and noninvasive modalities of imaging [98]. Annually, about 60 million of MR imaging cases are conducted in the clinic worldwide, and 30% of them use contrast agents [99]. Generally, the contrast agents are constituted of T1-shortening agents (containing Gd3+, Mn2+, etc.) and T2shortening agents (e.g. iron oxide nanoparticle). Considerable amount of research has been carried out to explore the potential application of CNTs for MR imaging [32,100–113]. For T1 weighted MR imaging, Sitharaman et al. first reported the nanoscale loading and confinement of aquated Gd3+-ion clusters within ultra-short SWNTs (US-tubes), obtaining Gd3+@US-tube with strong T1-contrast useful in MR imaging [107]. Richard et al. reported a noncovalent strategy to conjugate MWNTs with an amphiphilic gadolinium (III) chelate (GdL), making them useful to produce T1-contrast in MR imaging [108].

For T2 weighted MR imaging, Strano and coworkers first reported that SWNTs with iron oxide nanoparticles attached at the end of nanotubes could be used as T2 contrast agents for MR imaging, without the need of additional labeling [110]. Wu et al. reported MWNTs/cobalt ferrite synthesized by a solvothermal method. The obtained nanocomposite exhibited a significant negative contrast enhancement in T2weighted MR imaging of cancer cells [114]. Metal catalysts (e.g. Fe, Co) are commonly used during the synthesis of CNTs. Taking advantages of the impurities of iron contained in SWNTs, Faraj et al. studied the biodistribution of SWNTs by measuring MR signals in vivo [109]. Even after purification to remove the majority of catalyst metal nanoparticles in the nanotube sample, the purified SWNTs with trace amount of iron content have been found to be still effective to offer strong T2-contrast in MR imaging [115]. Stem cells have shown great potential in regenerative medicine and attracted tremendous interests in recent years [116,117]. Sensitive and reliable methods for stem cell labeling and in vivo tracking are thus urgently needed. Carbon nanotubes have also been used for stem cell labeling and tracking by several groups. Vittorrio et al. reported that MWNTs labeled mesenchymal stem cells (MSC) could be successfully tracked after being administrated into animals under T2-weighted MR imaging [118]. Our group recently used SWNTs to label human MSCs (hMSCs) for in vivo tracking based on triple modal imaging [32]. PEG functionalized SWNTs were conjugated with protamine, which remarkably enhanced the cellular uptake of SWNTs for highly efficient stem cell labeling (Fig. 7a,c&d). SWNT-labeled hMSCs showed unaffected differentiation and proliferation abilities compared to un-labeled cells. The strong inherent resonance Raman scattering of SWNTs was utilized for in vitro and in vivo Raman imaging of SWNT-labeled hMSCs, enabling ultrasensitive in vivo detection of as few as 500 stem cells administrated into a mouse. On the other hand, the metallic catalyst nanoparticles attached on nanotubes (Fig. 7b) can be utilized as the T2-contrast agent in

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Fig. 7. SWNTs used for stem cell tracking. (a) A schematic drawing of PEGylated SWNTs with protamine conjugation (SWNT–PEG–PRO). (b) A TEM images of SWNTs. (c,d) Raman images of hMSCs incubated with SWNT–PEG (c) and SWNT–PEG–PRO(d). (e) In vivo T2-weighted MR image of a mouse injected with SWNT-labeled hMSCs. Arrows pointed to the sites where unlabeled (left) and SWNT-labeled (right) hMSCs were injected. (f & g) In vivo Raman images of unlabeled (f) and SWNT-labeled (g) hMSCs. (h & i) In vivo PA images of unlabeled (h) and SWNT-labeled (i) hMSCs. The circles highlighted the locations were hMSCs were injected. PA signals in the rectangle highlighted in h were from a blood vessel crossing this area. Copyright 2012 Wiley [32].

magnetic resonance (MR) imaging of SWNT-labeled hMSCs (Fig. 7e). Moreover, in vivo photoacoustic imaging of hMSCs in mice is also demonstrated (Fig. 7h&i). This work reveals that SWNTs with appropriate surface functionalization could serve as multifunctional nanoprobes for stem cell labeling and multi-modal in vivo tracking. In conclusion, CNTs with appropriate modifications have been demonstrated to be useful contrast agents for both T1- and T2-weighted MR imaging. Particularly for T2-MR imaging, no additional treatment is needed since the metallic impurities in the CNT samples could be utilized to offer the MR contrast. Moreover, different from the previously discussed optical-based imaging techniques, MR imaging enables whole-body imaging without depth limit, and is thus a more clinical relevant imaging technique. Therefore, MR imaging with CNTs, if integrated with other abovementioned imaging techniques, may provide novel opportunities in bio-imaging.

6. Nuclear imaging Besides adopting the intrinsic characteristics of SWNTs, external labels such as radio-isotopes can also be introduced to increase the versatility of SWNT-based imaging probes. Wang et al. for the first time reported the 125I could be used to track the biodistribution of SWNTs in animals [119]. An alternative method using 14C instead of 125I was also realized by the same group to track the long-term biodistribution of MWNTs [120]. The modality of micro single photon emission computerized tomography (micro-SPECT) was successfully obtained by labeling CNTs with 111In [121]. Subsequently, McDevitt and coworkers labeled SWNTs with 86Y for position emission tomography (PET) imaging [122]. In vivo tumor imaging in mouse models by radionuclide labeled SWNTs has also been reported by several groups [123,124]. In 2007, Liu et al. used 64Cu to label PEGylated SWNTs with RGD peptide

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conjugation via a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator in vivo tumor-targeted PET imaging of U87MG tumors using 64Cu/DOTA-labeled SWNT–PEG–RGD was realized owing to the specific binding between RGD peptide and integrin avβ3 overexpressed on U87MG tumor cells as well as tumor vasculatures [123]. In addition to RGD peptide, anti-CD20 antibody was also used to target human Burkitt lymphoma by conjugating them with 111In labeled SWNTs [124]. Besides using traditional chelation chemistry to obtain radiolabeled CNTs, radioisotopes could also be inserted into nanotubes for radiolabeling [125]. Hong et al. reported that Na125I could be sealed inside the hollow structure of SWNTs, obtaining 125I-labeled SWNTs useful for SPECT/CT imaging. Compared with the modalities mentioned above, radio-labeled SWNTs exhibit several advantages, such as no tissue penetration depth limitation and high sensitivity. However, the progress of using CNTs for nuclear imaging has become relatively slow in the recent 2–3 years, without showing much significant advance to our best knowledge. Nevertheless, the combination of nuclear imaging with other imaging techniques may still be of great interests in the development of CNT-based bio-imaging probes. 7. Prospects and challenges Different imaging modalities of SWNTs have their respective advantages as well as limitations. The fluorescence imaging in the NIR-II biological transparent window with SWNTs enables in vivo optical imaging with deep tissue penetration and high spatial resolution, due to the low indigenous tissue scattering and the much reduced photon scattering in the NIR-II region compared to that for fluorescence imaging in visible (400–700 nm) and traditional NIR-I region (700–900 nm). However, the QY of SWNTs is still not high enough. Developing simple synthesis and purification strategies to get SWNTs with pure chirality would be of great importance to obtain new SWNT-based NIR-II imaging probes with bright and multi-colored fluorescence (Table 1). SWNTs have a large scattering cross-section and show strong resonance Raman scattering. Raman imaging by means of SWNT-probes has great sensitivity, and is resistant to photobleaching and quenching. Relying on the SERS effect, noble metal coated SWNTs show further enhanced Raman signals, enabling Raman mapping with a much faster speed. However, even with SERS enhancement, it still takes ~10 min to acquire a Raman image by conventional Raman mapping. The advances in instruments may be needed to make SWNT-based Raman imaging a viable tool in real biological research. Moreover, the use of chirality-purified SWNTs with the majority of nanotubes in resonance

Table 1 Various modalities of imaging based on carbon nanotubes. Imaging modalities

Examples

References

NIR-II fluorescence imaging

In vitro assay In vivo whole animal imaging High frame rate fluorescent video imaging combined with PCA Chirality sorted SWNTs for in vivo imaging In vitro cell imaging Multiplexed Raman imaging SERS enhanced Raman imaging In vivo imaging Cell imaging by photoacoustic Targeting in vivo PA imaging GNTs for in vivo imaging and CTCs Dye enhanced photoacoustic imaging T1 weighted MR imaging T2 weighted MR imaging

[56] [20] [26,28,43]

Raman imaging

Photoacoustic imaging

MR imaging

Nuclear imaging

Biodistribution of SWNTs PET imaging SPECT imaging

[42] [27,69–71] [22,78] [48,79–81] [72,73] [95] [19] [21,96] [49,97] [107,108] [32,109,110,114, 115,118] [119,120] [122,123] [121,124,125]

to the excitation laser would also significantly increase the Raman signals of SWNTs on a per mass basis. Other imaging techniques using CNTs, including PA imaging, MR imaging, and nuclear imaging, have also shown great potential in biomedical imaging. The integration of multiple imaging modalities could extend the advantages of each single imaging modality and overcome their inherent limitations. The real beauty of using CNTs as the imaging probe is thus their multi-functionalities. Unlike many other nanomaterials used in bio-imaging, CNTs with highly enriched optical and magnetic properties are intrinsic multimodal imaging probes, without the need to engineer complicated nanostructures to afford multiple functions. Moreover, the therapeutic functions of CNTs (e.g. drug & gene delivery, photothermal therapy) [31,93,126] in combination with imaging would further make them excellent theranostic nano-platforms. Besides the limitations of each modality mentioned above, one major challenge for the clinical application of CNTs is the concern of their potential long-term toxicity [127,128]. CNTs without appropriate surface functionalized have been found to be toxic in vivo, inducing a wide range of toxicity to animals [129–131]. On the other hand, researchers have also evidenced that CNTs with well design surface coatings such as PEGylation exhibit no obvious in vitro and in vivo toxicity [19,69,132–136], and may be gradually excreted from animals via renal and/or facial excretion pathways [137–140]. Several groups also claimed the possibility of biodegradation of CNTs under enzymeinduced oxidization [141,142]. Nevertheless, it is expected that while CNT-based biomedical imaging could indeed have the great potential in basic biomedical research as well as in vitro/ex vivo clinical diagnosis, there would still be significant challenges towards the use of those nanomaterials for real in vivo clinical applications. Acknowledgments This work was partially supported by the National Natural Science Foundation of China (51222203, 51002100, 51132006), the National “973” Program of China (2011CB911002, 2012CB932601), and a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. References [1] S. Iijima, Helical microtubules of graphitic carbon, Nature 354 (1991) 56–58. [2] H.J. Dai, Carbon nanotubes: synthesis, integration, and properties, Acc. Chem. Res. 35 (2002) 1035–1044. [3] M.S. Dresselhaus, H. Dai, Carbon nanotubes: continued innovations and challenges, MRS Bull. 29 (2004) 237–239. [4] H. Ago, K. Petritsch, M.S. Shaffer, A.H. Windle, R.H. Friend, Composites of carbon nanotubes and conjugated polymers for photovoltaic devices, Adv. Mater. 11 (1999) 1281–1285. [5] M. Ouyang, J.L. Huang, C.M. Lieber, Fundamental electronic properties and applications of single-walled carbon nanotubes, Acc. Chem. Res. 35 (2002) 1018–1025. [6] N.S. Lee, D.S. Chung, I.T. Han, J.H. Kang, Y.S. Choi, H.Y. Kim, S.H. Park, Y.W. Jin, W.K. Yi, M.J. Yun, J.E. Jung, C.J. Lee, J.H. You, S.H. Jo, C.G. Lee, J.M. Kim, Application of carbon nanotubes to field emission displays, Diam. Relat. Mater. 10 (2001) 265–270. [7] M.W. Rowell, M.A. Topinka, M.D. McGehee, H.-J. Prall, G. Dennler, N.S. Sariciftci, L. Hu, G. Gruner, Organic solar cells with carbon nanotube network electrodes, Appl. Phys. Lett. 88 (2006). [8] K. Besteman, J.O. Lee, F.G.M. Wiertz, H.A. Heering, C. Dekker, Enzyme-coated carbon nanotubes as single-molecule biosensors, Nano Lett. 3 (2003) 727–730. [9] B.L. Allen, P.D. Kichambare, A. Star, Carbon nanotube field-effect-transistor-based biosensors, Adv. Mater. 19 (2007) 1439–1451. [10] Z. Liu, K. Chen, C. Davis, S. Sherlock, Q. Cao, X. Chen, H. Dai, Drug delivery with carbon nanotubes for in vivo cancer treatment, Cancer Res. 68 (2008) 6652–6660. [11] Z. Liu, X. Sun, N. Nakayama-Ratchford, H. Dai, Supramolecular chemistry on water-soluble carbon nanotubes for drug loading and delivery, ACS Nano 1 (2007) 50–56. [12] F. Zhou, D. Xing, Z. Ou, B. Wu, D.E. Resasco, W.R. Chen, Cancer photothermal therapy in the near-infrared region by using single-walled carbon nanotubes, J. Biomed. Opt. 14 (2009)(021009-021009). [13] X. Liu, H. Tao, K. Yang, S. Zhang, S.-T. Lee, Z. Liu, Optimization of surface chemistry on single-walled carbon nanotubes for in vivo photothermal ablation of tumors, Biomaterials 32 (2011) 144–151. [14] G. Pastorin, W. Wu, S. Wieckowski, J.-P. Briand, K. Kostarelos, M. Prato, A. Bianco, Double functionalisation of carbon nanotubes for multimodal drug delivery, Chem. Commun. (2006) 1182–1184.

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