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: This article reviews the latest progresses regarding the applications of carbon nanotubes (CNTs), including single-
Accepted 16 October 2013 walled carbon nanotubes (SWNTs) and multi-walled carbon nanotubes (MWNTs), as multifunctional nano-
Available online 30 October 2013 probes 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
Keywords:
penetration and spatial resolution has shown great promise in recent years. Raman imaging based on the reso-
Carbon nanotubes
Biomedical imaging
nance Raman scattering of SWNTs has also been explored by a number of groups for in vitro and in vivo imaging
NIR-II fluorescence of biological samples. The strong absorbance of CNTs in the NIR region can be used for photoacoustic imaging, and
Raman scattering their photoacoustic signals can be dramatically enhanced by adding organic dyes, or coating with gold shells. Tak-
Photoacoustic ing advantages of metal nanoparticle impurities attached to nanotubes, CNTs can also serve as a T2-contrast
Magnetic resonance agent in magnetic resonance (MR) imaging. In addition, when labeled with radioactive isotopes, many groups
Nuclear imaging 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.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1951
2. Fluorescence imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1952
3. Raman imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1953
4. Photoacoustic imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1957
5. Magnetic resonance imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1958
6. Nuclear imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1959
7. Prospects and challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1960
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1960
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1960

1. Introduction

Carbon nanotubes (CNTs), including single-walled carbon nano-

Abbreviations: CNTs, carbon nanotubes; SWNTs, single-walled carbon nanotubes; NIR,
near infrared; MR, magnetic resonance; 1D, one dimensional; PA, photoacoustic; PET, posi-
tron emission tomography; SPECT, single photon emission computed tomography; SERS, sur-
face 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: rpeng@suda.edu.cn (R. Peng), zliu@suda.edu.cn (Z. Liu).
tubes (SWNTs) and multi-walled carbon nanotubes (MWNTs), have be-
come star materials since its first discovery in 1990 [1–3]. Various
applications related to CNTs, such as composite materials [4], nano-
electronics [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 atten-
tions. 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 inter-
ests [10–18]. In the direction of bio-imaging, CNT-based imaging probes
have also been widely investigated [19–24].

0169-409X/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.addr.2013.10.002
1952 H. Gong et al. / Advanced Drug Delivery Reviews 65 (2013) 1951–1963
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 ex-
tremely 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 intrin-
sic 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 func-
tionalized 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 com-
prehensive 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 tremen-
dous progresses made in the very recent few years to explore CNT-
based 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 re-
markable 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 dramat-
ically 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 fluores-
cence imaging [50]. To overcome this problem, researchers have been
focusing on developing and implementing fluorescent probes with exci-
tation 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 fluores-
cence 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 cho-
late showed relatively high QY, however appeared to be toxic in biolog-
ical systems. Non-covalent PEGylation of SWNTs, although can offer
nanotubes great water-solubility and enhanced biocompatibility, usual-
ly would also drastically decrease of QY of SWNTs. In 2009, an interest-
ing 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 son-
icated 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 intrave-
nously (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 NIR-
II contrast agent to perform the high frame rate fluorescent video imag-
ing 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 in-
jection, 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 SWNT-
injection. (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
 H. Gong et al. / Advanced Drug Delivery Reviews 65 (2013) 1951–1963 1953

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 differ-
entiated 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 mea-
sured in both ischemic and normal limbs, even at very low blood veloc-
ities, which are beyond the capabilities of ultrasonography. Therefore,
their results suggested that the NIR-II fluorescence imaging of vascula-
tures 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 chiral-
ities, and each chirality corresponds to a different set of excitation and
emission wavelengths. Therefore, in previous NIR-II fluorescence imag-
ing 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 re-
markably 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 in-
jection 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 de-
velopment in this direction requires better SWNT samples with high QY
and purified chiralities to provide even ‘brighter’ fluorescence. More-
over, different SWNTs with purified single chiralities would show sepa-
rated excitation and emission wavelengths, potentially useful for multi-
color 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 fluores-
cence [47], may also be integrated for further improved imaging and
detection sensitivity.
3. Raman imaging
Unlike fluorescence, Raman scattering also involves emission of pho-
tons with shifted wavelengths under light excitation, is a photon scat-
tering process rather than photoluminescence. The inherent Raman
scattering signals of molecules without involving enhancement mecha-
nism such as SERS are usually rather weak. However, the scattering ef-
ficiency 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 vibra-
tion of carbon atoms in the radical direction and in the tangential direc-
tion, 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,
1954 H. Gong et al. / Advanced Drug Delivery Reviews 65 (2013) 1951–1963

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 record-
ed 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 intra-
cellular distribution of carbon nanotubes after targeted delivery to carci-
noma 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 ligand-
conjugated SWNTs [72,73].
Raman scattering usually exhibits rather sharp peaks with varied lo-
cations 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 five-
color 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 nano-
particles 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 posi-
tively charged poly(allylamine hydrochloride) (PAH), those nanotubes
were then attached with negatively charged gold nano-seeds, which in-
duced 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,
 H. Gong et al. / Advanced Drug Delivery Reviews 65 (2013) 1951–1963 1955

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 cross-
sectional 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 SWNTs as a novel Raman tag exhibit several advantages over
labeling and Raman imaging, whose imaging time was shortened by other organic Raman dyes. Firstly, the Raman peaks of SWNTs are
one order of magnitude to enable fast mapping of biological samples simple, narrow, and intense, with a full width at half-maximum
(Fig. 4h). less than 2 nm, which is very easy to be distinguished from the
1956 H. Gong et al. / Advanced Drug Delivery Reviews 65 (2013) 1951–1963

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 nano-
composite. (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 multiple ‘colors’, allowing multiplexed Raman imaging. Lastly, the
are rather robust, without quenching or bleaching, enabling long- resonance Raman signals of SWNTs can be combined with the SERS
term tracking and imaging. Thirdly, the Raman shifts can be modu- technique, which further increases the detection sensitivity and re-
lated by changing the isotope composition within SWNTs to achieve duces the imaging time.
 H. Gong et al. / Advanced Drug Delivery Reviews 65 (2013) 1951–1963 1957

4. Photoacoustic imaging In order to further enhance the sensitivity of photoacoustic signal of

Photoacoustic (PA) imaging is a recently developed imaging modal-
ity, which has been widely used in the biological field [86–88]. The prin-
ciple 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 emis-
sion, which can be detected by an ultrasound microphone to construct
2D or 3D images. Compared with traditional optical imaging, PA imag-
ing 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 emis-
sion 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 photo-
acoustic 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 sen-
sitivity was as low as about 7 picogram, which allowed further applica-
tion 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].
SWNTs, a gold layer or some organic molecules with NIR absorbance
were coupled with SWNTs to increase their absorbance in the NIR re-
gion. 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 an-
tibody conjugated group (Fig. 5c&g) exceeded that of endogenous back-
ground 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 ex-
tended 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].
1958 H. Gong et al. / Advanced Drug Delivery Reviews 65 (2013) 1951–1963

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 im-
ages 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 multi-
color 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 mole-
cules 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 consti-
tuted of T1-shortening agents (containing Gd3+, Mn2+, etc.) and T2-
shortening 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 gado-
linium (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 nano-
tubes 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 nanocom-
posite exhibited a significant negative contrast enhancement in T2-
weighted 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 remark-
ably enhanced the cellular uptake of SWNTs for highly efficient stem cell
labeling (Fig. 7a,c&d). SWNT-labeled hMSCs showed unaffected differ-
entiation 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 at-
tached on nanotubes (Fig. 7b) can be utilized as the T2-contrast agent in
 H. Gong et al. / Advanced Drug Delivery Reviews 65 (2013) 1951–1963 1959

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 dem-
onstrated (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 dem-
onstrated 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 uti-
lized 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 inte-
grated with other abovementioned imaging techniques, may provide
novel opportunities in bio-imaging.
6. Nuclear imaging
Besides adopting the intrinsic characteristics of SWNTs, external la-
bels such as radio-isotopes can also be introduced to increase the versa-
tility 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 com-
puterized tomography (micro-SPECT) was successfully obtained by la-
beling CNTs with 111In [121]. Subsequently, McDevitt and coworkers
labeled SWNTs with 86Y for position emission tomography (PET) imag-
ing [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
1960 H. Gong et al. / Advanced Drug Delivery Reviews 65 (2013) 1951–1963

conjugation via a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic to the excitation laser would also significantly increase the Raman
acid (DOTA) chelator in vivo tumor-targeted PET imaging of U87MG signals of SWNTs on a per mass basis.
tumors using 64Cu/DOTA-labeled SWNT–PEG–RGD was realized owing Other imaging techniques using CNTs, including PA imaging, MR
to the specific binding between RGD peptide and integrin avβ3 over- imaging, and nuclear imaging, have also shown great potential in bio-
expressed on U87MG tumor cells as well as tumor vasculatures [123]. medical imaging. The integration of multiple imaging modalities could
In addition to RGD peptide, anti-CD20 antibody was also used to target extend the advantages of each single imaging modality and overcome
human Burkitt lymphoma by conjugating them with 111In labeled their inherent limitations. The real beauty of using CNTs as the imaging
SWNTs [124]. Besides using traditional chelation chemistry to obtain probe is thus their multi-functionalities. Unlike many other nano-
radiolabeled CNTs, radioisotopes could also be inserted into nanotubes materials used in bio-imaging, CNTs with highly enriched optical and
for radiolabeling [125]. Hong et al. reported that Na125I could be sealed magnetic properties are intrinsic multimodal imaging probes, without
inside the hollow structure of SWNTs, obtaining 125I-labeled SWNTs the need to engineer complicated nanostructures to afford multiple
useful for SPECT/CT imaging. Compared with the modalities mentioned functions. Moreover, the therapeutic functions of CNTs (e.g. drug & gene
above, radio-labeled SWNTs exhibit several advantages, such as no tis- delivery, photothermal therapy) [31,93,126] in combination with imaging
sue penetration depth limitation and high sensitivity. However, the would further make them excellent theranostic nano-platforms.
progress of using CNTs for nuclear imaging has become relatively slow Besides the limitations of each modality mentioned above, one
in the recent 2–3 years, without showing much significant advance to major challenge for the clinical application of CNTs is the concern of
our best knowledge. Nevertheless, the combination of nuclear imaging their potential long-term toxicity [127,128]. CNTs without appropriate
with other imaging techniques may still be of great interests in the surface functionalized have been found to be toxic in vivo, inducing a
development of CNT-based bio-imaging probes. wide range of toxicity to animals [129–131]. On the other hand, re-
searchers have also evidenced that CNTs with well design surface coat-
7. Prospects and challenges ings such as PEGylation exhibit no obvious in vitro and in vivo toxicity
[19,69,132–136], and may be gradually excreted from animals via
Different imaging modalities of SWNTs have their respective advan- renal and/or facial excretion pathways [137–140]. Several groups also
tages as well as limitations. The fluorescence imaging in the NIR-II claimed the possibility of biodegradation of CNTs under enzyme-
biological transparent window with SWNTs enables in vivo optical im- induced oxidization [141,142]. Nevertheless, it is expected that while
aging with deep tissue penetration and high spatial resolution, due to CNT-based biomedical imaging could indeed have the great potential
the low indigenous tissue scattering and the much reduced photon scat- in basic biomedical research as well as in vitro/ex vivo clinical diagnosis,
tering in the NIR-II region compared to that for fluorescence imaging there would still be significant challenges towards the use of those
in visible (400–700 nm) and traditional NIR-I region (700–900 nm). nanomaterials for real in vivo clinical applications.
However, the QY of SWNTs is still not high enough. Developing simple
synthesis and purification strategies to get SWNTs with pure chirality Acknowledgments
would be of great importance to obtain new SWNT-based NIR-II
imaging probes with bright and multi-colored fluorescence (Table 1). This work was partially supported by the National Natural Science
SWNTs have a large scattering cross-section and show strong reso- Foundation of China (51222203, 51002100, 51132006), the National
nance Raman scattering. Raman imaging by means of SWNT-probes “973” Program of China (2011CB911002, 2012CB932601), and a Project
has great sensitivity, and is resistant to photobleaching and quenching. Funded by the Priority Academic Program Development of Jiangsu
Relying on the SERS effect, noble metal coated SWNTs show further en- Higher Education Institutions.
hanced Raman signals, enabling Raman mapping with a much faster
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