NIR2

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org/JACS Perspective
Advanced Fluorescence Imaging Technology in the Near-Infrared-II

Window for Biomedical Applications
Chunyan Li,‡ Guangcun Chen,‡ Yejun Zhang, Feng Wu, and Qiangbin Wang*
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ABSTRACT: Fluorescence imaging has become a fundamental tool for biomedical applications; nevertheless, its intravital imaging
capacity in the conventional wavelength range (400−950 nm) has been restricted by its extremely limited tissue penetration. To
tackle this challenge, a novel imaging approach using the fluorescence in the second near-infrared window (NIR-II, 1000−1700 nm)
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has been developed in the past decade to achieve deep penetration and high-fidelity imaging, and thus significant biomedical
applications have begun to emerge. In this Perspective, we first examine recent discoveries and challenges in the development of
novel NIR-II fluorophores and compatible imaging apparatuses. Subsequently, the recent advances in bioimaging, biosensing, and
therapy using such a cutting-edge imaging technique are highlighted. Finally, based on the achievement in the representative studies,
we elucidate the main concerns regarding this imaging technique and give some advice and prospects for the development of NIR-II
imaging for future biomedical applications.
■ INTRODUCTION
Intravital imaging technology provides a favorable approach for
light, owing to decreased photon absorbance, scattering, and
autofluorescence. The NIR-I fluorescence dyes indocyanine
achieving insight into the anatomical structures, molecular green (ICG) and methylene blue (MB) (approved by the U.S.
biomarkers, and physiological activities in living organisms, Food and Drug Administration (FDA)) have made significant
which opens new avenues of biomedical research and clinical contributions to clinical diagnostics and interventions,3,4
practice.1 Among various imaging modalities, including especially for fundus angiography and lymphography. Despite
computed tomography (CT), magnetic resonance imaging this, achieving tissue penetration at the millimeter level in the
(MRI), ultrasound (US), positron emission tomography (PET), NIR-I region remains difficult to meet the multilevel and diverse
and single-photon-emission CT (SPECT), fluorescence imag- requirements of practical applications. To this end, scientists
ing simultaneously features a series of salient merits such as rapid resurveyed the interactions between photons and biological
feedback, multiple signal acquisition capability, high sensitivity, tissues and executed exploratory research.
and the absence of ionizing radiation; thus, it is one of the fastest In 2009, a pioneering work by Dai at Stanford University
developing and most widely used imaging technologies in the revealed a new bioimaging window, commonly termed as the
biomedical field. However, challenges remain. A major NIR-II window (1000−1700 nm) (Figure 1b),5,6 which displays
limitation of fluorescence imaging is its restricted tissue superior performance in in vivo bioimaging. Compared with the
penetration depth. Acquiring fluorescence signals is greatly NIR-I region, photon absorption of water in the NIR-II region is
dependent on the interaction between photons and biological somewhat stronger (e.g., 970, 1200, and 1450 nm) due to
tissues, such as reflection, absorbance, scattering, and auto- vibrational overtone bands and combination transitions (Figure
fluorescence (Figure 1a).2 The wavelengths used in classical 1c). Despite this, decreased tissue scattering and ultralow
fluorescence imaging for both excitation and emission are autofluorescence (nearly zero background when the wavelength
mainly located in the visible range (400−650 nm), where is larger than 1500 nm) play predominant roles (Figure 1d,e),7
significant absorption and scattering effects induced by enabling unprecedented improvements in detection depth,
biological tissues as well as strong autofluorescence originating resolution, and sensitivity. Taking each aspect into consid-
from specific biomolecules (e.g., flavins, lipofuscin, reticulin, and eration, further optimized optical sub-windows NIR-IIa (1300−
exogenous foods) result in low tissue penetration (<3 mm), 1400 nm) and NIR-IIb (1500−1700 nm) have been identified.8
leading to a significant loss of physiological and pathological Based on the above-mentioned unique optical properties, there
information at the whole-body level.
The discovery of the biological-tissue transparency window
and advances in near-infrared (NIR) technology suggested Received: June 30, 2020
exciting prospects for in vivo fluorescence imaging. Wavelengths Published: August 7, 2020
ranging from 650 to 950 nm is the first confirmed biological-
tissue transparency window (denoted as the first near-infrared
window, or the NIR-I window), and this range exhibits
significantly increased tissue penetration compared with visible
© 2020 American Chemical Society https://dx.doi.org/10.1021/jacs.0c07022

14789 J. Am. Chem. Soc. 2020, 142, 14789−14804
Journal of the American Chemical Society pubs.acs.org/JACS Perspective
Figure 1. (a) Schematic diagram of the interactions between the photons and tissue when executing fluorescence imaging. (b) Effective attenuation
coefficient of various biological components including oxygenated blood, deoxygenated blood, skin, and fatty tissue. (c) Absorption spectrum of water
in the range of 400−1800 nm measured through a 1-mm-long path. (d) Reduced scattering of different biological tissues and intralipid solution in the
range of 400−1700 nm. (e) Autofluorescence spectra of ex vivo mouse liver (black), spleen (red), and heart tissue (blue) under 808 nm excitation.
Panels a, c, d, and e reproduced with permission from ref 2. Copyright 2017, Nature Publishing Group. Panel b reproduced with permission from ref 6.
Copyright 2009, Nature Publishing Group.
Figure 2. Timeline of major milestones in NIR-II fluorescence imaging technology. Reproduced with permission from ref 22. Copyright 2011,
National Academy of Sciences. Reproduced with permission from ref 57. Copyright 2019, Wiley-VCH. Reproduced with permission from ref 58.
Copyright 2018, Nature Publishing Group. Reproduced with permission from ref 59. Copyright 2020, Nature Publishing Group. Reproduced with
permission from ref 60. Copyright 2017, Wiley-VCH. Reproduced with permission from ref 61. Copyright 2018, Wiley-VCH. Reproduced with
permission from ref 62. Copyright 2019, Nature Publishing Group.
has been greatly increased attention focused on the development we examine recent discoveries and challenges in the develop-
of novel NIR-II fluorophores, imaging instruments, and ment of novel NIR-II fluorophores and compatible imaging
biomedical applications in the past decade. In this Perspective, apparatuses, provide representative applications in bioimaging,
14790 https://dx.doi.org/10.1021/jacs.0c07022
J. Am. Chem. Soc. 2020, 142, 14789−14804
biosensing, and theranostic applications, and propose potential fluorescence by thermal decomposing a single-source precursor
solutions and ideas for future research. of Ag(DDTC)[(C2H5)2NCS2Ag]. Thereafter, a series of high-
■ NIR-II FLUOROPHORES
The emergence of such a new biological-tissue transparency
quality Ag2S QDs with high QY (approximately 20%) and
tunable fluorescence emission ranging from 900 to 1250 nm
were obtained.30,31 Compared with Ag2S QDs, Ag2Se QDs have
window has aroused extensive interest in the fields of chemistry, a narrower bandgap (∼0.15 eV) and exhibit great promise for
materials science, and biology. The design and construction of fluorescence emission at longer wavelength. In 2013, the same
NIR-II fluorophores based on organic, inorganic, and hybrid- group developed such a new type of NIR-II QDs by facile
material systems have achieved a substantial progress in the past solvothermal synthesis; after a coating of C18-PMH-PEG,
decade. Representative fluorescent materials (Figure 2), Ag2Se QDs displayed good dispersibility in aqueous solution
including single-walled carbon nanotubes (SWCNTs),5 quan- when emission was centered at 1300 nm.10 Such novel QDs
tum dots (QDs), 9−12 rare earth-doped nanoparticles containing no toxic heavy metal components exhibit high
(RENPs),13−15 semiconducting polymer-based nanoparticles chemical stability and hold great potential in biomedical
(SPNPs),16,17 small-molecule dyes (SMDs),18−20 and aggrega- applications. In addition, despite existing concerns over heavy
tion-induced emission luminogens (AIEgens),21 have greatly metal ions, some effective strategies have been executed to
extended the arsenal of currently available fluorophores for alleviate these problems and improve the optical properties of
biomedical applications. QDs at the same time. Most recently, Bawendi and co-workers
SWCNTs. SWCNTs are a type of 1D carbon nanomaterial fabricated InAs-based core/shell (CS) and core/shell/shell
that is formed from a single sheet of graphite composed of (CSS) QDs, which displayed narrow and size-tunable emission
carbon in a honeycomb lattice and rolled into a tube with a in the NIR-II window and a remarkably high emission QY by up
diameter ranging from sub-nanoscale to several nanometers. In to 30% in aqueous solution.12 Aside from constructing a CS to
addition to special physical and chemical properties such as avoid heavy metal ion leakage, biomacromolecule wrapping also
Raman scattering and UV/visible/NIR absorption, SWCNTs provides an alternative approach. Whey protein and ribonu-
also display intrinsic fluorescence in the NIR-II window owing clease-A were introduced onto the surface of the PbS QDs as
to van Hove transitions across bandgaps. SWCNTs were first shield layers to avoid interaction between QDs with
employed by Dai et al. as NIR-II nanoprobes by phospholipid- biointerfaces, minimizing their toxic effects.32,33 Such strategies
polyethylene glycol functionalization for intravital fluorescence may be effective for obtaining various biocompatible QDs
imaging.5 Subsequently, a series of biomedical studies were containing heavy metal. Even so, nontoxic QDs with high QY
conducted with SWCNTs, and some important advances have deserve more attention in the future studies.
been achieved.8,22−27 For example, Belcher and co-workers have RENPs. Generally, RENPs are composed of an inorganic
demonstrated that the filamentous M13 virus could be used as crystalline host matrix and trivalent lanthanide ions (Ln3+)
stabilizer to achieve good dispersion of SWCNTs in aqueous embedded in the host lattice. The process of fluorescence
solution.25 Furthermore, by displaying ovarian cancer targeted generation in RENPs is due to the resonant transfer of energy
peptides SBP, this targeted nanoprobe (SBP-M13-SWCNTs) from a sensitizer to a rare earth (RE)-activator dopant. By
exhibited higher signal-to-noise ratio compared with visible and regulating different Ln3+ components, it can obtain specific
NIR-I dyes for in vivo detection of tumor nodules. upconversion or downconversion luminescence. In the past two
Mukhopadhyay et al. fabricated a specific DNA-wrapped
decades, some researchers including Prasad, Liu, Li et al., have
SWCNT and demonstrated its feasibility to determine the
focused on the upconversion luminescence property of RENPs
therapeutic response of pancreatic ductal adenocarcinoma by
and made tremendous efforts for bioimaging.34−41 To achieve
precisely monitoring H2O2 in the lesion locations.27 Typically,
efficient downconversion luminescence in the NIR-II window,
strong polydisperse infrared absorbance of SWCNTs weakens
the NIR-II emission, resulting in low quantum yield (QY) less aside from the host matrix, the appropriate sensitizers and
than 3% as well as accompanying thermal effect. Thus, activators should be taken into account. Because of their large
increasing the QY once sacrificed for avoidance of self- absorption cross sections in the NIR-I region, Nd3+, Yb3+, and
absorption and improving biocompatibility will be the major Er3+ can serve as efficient sensitizers; additionally, Pr3+, Nd3+,
focuses of future research into SWCNTs. Ho3+, Er3+, and Tm3+ with ladder-like energy levels are often
QDs. QDs are semiconductor nanocrystals (NCs) with used as activators in the NIR-II region. Moghe and co-workers
diameters in the range of 2−10 nm and display unique optical fabricated a series of CS structure RENPs, containing rare earth
properties when their radii are smaller than the exciton Bohr ion-doped NaYF4 as the core and undoped NaYF4 as the shell
radius. Since they were first introduced for biomedical studies by layer, and achieved tunable multispectral emissions (e.g., 1185,
Alivisatos and Nie in 1998,28,29 QDs have enjoyed great success 1310, 1475, and 1525 nm).13 Zhang et al. developed a β-
in in vitro analysis and diagnosis. To gain NIR-II emitting QDs, NaGdF 4 /Na(Gd,Yb)F 4 :Er/NaYF 4 :Yb/NaNdF 4 :Yb core/
one fundamental principle is to reduce their bandgap, thereby shell1/shell2/shell3 (C/S1/S2/S3) multishell NCs by epitaxial
decreasing the energy of an electron jumping from the ground seeded growth. The synthesized probe can efficiently transfer
state valence band to an excited state conduction band. By 800 nm near-infrared to 1525 nm short-wavelength infrared via a
manipulating chemical components, narrow bandgap QDs can down conversion process.14 Prasad et al. demonstrated a hybrid
be obtained, which are mainly located in groups IV−VI, III−V, organic−inorganic system consisting of CSS RENPs with
II−VI, and I−VI. However, most of these QDs contain highly organic dye ICG attached on the surface. Thus, the hybrid
toxic components such as Hg, Pb, and Cd, resulting in potential probe can possess a broadly excitable spectral range (700−860
toxicity in biomedical applications. nm) and a significantly improved NIR-II fluorescence emission
One of the most important advances in fabrication of with a QY of ∼13%.15 Despite their great potential for
biocompatible NIR-II QDs was reported by Wang et al. in bioimaging, improving the water solubility and avoiding Ln3+
2010.9 They first reported Ag2S QDs with favorable NIR-II concentration quenching effect of RENPs remain to be solved.
J. Am. Chem. Soc. 2020, 142, 14789−14804
Organic Fluorophores. As is well-known, the photo- improved signal-to-noise ratio, the fluorescence turn-on nature,
luminescence properties of SMDs are highly correlated with the optimal QY (0.18%−14.8%), etc.,21,53,54 which further
the chemical structures of the molecules created through π expands the library of NIR-II fluorophores for different studies.
interactions. In the past decades, great efforts have been made to The rapid development of NIR-II fluorophores in the past
tailor the fluorescence emission of small molecules in the NIR decade has provided rich probes for biomedical imaging.2 Each
region, and a series of NIR-emissive dyes with molecular NIR-II fluorophore has its advantages and disadvantages, which
skeletons such as cyanine, BODIPY, rhodamine, porphyrin, and should be taken into account for different studies. For
squaraine have been designed and synthesized. Among them, photostability, inorganic probes, including SWCNTs, QDs,
cyanine- and donor−acceptor−donor (D-A-D)-based struc- and RENPs, generally possess better photostability than organic
tures hold great promise for construction of NIR-II probes. For QY, among the available NIR-II fluorophores, the
fluorophores.42−47 Cyanine dyes contain polymethine bridges one with the highest QY is currently the QD-based probe.55
between two nitrogen atoms with a delocalized charge. However, the QY of each NIR-II probe is still much lower than
Prolonging the conjugated structures or tuning the chemical that of its corresponding type of probe emitting in the visible
substitutions are effective approaches to reduce the energy gap range. And there is plenty of room for further improving their
between the ground state and the excited state, thereby QYs. For biocompatibility, metal element-containing inorganic
achieving the red-shift of emission to NIR-II region. In 2016, probes (such as QDs and RENPs) have concerns about the
Dai et al. reported the first D-A-D structure-based small- toxicity caused by the release of metal elements, inorganic
molecule dye with bright NIR-II fluorescence emission and a QY probes also have concerns about generating a large number of
of 0.3%, CH1055, in which aromatic units conjugated with a D- oxidative free radicals and causing toxicity during imaging. For
A-D structure and a benzobisthiadiazole core contribute to NIR- pharmacokinetic, several SMDs can be rapidly eliminated
II fluorescence.18 After that, a series of SMDs have been through the renal route, so there is a low residual risk after
developed to further improve the QY, water solubility, and imaging.18 And nanoprobes are more likely to be captured by the
biocompatibility of SMDs.19,20,42−47 For instance, a small- reticuloendothelial system, thus requiring a long elimination
molecule fluorophore FD-1080 with a heptamethine structure process.56
was designed by Zhang’s group for NIR-II imaging in 2018. After
combining with fetal bovine serum, the QY of FD-1080
significantly increased to 5.94%. The high QY of FD-1080
■ NIR-II FLUORESCENCE IMAGING SYSTEMS
The NIR-II imaging system is another indispensable element for
makes it promising for noninvasive high-resolution deep-tissue fluorescence bioimaging because it can efficiently collect NIR-II
imaging.19 Now, a number of NIR-II SMDs are commercially emission signals from NIR-II fluorophores, thereby providing
available; however, they are mostly hydrophobic. In 2020, Kilian precise anatomical, functional, and molecular images. Unlike the
et al. developed a facile formulation strategy to prepare NIR-II traditional fluorescence imaging apparatuses which could be
SMDs for injection by simply dissolving them in biocompatible easily obtained from commercial channels, as an emerging
surfactants. By testing 13 hydrophobic NIR-II SMDs, they imaging technology, lack of compatible NIR-II imaging systems
found the benzo indole butyl diphenylaminocyclopentene and components was a major issue. Specifically, previous studies
heptamethine tetrafluoroborate in Kolliphor HS15 showed the of fluorescence imaging in biomedical areas focused primarily on
best performance.20 the visible region, where the photodetectors with a high QY,
In contrast to the aforementioned SMDs, the organic such as a charge-coupled device (CCD) or a complementary
semiconducting materials (SPNPs) have been widely used in metal oxide semiconductors (CMOS) camera, are available.
electronic components, e.g. organic field-effect transistors However, such silicon-based detectors display ultralow quantum
(OFETs), organic light-emitting diodes (OLEDs), solar cells efficiency at wavelength >1000 nm, which makes it unsuitable
(organic photovoltaic, OPV), etc. Their introduction into for NIR-II imaging. The emergence of shortwave infrared
biomedical imaging has already proven to be successful. (SWIR) cameras based on semiconductor alloys with narrower
Nevertheless, how to tune the spectrum into the NIR-II window band gaps, such as InGaAs and HgCdTe, make NIR-II imaging
is still a challenge. One effective strategy is prolonging the π- possible.
conjugation length by designing quinoid stabilized D−A Dai’s group built the first intravital NIR-II imaging prototype
polymers, which can reduce the energy bandgap and result in device,22 which was mainly composed of a liquid-nitrogen-
the spectrum red-shift into the NIR-II window. Pu et al. have cooled InGaAs detector (320 × 256 pixel), a diode laser coupled
explored a series of organic semiconducting-based NIR-II to a collimator with a focal length of 4.5 mm as well as
probes with a QY of approximate 2.2%, which have been appropriate filter sets and objective lens. This home-built NIR-II
successfully applied in various intravital biomedical studies, imaging device provided high-quality fluorescence images and
including molecular detection, dynamic monitoring and dynamic videos at the whole-animal level that benefitted from
evaluation of renal function, and imaging-guided precise the advantageous photophysical properties of the NIR-II region.
tumor ablation.48−51 Meanwhile, Wang’s group began to develop an NIR-II imaging
Unlike common organic materials with the aggregation- system based on a two-dimensional InGaAs detector (640 × 512
caused quenching (ACQ) property, AIEgens are a class of pixel), and continuous efforts were put forth to improve its
heterodox molecules that display intense fluorescence emission performance.10,57 Subsequently, various novel NIR-II imaging
by aggregate formation, thereby restricting their intramolecular systems including broadband (400−1700 nm) multiplexed in
motions. Since the first report by Tang’s group in 2001,52 vivo imaging system, time-resolved in vivo imaging system,
AIEgens have attracted extensive attention in biomedical field intraoperative navigation system, confocal microscopy, two-
and have been widely used in biolabeling, diagnosis, and photon microscopy, broadband multiplexed microscopy, and
imaging. Most recently, novel NIR-II AIEgens have been light-sheet microscopy have been developed, providing in vivo
developed, and such fluorophores exhibit favorable optical biological information from macroscopic22,57−59 to mesoscopic
advantages such as a high photobleaching threshold, an and microscopic scale (Figure 2).60−63
J. Am. Chem. Soc. 2020, 142, 14789−14804
Among the latest developed macroscopic NIR-II imaging Aside from the macroscopic and microscopic scopes, there is
systems, the design and integration of multiple functional plenty of room for biomedical studies on the mesoscopic scale,
modules have greatly expanded the functions of the NIR-II especially in brain science. Dai and co-workers developed NIR-II
imaging system. In 2018, Zhang’s group reported a time- light-sheet microscopy (LSM), achieving long-wavelength
resolved NIR-II imaging system by coupling a customized time- excitation and emission up to approximately 785−1320 nm
gating module to a cooled InGaAs camera.58 This imaging and 1000−1700 nm, respectively.62 With organic dyes and PbS/
system offered a possibility to perform time-domain multi- CdS core/shell QD probes, they achieved volumetric imaging of
plexing NIR-II imaging using probes with engineered glycerol-cleared mouse brain tissue of up to 10 mm3 with a
luminescence lifetimes. In 2019, Wang’s group designed a penetration depth of ∼2 mm. Furthermore, in cases of mouse
broadband (400−1700 nm) multiplexed imaging system by brain tumors and traumatic brain injury (TBI), NIR-II LSM
integrating Si-based CCD for visible and NIR-I imaging and exhibited favorable capabilities for noninvasive 3D observation
SWIR InGaAs camera for NIR-II imaging.57 This system can be of abnormal tumor microcirculation, inflamed immune cell
used to perform fluorescence imaging from visible to NIR-II recruitment to the injured region as well as immune checkpoint
region and bioluminescence imaging, thus providing great proteins in living mice.62
opportunities to simultaneously monitor multiple structural and Although such emerging NIR-II setups represent remarkable
functional information on organisms by using different imaging methodological advances and have made significant contribu-
channels. More recently, Tian et al. developed a visible and NIR- tions to the biomedical field, even have been used in clinical
Ι/II multispectral imaging instrument for image-guided tumor trials,59 several technical challenges remain. First, the absence of
surgery in patients suffering from liver cancer.59 The visible and SWIR cameras with high resolution and sensitivity. The quality of
NIR-Ι/II multispectral imaging can provide accurate tumor SWIR focal plane array (FPA) chips is limited by the available
boundary information for surgeons to achieve precise tumor technology. For coupling the light-receiving photodiodes
surgery. And the development of this equipment opens up a (InGaAs or HgCdTe layer) and the readout circuit (Si layer),
possibility of applying NIR-II imaging in the clinic. traditional approaches use bump connections that are necessary
In contrast to the above-mentioned macroscopic imaging to secure a certain bump pitch, resulting in difficulty to obtain
systems, confocal and two- or multi-photon (2P/MP) smaller pixel size. SWIR detectors with mainstream availability
microscopy are powerful tools for the investigation of micro- are 640 × 512 pixels, which cannot compare with the current
species. Compared with wide-field imaging setups, confocal CCD or CMOS sensors with pixels of million to tens of million.
microscopy can obtain high-clarity images with a horizontal Another major challenge of the SWIR detector is the relatively
resolution up to the diffraction limit by focusing its laser beam poor quantum efficiency (QE), which could not achieve high-
inside the specimen and using a pinhole to effectively block sensitive imaging in a broad range of wavelengths from 900 to
photons from out-of-focus regions from entering the detector. 1700 nm. Therefore, future efforts should be devoted to
By scanning the sections at different tissue depths, three- improving the QE and achieving pixel miniaturization of SWIR
dimensional images are obtained. To acquire high-resolution chips. Second, the limitations of the illumination mode. As a
NIR-II microscopic imaging, a NIR-II confocal microscope was preferred illumination approach, NIR lasers currently serve as
successfully developed by designing and optimizing the NIR the excitation source for NIR-II imaging due to their high power
excitation source, the IR compatible optical lens, and the NIR and monochromaticity. Despite this, a major challenge of the
photomultiplier diode (PMT) of confocal microscope by Zhu NIR laser’s illumination is conversion of the Gaussian beam to a
and co-workers in 2018.61 The 2P/MP microscope is another flattened beam to achieve even illumination for large samples
kind of microscopic imaging instrument using focused femto- like whole animals. With the development of beam shaping
second laser pulses as the excitation source. In the 2P/MP techniques, this issue is expected to be resolved in the near
microscope, the beam energy can be concentrated within the future. Furthermore, utilization of multilight source or ring-light
spatially confined area of the focus point to generate a source strategies may further improve the illumination effect.
substantial signal based on 2P/MP absorption. In 2017, Landry Third, the absence of sof tware algorithms. SWIR imaging was first
and co-workers developed a dual near-infrared 2P microscope applied in military and industrial areas. After introduction into
by optimizing excitation and emission wavelengths. In this case, the biomedical field, signal processing and image acquisition
besides a CW 633 nm He−Ne laser, a 1560 nm femtosecond need to be redesigned to eliminate the undesirable thermal noise
pulsed erbium laser was also used for 2P illumination, which often associated with NIR-II imaging and improve the signal-to-
overcame traditional limitations in deep-tissue fluorescence noise ratio. Thus, an appropriate software algorithm needs to be
microscopy and demonstrated its great promise for neuro- formulated. In addition, the development of high cutoff filters
transmitter imaging of a living brain.60 Taking advantage of and high numerical aperture NIR focusing lenses associated with
different imaging implementations is also to be considered.
■
reduced photon absorption, scattering, and negligible tissue
autofluorescence in the NIR-II window, such novel confocal and
2P microscopy provide powerful tools for investigating the RECENT ADVANCES OF NIR-II FLUORESCENCE
structure, function and molecular events in living bodies. IMAGING IN BIOMEDICAL APPLICATIONS
It should be noted that considering most of the endogenous With the development of novel NIR-II fluorophores and
labeling agents such as fluorescent proteins whose fluorescence imaging instruments, NIR-II imaging has emerged as a powerful
spectra locate in the visible and NIR-I regions, Wang’s group has tool in biomedical research. Herein, we give some representative
developed a broadband microscopy by incorporating Si-based studies of NIR-II imaging-based biomedical research, including
CCD and SWIR InGaAs camera into one system and revealed bioimaging, biosensing, and theranostic applications.
the location of QDs endocytosed by cells by colocalization NIR-II Bioimaging. Structural Imaging. Due to its deep
imaging of the green fluorescence of the enhanced green tissue penetration depth and high spatial resolution, NIR-II
fluorescent protein (EGFP) and the NIR-II fluorescence of Ag2S imaging is a promising method for in vivo imaging of the fine
QDs in cells.63 structure of living tissues, such as the blood vascular system,
J. Am. Chem. Soc. 2020, 142, 14789−14804
Figure 3. Structural and functional imaging using NIR-II emitting fluorophores. (a) Whole-body blood pool imaging of the nude mouse using NIR-II
emitting Ag2S QDs. (b) Comparative study of Ag2S QDs (1200 nm, NIR-II) (upper) and ICG (835 nm, NIR-I) (below) for in vivo lymphatic imaging.
(c) Two-color fluorescence imaging of tumor vasculatures and tumor tissues in the NIR-II window. p-EF channel: tumor vasculatures; CNT channel:
tumor. (d) A 3D confocal image of cerebral blood vessels of the rhesus macaque. Bars: 100 μm. (e) In vivo imaging of blood flow velocities of the rhesus
macaque using a wide-field NIR-II microscopy. Panels a and b reproduced with permission from ref 65. Copyright 2014, Elsevier Inc. Panel c
reproduced with permission from ref 72. Copyright 2018, Nature Publishing Group. Panels d and e reproduced with permission from ref 68. Copyright
2020, Theranostics.
lymphatic system, and tumors.61,62,64−69 Recently, NIR-II scalp.53,71 With the development of wild-field and confocal NIR-
probes with high photochemical stability and a long blood II microscopy, a much better spatial resolution has been
circulation time showed numerous advantages in vascular achieved during blood vascular imaging. In Dai’s group, 3D
imaging. In 2012, a mouse hindlimb vascular structure was imaging of vasculatures with a depth of ∼1.3 mm and a spatial
successfully imaged down to ∼30 μm using SWCNTs as the resolution of sub-10 μm in the brains of mice were obtained
fluorophores.23 In Wang’s group, polyethylene glycol (PEG)-
using an organic fluorophore named p-FE.72 In addition to small
capped Ag2S QDs with a long circulation time (circulation half-
rodents, in vivo cortical vasculature imaging has also been
time = 4.1 h) were synthesized for blood vascular imaging. In
their study, peripheral vasculature (∼100 μm) and brain achieved in nonhuman primates by Qian’s group.68 In their
microvasculature (∼24.3 μm) were clearly imaged in vivo with study, a microvessel with a diameter of 6.6 μm and the 3D
a micrometer resolution (Figure 3a).65,70 In addition, the bright structure of cerebral blood vessels of rhesus macaque were
NIR-II AIEgens developed by Tang’s group also showed as an clearly imaged using NIR-II fluorescence confocal microscopy
excellent probe for imaging the blood vessels in hindlimb and (Figure 3d).
J. Am. Chem. Soc. 2020, 142, 14789−14804
Figure 4. Activatable NIR-II probes for biological sensing. (a) The ONOO−-activatable V&A@Ag2S probe for in vivo detection of traumatic brain
injury. (b) Temperature sensing by a core/shell/shell PbS/CdS/ZnS QD emitting in the NIR-II window (1270 nm). (c) pH sensing by pentamethine
cyanine fluorophores (BTCs). (d) A H2S-activated ratiometric fluorescence nanoprobes containing a H2S-activable boron-dipyrromethene (ZX-NIR)
dye and an aza-BODIPY (aza-BOD) dye. (e) The MMP-activatable PbS/CdS/ZnS core/shell/shell QDs for colorectal tumor detection. Panel a
reproduced with permission from ref 88. Copyright 2020, Wiley-VCH. Panel b reproduced with permission from ref 90. Copyright 2015, Wiley-VCH.
Panel c reproduced with permission from ref 91. Copyright 2018, Wiley-VCH. Panel d reproduced with permission from ref 93. Copyright 2019,
Nature Publishing Group. Panel e reproduced with permission from ref 94. Copyright 2017, American Chemical Society.
In addition to the blood vessel system, the lymphatic system imaging for in vivo detection of deep anatomical features of the
imaging is also widely used in clinical trials.73 Currently, NIR-II lymphatic system.
imaging offers the possibility of in vivo imaging lymphatic system Structural imaging of tumors is also gaining the interest of
in deep tissues with high clarity.44,65 For example, research by researchers for its crucial role in exploring the mechanisms of
Wang’s group showed the Ag2S QD was a stable NIR-II tumorigenesis as well as the diagnosis and treatment of tumors.
fluorophore for imaging the lymphatic system with a better Currently, NIR-II imaging has been extensively used in early
resolution and deeper penetration depth than ICG-based NIR-I diagnosis of tumors with a high tumor-to-background ratio
imaging (Figure 3b).65 Similarly, Antaris et al. comparatively (TBR).30,74−76 More recently, the development of multi-
analyzed lymph node imaging in deep tissue (∼5−8 mm depth) channel NIR-II imaging and the 3D light-sheet imaging
with NIR-II emitting organic dye (CH-4T) and NIR-I emitting techniques has greatly promoted assays of tumor structure. In
ICG.44 Their results illustrated the unique advantages of NIR-II 2018, Wan et al. obtained the 3D structure of 4T1 tumors in
J. Am. Chem. Soc. 2020, 142, 14789−14804
living mice by two-channel NIR-II confocal microscopy.72 In probes have been developed. In Zhang’s group, a peroxynitrite
this study, the vasculatures of tumors were highlighted by p-FE activatable organic probe (named IRBTP-B) was designed for
emitting 1100−1300 nm, and the tumors were highlighted by drug-induced hepatotoxicity monitoring.86 Furthermore, the
CNTs emitting 1500−1700 nm (Figure 3c). Thus, the internal same group developed a panel of fluorescent dyes (CX) to sense
structures of the tumor were clearly identified; this showed an ONOO− via the principle of Förster resonance energy transfer
abundance of blood vessels exist around and in the tumor to fuel (FRET) between CX dyes.87 In addition to the organic dyes, a
tumor growth. QD-based ONOO−-activatable probe was recently developed
Functional Imaging. In addition to portraying the fine via a FRET principle in Wang’s group for TBI imaging.88 In this
structures of deep tissues, NIR-II imaging is also a powerful tool system, the ONOO−-responsive A1094 chromophore was
to analyze the functions of cells and tissues.16,68,77,78 Currently, conjugated with Ag2S QDs to generate the V&A@Ag2S probe
real-time monitoring of blood flow and heart rate are the most (Figure 4a). Due to the FRET between Ag2S QDs and A1094,
important applications of NIR-II functional imaging.16,68,78 In the intact V&A@Ag2S remained quenched. After exposure to
2014, Hong et al. developed a NIR-II method for real-time ONOO−, A1094 was rapidly bleached, and the NIR-II
monitoring of mouse arterial blood flow via a pDA dot (Em = fluorescence of Ag2S QDs was turned on. For RSS, Fan’s
1047 nm).16 With high speed NIR-II imaging (>25 frames per group developed hyaluronidase and thiols cooperatively
second), the highest instantaneous blood velocity and the lowest activatable NIR-II fluorescence nanoprobes (HISSNPs) for
instantaneous blood velocity were accurately measured to be ∼8 ultrahigh specific tumor imaging.89 In their study, HISSNPs
cm s−1 and ∼2 cm s−1, respectively. In addition, the heart rate were synthesized by locking the fluorescence-quenched IR-1061
was also successfully measured to be 290 beats per minute in aggregation in hyaluronic acid chains and disulfide bonds. Thus,
mice. In 2019, Dai’s group observed the on−off, intermittent, the fluorescence of HISSNPs could be turned on via unlocking
and reversed blood flow in the tumor using a light-sheet imaging the hyaluronic acid chains and disulfide bonds by hyaluronidase
system.62 In 2020, Qian’s group successfully monitored the and GSH, respectively.
blood flow velocity of capillaries and the cardiac impulse period Temperature Sensing. Temperature is one of the most
in macaque monkeys by using a high speed wide-field important physiological parameters of organisms. In 2015,
microscope (25 frames per second).68 Then, a blood flow Vetrone and co-workers synthesized a core/shell/shell PbS/
velocity of approximately 0.65 mm/s was accurately calculated CdS/ZnS QD emitting in the NIR-II window (1270 nm).90 In
by NIR-II imaging (Figure 3e). In view of the excellent temporal this study, strong temperature-dependent emission intensity
resolution, NIR-II imaging has possible applications in the variation of PbS/CdS/ZnS QDs was observed (Figure 4b). With
diagnosis and evaluation of various cardiovascular diseases. temperatures varying between 20 and 70 °C, a sensitivity of 1%
These novel 2D, 3D, and multi-channel NIR-II imaging per °C was found, suggesting the promise of QDs for sensing the
techniques offer the opportunity to perform in vivo assays of the temperature in biological systems. Then, an ex vivo study in
fine structures and functions of deep tissues at macroscopic, chicken breast tissue suggested the temperature of tissues can be
mesoscopic, and microscopic levels. The development of measured by thermal-sensitive QDs at a tissue depth of 1 cm.
clinically available NIR-II probes with high safety and high QY This study opens the possibility of sensing biological temper-
is currently the main challenge of NIR-II fluorescence-based ature in deep tissues by NIR-II imaging.
bioimaging. It is believed that, with further development of Gas Sensing. Biological gases, such as hydrogen sulfide (H2S)
clinically available NIR-II fluorophores, NIR-II imaging will be a and NO, are also associated with many pathological processes.
promising alternative to traditional optical imaging for in situ and In 2018, Xu and co-workers developed H2S-activated ratio-
high-fidelity structural and functional imaging in the clinic. metric fluorescence nanoprobes with NIR-II emission at 900−
NIR-II Biosensing. In the past several years, another 1300 nm.91 In their study, a hydrogen sulfide (H2S)−activable
significant advance in NIR-II imaging research was the boron−dipyrromethene (ZX-NIR) dye and an aza-BODIPY
development of activatable NIR-II fluorophores for biosens- (aza-BOD) dye were encapsulated in the hydrophobic interior
ing.77,79−81 Activatable NIR-II fluorophores can alter their of the core−shell silica nanocomposites (Figure 4c). The ZX-
fluorescence intensity or emission wavelength according to NIR can be activated by H2S to generate NIR-II fluorescence,
specific microenvironment parameters, thus showing higher and the aza-BOD dye can serve as the internal reference. With
signal-to-background ratio, higher sensitivity, and better the H2S-activated ratiometric probe, colorectal tumors in animal
specificity than “always-on” fluorophores. So far, NIR-II models can be accurately identified in vivo. For NO detection,
fluorophores that can sense reactive oxygen species (ROS), Strano and co-workers synthesized an alginate-encapsulated
reactive nitrogen species (RNS), reactive sulfur species (RSS), SWCNT for in vivo sensing of inflammation.92 In this system, an
temperature, gas, pH, or a specific enzyme have been developed, NO-responsive DNA oligonucleotide ds(AAAT)7 was wrapped
offering possibilities for deciphering the biological activities of in SWCNT to sense NO. Consequently, the fluorescence
cells and tissues at the molecular level.80,81 emission of SWNTs can be gradually quenched by NO, thus
ROS/RNS/RSS Sensing. The imbalance of the redox environ- detecting the NO level in implantable inflammation.
ment in the organism is related to the occurrence and pH Sensing. pH is a crucial physiological parameter of
development of many diseases, such as cancer, tissue injury, organisms, and abnormal pH can also be used as a pathological
infection, etc.81−83 Currently, several NIR-II fluorophores have microenvironment feature for the diagnosis and treatment of
been developed to monitor the redox status in organisms, diseases. Recently, researchers have also developed NIR-II
including ROS, RNS, and RSS.81,84,85 probes for in vivo pH sensing. In 2019, Zhang’s group reported a
In 2018, Chen and co-workers synthesized H2O2-responsive series of NIR-II pentamethine cyanine fluorophores (BTCs)
NaCeF4:Er/Yb NCs for uric acid detection.84 In this system, that exhibit pH-responsive fluorescence.93 When pH changed
H2O2 reacted with Ce3+ ions in NaCeF4:Er/Yb NCs, thus from 5 to 0, a large peak shift from 1065 to 980 nm was observed,
quenching NIR-II emission of NaCeF4:Er/Yb NCs. For RNS, suggesting a good ratiometric fluorescence response to pH in
several organic and inorganic ONOO−-responsive NIR-II BTCs (Figure 4d). Consequently, they successfully applied
J. Am. Chem. Soc. 2020, 142, 14789−14804
Figure 5. NIR-II imaging-guided therapy. (a) In vivo tracking of Ag2S QD-labeled stem cells for liver regeneration in a mouse with acute liver failure.
(b) NIR-II imaging-guided bone-targeted delivery of Ald/DOX@Ag2S nanodrugs for bone tumor therapy. (c) A tumor microenvironment-activated
NIR-II nanotheranostic system (FEAD1) for precise drug release monitoring, diagnosis, and treatment of peritoneal metastases. (d) In-human liver-
tumor surgery guided by multispectral optical imaging in the visible and NIR-I/II windows. (e) NIR-II imaging-guided PTT for mammary carcinoma
tumor treatment using a macromolecular fluorophore (PF) agent. Panel a reproduced with permission from ref 99. Copyright 2014, Wiley-VCH. Panel
b reproduced with permission from ref 105. Copyright 2017, Wiley-VCH. Panel c reproduced with permission from ref 106. Copyright 2020, Wiley-
VCH. Panel d reproduced with permission from ref 59. Copyright 2020, Nature Publishing Group. Panel e reproduced with permission from ref 114.
Copyright 2019, Wiley-VCH.
BTC1070 for in vivo measurement of gastric pH, showing a good (ALP), caspases, etc., have been widely used to activate
measurement accuracy at a depth of up to 4 mm. fluorescent probes and report pathological processes.94−96
Enzyme Sensing. Enzymes, including matrix metalloprotei- Currently, several enzyme-activable NIR-II probes have been
nase (MMP), nitroreductase (NTR), alkaline phosphatase developed. As a hallmark of the cancer microenvironment,
J. Am. Chem. Soc. 2020, 142, 14789−14804
MMPs are often used as a biomarker for tumor diagnosis and imaging, the dynamic translocation of transplanted stem cells
treatment. In 2017, Kim and co-workers developed MMP- from the lung to the liver was clearly observed with a temporal
activatable PbS/CdS/ZnS CSS QDs for tumor detection resolution of 100 ms (Figure 5a). Thus, in the mouse models of
(Figure 4e).94 In this system, the fluorescence of QDs were acute liver injury and skin injury, Ag2S QD-based NIR-II
quenched via a photoexcited electron transfer (PET) quenching imaging was successfully used to develop cell transplantation
process between methylene blue and QDs. In tumor micro- strategies to promote the migration of stem cells to the injury
environment, highly active MMP cleaved the linker peptide and site.99,100 In another example, Yang and co-workers developed a
released MB, thus turning on the fluorescence of QDs. In PbS QD-based stem cell tracking strategy for optimizing MSC
another example, Cai and co-workers reported an NTR- therapy in a mouse model of the supraspinatus tendon.101 More
triggered NIR-II probe (IR1048-MZ) for solid tumor diagnosis recently, multiplexed NIR-II fluorescence/bioluminescent
and therapy.96 In this study, a NIR-II emitting IR-1048 dye was imaging (BLI) methods were developed by Wang’s group.
conjugated with a nitroimidazole group (2-(2-nitroimidazolyl)- Thus, the dynamic translocation, viability, and differentiation of
ethylamine, MZ) to generate IR1048-MZ. Thus, the fluo- transplanted stem cells can be simultaneously monitored in
rescence of IR-1048 was quenched via the MZ group induced vivo.57,63
electron transfer. In the hypoxia microenvironment of a solid In addition to stem cell tracking, NIR-II imaging is also
tumor, the highly active NTR reduced the MZ group in IR1048- promising for immune cell tracking and imaging-guided
MZ, thus recovering the NIR-II fluorescence of IR1048-MZ. immunotherapy. In 2018, Hao and co-workers developed a
With the numerous advantages of high SBR, high sensitivity, programmable chemotherapy and immunotherapy strategy
and excellent specificity, we believe that activatable NIR-II under the guidance of multiplexed NIR-II imaging. In their
probes will greatly promote the application of fluorescence study, Ag2Se QDs (λEm = 1350 nm) were used to monitor
imaging technologies in the early detection of diseases. To doxorubicin (DOX) and stromal-cell-derived factor-1α (SDF-
achieve this goal, the NIR-II biosensing technology may need to 1α) in the tumor site. After the arrival of DOX and SDF-1α, the
be further advanced in the following aspects. First, the single fluorescence of Ag2S QDs (λEm = 1050 nm) was used to track the
physiological parameter-activatable probe will still face non- chemotactic migration behavior of intravenously transplanted
specific signal interference due to a physiological parameter natural killer (NK)-92 in the tumor site. Multiplexed NIR-II
often appears under different pathological conditions. Thus, the imaging offers spatiotemporal distribution information on DOX,
development of NIR-II probes that can be activated by SDF-1α, and NK cells in the tumor site, thus facilitating
multiphysiological parameters in target tissues may be an optimization of administered treatments and enhanced tumor
effective strategy to further improve the specificity of biosensing. therapy.64
Second, the courses of the disease are often accompanied by Imaging-Guided Drug Delivery/Release Monitoring. The
dynamic changes of various interrelated physiological con- targeted delivery and precise release of drugs are major
ditions. Thereby, the development of multi-channel activatable challenges in the field of precise medicine. NIR-II imaging
NIR-II imaging to simultaneously sensing different physiological offers a promising tool for in vivo monitoring of drug delivery
parameters in a target tissues may be useful for fully disclosing and release, thus facilitating drug development and optimization
the underlying mechanism of disease occurrence and develop- of drug delivery.102−106
ment. In 2017, Li and co-workers reported a Ag2S QD-based
NIR-II Imaging-Guided Therapeutic Applications. In nanodrug (Ald/DOX@Ag2S) for drug delivery monitoring and
the past decades, NIR-II imaging technique has greatly bone tumor therapy (Figure 5b).105 The benefits of dynamic
promoted the application of fluorescence imaging technology translocation, the deep tissue penetration of NIR-II imaging, and
in structural and functional imaging of biological tissues and the bone targeting of Ald/DOX@Ag2S can be monitored in real
early detection of diseases. At the same time, due to the low time, thus helping to design efficient bone tumor therapies with
absorption and scattering characteristics of NIR-II light in living simultaneous stereotactic chemotherapy and inhibition of
tissue, it also provides a new tool for the precise treatment of osteolysis. In addition to guided drug delivery, NIR-II
diseases. Currently, a series of NIR-II-based treatment strategies, fluorescence can also be used to monitor drug release in target
including imaging-guided cell therapy, imaging-guided surgery, tissues. In 2020, Lin and co-workers reported a tumor
imaging-guided drug delivery/release monitoring, and imaging- microenvironment-activated NIR-II nanotheranostic system
guided PDT/PTT, have been developed and show numerous (FEAD1) (Figure 5c).106 In their study, Ag2S QDs, DOX,
advantages for precise disease treatment.74,97,98 NIR absorber A1094, and the peptide Fmoc-His were self-
Imaging-Guided Cell Therapy. Cell therapy, including stem assembled into nanoparticles. Because of the FRET between the
cell therapy and immune cell therapy, is bringing a revolution to Ag2S QDs and A1094, the NIR-II fluorescence of Ag2S QDs was
modern medicine because it shows great potential for the quenched in the intact FEAD1. Upon delivery of FEAD1 to the
treatment of a series of incurable human diseases, such as cancer, tumor, FEAD1 was disassembled in the acidic tumor micro-
neurodegenerative diseases, and cardiovascular diseases. In the environment to release A1094, DOX, and Ag2S QDs, and
past few years, NIR-II imaging has served as a powerful tool for thereafter the NIR-II fluorescence of Ag2S QDs was turned on.
in vivo tracking the fate of cells, exploring the underlying In this way, the NIR-II fluorescence of Ag2S QDs precisely
mechanisms of cell therapy, and guiding precision cell reflects the release of DOX within the tumor tissue, thus
therapy.77,97 facilitating precise tumor theranostics.
For stem cell tracking, the first whole-body tracking of Imaging-Guided Surgery. Currently, surgery is the most
transplanted stem cells in the NIR-II window was achieved by common strategy for solid tumor treatment. Because of its
Wang et al. using the Tat peptide-capped Ag2S (Tat-Ag2S) noninvasive and high spatiotemporal resolution, intraoperative
QDs.99 In their study, Tat-Ag2S can be used to track 1000 optical imaging has been extensively used to help surgeons
subcutaneously transplanted cells for a period of 30 days. perform surgery quickly and precisely. Recently, NIR-II
Moreover, due to the high spatiotemporal resolution of NIR-II imaging-guided surgery methods have greatly advanced the
J. Am. Chem. Soc. 2020, 142, 14789−14804
accuracy, sensitivity, and specificity of tumor surgery in both clinically available NIR-II probes and NIR-II imaging equipment
animal research and clinical practice.98,107−109 will be needed to promote the therapeutic and theranostic
For example, Wen and co-workers developed a NIR-II applications of NIR-II imaging in the clinic.
emitting nanochain probe (APP-Ag2S-RGD) for intraoperative
NIR image-guided surgery.110 Due to geometrically enhanced
multivalent targeting, APP-Ag2S-RGD is more readily taken up
■ CONCLUSIONS AND PERSPECTIVES
In the 10 years since the concept of NIR-II fluorescence imaging
by tumor cells than RGD-functionalized Ag2S QDs, providing a was first proposed, various NIR-II fluorophores and compatible
high TBR of 13.6. As a result, tiny metastatic tumor foci (∼0.2 imaging instruments for macroscopic, mesoscopic, and micro-
mm in diameter) were detected and eliminated under NIR-II scopic scales have been developed, providing powerful tools for
imaging guidance. In addition to inorganic nanoprobes, biomedical applications. However, such a cutting-edge imaging
excretable SMDs have also been developed for imaging-guided technology is still at a relatively early stage in its development,
surgery. In 2016, Antaris and co-workers synthesized a NIR-II and some essential issues should be resolved before its
emitting organic molecule (CH1055) with a rapid excretion substantial and extensive applications in preclinical studies and
property.18 In this study, approximately 90% of CH1055 can be clinical practice. In the following points, we elucidate the main
excreted through the kidneys within 24 h after injection, thus concerns regarding this imaging technique and give some advice
greatly reducing the potential side effects caused by probe and prospects for the development of NIR-II imaging for future
residue after surgery. More recently, the first NIR-II imaging- biomedical applications.
guided tumor surgery in a human was achieved by Hu and co- NIR-II Fluorophores. In view of their bioapplications, the
workers (Figure 5d).59 In their study, FDA-approved ICG was first and foremost issue is the biosafety of NIR-II fluorophores.
used as the fluorophore. Thus, the NIR-I and NIR-II emissions Some important qualities should be met such as outstanding
of ICG can be simultaneously detected by different detectors optical properties, facile functionalization, and good compati-
that integrated in an optical-imaging instrument. In a test of bility. At the same time, developing novel strategies for
liver-tumor surgery in 23 patients, intraoperative NIR-II imaging endogenous labeling should also be taken into account.
showed a better tumor detection sensitivity, higher TBR, and
higher tumor detection rate than intraoperative NIR-I imaging. (1) Decent biocompatibility. Aside from applications in
With such unique merits, the novel NIR-II imaging strategies preclinical studies and in vitro assays, they are crucial to
may have great potential for improving preoperative diagnosis achieving NIR-II clinical translation. The arsenal of NIR-
and intraoperative navigation in the future. II fluorescence probes has expanded substantially in the
Imaging-Guided PDT/PTT. Light-based therapy, including past decade. Despite this, to date, there are no FDA-
photothermal therapy (PTT) and photodynamic therapy approved NIR-II fluorophores available for clinical use.
(PDT), is emerging as a noninvasive, remote-controllable, and Thus, when optimizing present probes or designing new
highly specific strategy for cancer treatment.111−116 In vivo NIR-II fluorophores, great effort should be made to make
imaging techniques that can clearly indicate the location and sure that the probes contain nontoxic components. In
boundaries of the tumor are of great significance for guiding addition, optimizing the size (<5 nm) and surface coating
accurate phototherapy. of probes for rapid renal excretion is another promising
In 2019, Li and co-workers developed an amphiphilic way for designing safe probes.
polypeptide-conjugated NIR-II fluorophore (Flav7) for simulta- (2) Outstanding optical properties. High fluorescence QY of
neous tumor imaging and PTT (Figure 5e).114 The synthesized NIR-II fluorophores is especially important for increasing
macromolecular fluorophore (PF) nanoparticles possessed both the sensitivity and broadening the applications of this
NIR-II emission at 1081 nm and high photothermal conversion technology. Most currently available NIR-II fluorophores
efficiency (42.3%). By integrating tumor imaging and precise have a quite low QY, which should be further improved by
PTT, the diagnostic accuracy and treatment outcomes for a optimizing the probe in several aspects, such as molar
murine mammary carcinoma tumor were distinctly improved. In absorption coefficient, electronic transition, surface
another example, Gao and co-workers synthesized a lipophilic chemistry, etc. Meanwhile, improvement of chemical
NIR-II fluorophore (BPBBT) with both twisted intramolecular and irradiation stability against photobleaching and
charge transfer and AIE characteristics. By using the BPBBT- blinking is another key point to be resolved to ensure
based NIR-II imaging and PTT, the primary orthotopic colon the accuracy of imaging data. Simultaneous multiplexed
tumor and metastatic lesions in mouse were preciously imaging with different fluorophores is often required to
delineated and treated.115 In addition to PTT, NIR-II investigate complex physiological and pathological
imaging-guided PDT has also been developed. In 2019, Wang processes. To avoid crosstalk, a primary principle for
and co-workers reported a red blood cell-based multimodal spectrum tuning is to develop NIR-II fluorophores with a
theranostic probe (RBCp) for image-guided tumor surgery and large Stokes shift and a sharp emission spectrum with a
photodynamic therapy.117 The RBCp can accumulate and stably narrow full width at half-maximum.
remain in tumors for approximately 4 h after an intravenous (3) Facile functionalization and good compatibility. Besides
injection, thus offering sufficient time for guiding tumor surgery. NIR-II fluorescence architectures, appropriate strategies
In addition, the intratumoral RBCp can be irradiated by an NIR to introduce functional components to improve the water
laser to release O2, thus enhancing the PDT efficiency for solubility and targeting capabilities of probes are very
metastatic tumors. important for biomedical applications. In addition,
Overall, the emergence of NIR-II-guided therapy shows great developing multimodal probes by doping or conjugating
promise for improving the specificity, efficiency, and safety of other contrast agents (such as MRI and CT contrast
disease treatment. It is believed that NIR-II imaging will play an agents) with NIR-II probes is vital to make NIR-II probes
increasingly important role in both accurate diagnosis and compatible for multimodal imaging or treatment. There-
precise treatment of diseases. In the future, the development of fore, the fact NIR-II fluorophores could be easily modified
J. Am. Chem. Soc. 2020, 142, 14789−14804
while maintaining favorable fluorescence properties is and function of deep tissues as well as guiding precise therapy. In
important. the future, we believe that NIR-II imaging will aid in a broad
(4) Endogenous labeling. Although abundant NIR-II fluo- range of fundamental and clinical research.
rophores have been developed by various chemical (1) For oncology research, NIR-II imaging offers the
synthesis methods; such exogenous probes are not possibility for intravital imaging of 3D structures,
heritable in living organisms and are not suitable for vasculature distribution, blood flow, and the dynamic
tracking of long-term and dynamic bioinformation such as immune cell infiltration process in tumors. However,
gene expression, or cell proliferation and differentiation. exogenous NIR-II probe-based imaging only provides
Thus, another effort should be focused on development of instantaneous information, and continuous tracking of the
genetically encoded NIR-II fluorescent proteins to allow entire tumor development process has not been achieved.
better tissue penetration depth, spatial resolution, and Further development of multiple spectral imaging
sensitivity over currently available fluorescent proteins. methodologies by combining multiple endogenous and
Imaging Systems. Because of the complexity and the exogenous NIR-II probes will offer an exceptional tool for
dynamic change characteristics of physiological and pathological comprehensively analyzing the occurrence, development,
processes, we should assess them on different spatial and time and metastasis of tumors, thus providing a theoretical
scales. Despite substantial progress in the area of imaging basis for the precise diagnosis and treatment of tumors.
apparatuses, there are still many important problems to be (2) In the field of regenerative medicine, noninvasive NIR-II
further solved. imaging will also play an important role in exploring
(1) NIR-II real-time multi-channel imaging system. Because fundamental biological issues such as the developmental
of the complexity and dynamic change properties of living process of embryos and organs and the lineage and fate of
organisms, static single-source signal acquisition cannot stem cells. For instance, the complex embryonic develop-
give the whole profiles of physiological and pathological ment process in living mammals has not been fully
changes. In this respect, traditional fluorescence imaging elucidated due to the fact traditional fluorescence (400−
has been restricted by temporal resolution and tissue 900 nm) cannot penetrate living tissue to report embryo
penetration depth. Real-time multi-channel NIR-II development in situ. Due to the deep tissue penetration of
imaging systems can simultaneously record multiple NIR-II imaging, the developmental dynamics of living
events, which might provide wonderful insights into the embryos, including angiogenesis, neurogenesis, and
mysteries of living bodies and the mechanisms of diseases. organogenesis, may be observed by multiple spectral
(2) NIR-II intravital endoscopy imaging system. As the NIR-II imaging in combination with cell lineage tracking
clinical gold standard of detection, endoscopy dominates techniques. In addition, NIR-II imaging also has great
examination of interior body cavities, and hollow tissues potential for revealing the functions and fates of
and organs. Due to the ultralow background signal in the endogenous and exogenous stem cells. The application
NIR-II region which is nearly zero when the wavelength is of multiple spectral NIR-II imaging technology may offer
greater than 1500 nm, NIR-II endoscopy can achieve abundant imaging channels to simultaneously monitor
ultrahigh sensitivity detection that cannot be achieved the translocation, viability, paracrine, differentiation, and
using traditional endoscopy. A prototype of NIR-II aging of stem cells, thus offering a comprehensive
endoscopy was first reported by Cheng and co-workers; understanding of the processes and underlying mecha-
combination with ICG-conjugated bevacizumab (Bev- nisms of stem cell-based regeneration.
ICG) showed NIR-II fluorescence and white-light (3) For neuroscience research, NIR-II imaging also has broad
imaging of VEGF at the same time in an orthotopic rat application prospects. For instance, further development
colorectal cancer model.118 Future iterations should of membrane potential-sensitive NIR-II probes may offer
preferentially aim for a “see-and-treat” strategy, that is, the possibility to simultaneously monitor neural activities
diagnosis and treatment synchronization. of large numbers of nerve cell populations in deep tissues
(3) NIR-II fluorescence integrated multimodal tomography with a sub-millisecond temporal resolution and a
imaging system. Although there has been substantial subcellular spatial resolution. Additionally, the develop-
progress in the development of NIR-II fluorescence ment of activable NIR-II probes that can specifically sense
systems in the past decade, a major limitation of in vivo ions and neurotransmitters, such as K+, Ca2+, and
imaging is the difficulty of acquiring comprehensive data. dopamine, will greatly enhance research on the chemical
Combining modalities has certainly been an area of great mechanisms of neural activity. We believe these novel
interest recently because it could prevent misdiagnosis or neural imaging techniques will not only promote the
loss of valuable information. Another challenge of exploration of advanced neural activities (such as memory
fluorescence imaging in whole animals is how to achieve and learning), but also aid in revealing the fundamental
precision quantitative analysis. NIR-II fluorescence mechanisms of neurological diseases and developing
photons with deep-tissue penetrating capabilities may effective therapies.
significantly facilitate 3D tomography imaging. Com- (4) For clinical application, the most promising application of
bined with other imaging technologies, such as MRI and NIR-II imaging is image-guided tumor surgery; its
CT, NIR-II imaging could provide powerful tools to parse superiority has just been verified by Hu and co-workers
complex anatomical structures and gain functional in liver-tumor surgery in human. In the future, the
information on living bodies. advanced NIR-II imaging technology may greatly
Future Applications. With the development of novel NIR- improve the precision of tumor surgery and its prognosis.
II probes and NIR-II imaging systems, NIR-II imaging has Moreover, NIR-II imaging-guided PDT/PTT may also be
become a powerful imaging tool for in vivo assays of the structure used in the clinical trials in the near further to achieve a
J. Am. Chem. Soc. 2020, 142, 14789−14804
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compared to the FDA-approved ICG-based NIR-I
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■
guidance in parathyroid surgery using near-infrared fluorescence
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Technology, Division of Nanobiomedicine and i-Lab, Suzhou
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Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Near-infrared photoluminescent Ag2S quantum dots from a single
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https://pubs.acs.org/10.1021/jacs.0c07022 (14) Wang, R.; Li, X.; Zhou, L.; Zhang, F. Epitaxial seeded growth of
rare-earth nanocrystals with efficient 800 nm near-infrared to 1525 nm
Author Contributions short-wavelength infrared downconversion photoluminescence for in
‡
C.L. and G.C. contributed equally. vivo bioimaging. Angew. Chem., Int. Ed. 2014, 53 (45), 12086−12090.
Notes (15) Shao, W.; Chen, G.; Kuzmin, A.; Kutscher, H. L.; Pliss, A.;
The authors declare no competing financial interest. Ohulchanskyy, T. Y.; Prasad, P. N. Tunable narrow band emissions
■
from dye-sensitized core/shell/shell nanocrystals in the second near-
infrared Biological Window. J. Am. Chem. Soc. 2016, 138 (50), 16192−
ACKNOWLEDGMENTS 16195.
This work was financially supported by the National Key (16) Hong, G.; Zou, Y.; Antaris, A. L.; Diao, S.; Wu, D.; Cheng, K.;
Research and Development Program of China (Grant Nos. Zhang, X.; Chen, C.; Liu, B.; He, Y.; Wu, J. Z.; Yuan, J.; Zhang, B.; Tao,
2017YFA0205503, 2016YFA0101503), the National Natural Z.; Fukunaga, C.; Dai, H. Ultrafast fluorescence imaging in vivo with
Science Foundation of China (Grant Nos. 21778070, 21703282, conjugated polymer fluorophores in the second near-infrared window.
21934007), the Strategic Priority Research Program of CAS Nat. Commun. 2014, 5, 4206.
(Grant No. XDB36000000), Key Research Program of Frontier (17) Shou, K.; Qu, C.; Sun, Y.; Chen, H.; Chen, S.; Zhang, L.; Xu, H.;
Hong, X.; Yu, A.; Cheng, Z. Multifunctional biomedical imaging in
Sciences, CAS (Grant No. ZDBS-LY-SLH021), and the Youth
physiological and pathological conditions using a NIR-II probe. Adv.
Innovation Promotion Association of CAS.
■
Funct. Mater. 2017, 27 (23), 1700995.
(18) Antaris, A. L.; Chen, H.; Cheng, K.; Sun, Y.; Hong, G.; Qu, C.;
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