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REVIEW
1805875 (1 of 31) © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Photoacoustic Imaging: Contrast Agents and Their
Biomedical Applications
Qinrui Fu, Rong Zhu, Jibin Song,* Huanghao Yang,* and Xiaoyuan Chen*
DOI: 10.1002/adma.201805875
is caused by absorbed light energy, cre-
ating a broadband US wave that can be
detected by a US transducer, converted to
electric signals that are duly processed to
get a PA image. PA imaging is a noninva-
sive imaging strategy that depends on the
light-absorption coefficient of the imaged
tissue. Since the PA signal varies according
to the distribution of light absorption in
biological tissue, therefore, PA imaging is
similar to optical imaging, which achieves
a high imaging contrast and is sensitive
to the tissue characteristics. However, the
carrier of the light-absorption information
is not an optical signal but rather a US
wave signal processed to obtain an image,
with the merits of negligible scattering
and dissipation in biological tissue. There-
fore, PA imaging integrates the excellent
contrast achieved in optical biomedical
imaging with the deep penetrability of US
imaging.[9] Thus, PA imaging can be used
for the imaging of deeper tissue com-
pared to other optical imaging technolo-
gies.[10,11] However, in comparison with
US imaging, the light intensity and PA
signal-to-noise ratio exhibit exponential
attenuation with increasing tissue depth due to the strong laser-
scattering effect. To improve the PA-imaging contrast, resolu-
tion, and penetrability to tissue, externally injected PA-imaging
contrast agents with high PA-imaging property in the tissue
need to be developed.[12–15]
In PA imaging based on contrast agents, the optical energy of
a pulse laser is absorbed by PA contrast agents and subsequent
converted to thermal energy with an increase of temperature.
The instantaneous temperature rise results in thermoelastic
expansion and subsequent ultrasonic emission that can be
detected by employing a US transducer to reconstruct the PA
image. Overall, the PA-imaging contrast mainly rests with
optical absorbance and thermoacoustic conversion efficiency,
since the generated PA signal amplitude is proportional to the
light absorption and the thermoelastic performances of the
absorbing agent. To further improve the PA imaging quality,
various PA imaging modalities and agents have been explored
to enhance the PA signal.[16–23] Commonly used contrast agents
for PA imaging include endogenous chromophores, such as
melanin,[24] oxyhemoglobin/deoxyhemoglobin,[25] lipids,[26] or
collagen,[27] as well as exogenous contrast agents (henceforth
referred to as contrast agents). Such agents are required to dia-
gnose and treat diseases such as breast carcinoma or glioma,
Photoacoustic (PA) imaging as a fast-developing imaging technique has great
potential in biomedical and clinical applications. It is a noninvasive imaging
modality that depends on the light-absorption coefficient of the imaged
tissue and the injected PA-imaging contrast agents. Furthermore, PA imaging
provides superb contrast, super spatial resolution, and high penetrability
and sensitivity to tissue functional characteristics by detecting the acoustic
wave to construct PA images. In recent years, a series of PA-imaging contrast
agents are developed to improve the PA-imaging performance in biomedical
applications. Here, recent progress of PA contrast agents and their bio-
medical applications are outlined. PA contrast agents are classified according
to their components and function, and gold nanocrystals, gold-nanocrystal
assembly, transition-metal chalcogenides/MXene-based nanomaterials,
carbon-based nanomaterials, other inorganic imaging agents, small organic
molecules, semiconducting polymer nanoparticles, and nonlinear PA-imaging
contrast agents are discussed. The applications of PA contrast agents as
biosensors (in the sensing of metal ions, pH, enzymes, temperature, hypoxia,
reactive oxygen species, and reactive nitrogen species) and in bioimaging
(lymph nodes, vasculature, tumors, and brain tissue) are discussed in detail.
Finally, an outlook on the future research and investigation of PA-imaging
contrast agents and their significance in biomedical research is presented.
Photoacoustic Imaging
Q. Fu, R. Zhu, Prof. J. Song, Prof. H. Yang
MOE Key Laboratory for Analytical Science of Food Safety and Biology
College of Chemistry
Fuzhou University
Fuzhou 350108, China
E-mail: jibin.song@nih.gov; hhyang@fzu.edu.cn
Prof. X. Chen
Laboratory of Molecular Imaging and Nanomedicine (LOMIN)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
National Institutes of Health (NIH)
Bethesda, MD 20892, USA
E-mail: shawn.chen@nih.gov
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/10.1002/adma.201805875.
1. Introduction
Photoacoustic (PA) imaging is a promising biomedical imaging
modality that exhibits the superb contrast of traditional optical
imaging with the outstanding spatiotemporal resolution of
ultrasound (US) imaging.[1–6] PA imaging exploits the PA
effect[7] that was first reported by Alexander Graham Bell.[8]
Briefly, an instant thermoelastic expansion of a tissue structure
Adv. Mater. 2019, 31, 1805875
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because the diseases do not generate endogenous contrast
agents and are therefore difficult to detect via PA imaging. Con-
trast agents for PA imaging reinforce the image contrast ratio
and enhance the resolution by altering the optical and acoustic
properties of local tissue, thus remarkably improving the image
output. An excellent contrast agent should possess the photo-
physical properties of low quantum yield, high molar-extinction
coefficient, near-infrared (NIR) window peak absorption,
and excellent photostability as well as having low toxicity and
immunogenicity, high target affinity and specificity, and high
biocompatibility.[17] To date, a wide variety of contrast agents for
PA imaging have been reported, including gold nanocrystals,[28]
carbon nanotubes,[29,30] graphene-based agents,[31] 2D graphene
analogues,[32] organic nanoparticles,[33,34] and semiconducting
polymer nanoparticles (SPNs),[35–40] among others. Neverthe-
less, given their importance in the early diagnosis, treatment,
and monitoring of various diseases, assessment of tissue mor-
phological structure, metabolism and physiological function,
and pathological characteristics, much work is ongoing in this
area.[10,12,15,41] To date, PA imaging has been applied in the
biological sensing of metal ions, pH, enzymes, temperature,
hypoxia, reactive oxygen species (ROS), and reactive nitrogen
species (RNS), as well as in the imaging of tumors, lymph
nodes (LNs), vasculature, and brain tissue.[10,42–48]
Here, we focus on the developments of PA contrast agents
and their biomedical applications in recent years (Figure 1).
First, we provide a comprehensive summary and review of
the available contrast agents, including gold nanocrystals,
gold-nanocrystal assembly, transition-metal chalcogenides/
MXene-based nanomaterials, carbon-based nanomaterials,
other inorganic imaging agents, small organic molecules, semi-
conducting polymer nanoparticles, and nonlinear PA-imaging
contrast agents. These contrast agents are highly effective and
enable PA imaging with desired contrast and superb spatial
resolution. We then focus on the recent development in the bio-
medical applications of PA-imaging contrast agents, including
biosensing of metal ions, pH, reactive oxygen species, reac-
tive nitrogen species, enzymes, temperature, and hypoxia, as
well as in the bioimaging of tumors, lymph nodes, vascula-
ture, and brain function (Table 1). Finally, the future paths in
the research and development of PA imaging and its contrast
agents are discussed.
Jibin Song obtained his
Ph.D. degree in chemical
and biomedical engineering
at Nanyang Technological
University, Singapore, in
2014. He then worked with
Prof. Xiaoyuan (Shawn) Chen
as a postdoctoral fellow at the
National Institutes of Health
(NIH). He joined Fuzhou
University as a Min Jiang
Scholar Professor of analytical
chemistry in 2018. His research focuses on developing
molecular-imaging nanoprobes for bioimaging, biosensing,
and drug/gene delivery.
Huanghao Yang received his
Ph.D. from Xiamen University
in 2002 and then carried
out postdoctoral research
at Hong Kong University
of Science and Technology
(2002–2004). He joined
Fuzhou University in 2008 as
a Min Jiang Scholar Professor.
His research interests mostly
focus on nanotechnology and
cancer therapy.
Xiaoyuan (Shawn) Chen
received his Ph.D. in chem-
istry from the University of
Idaho in 1999. He joined
the University of Southern
California as an assistant pro-
fessor of radiology in 2002.
He then moved to Stanford
University in 2004 and was
promoted to associate
professor in 2008. In 2009,
he joined the Intramural
Research Program of the NIBIB/NIH as a Senior
Investigator and Chief of the Laboratory of Molecular
Imaging and Nanomedicine (LOMIN).
Adv. Mater. 2019, 31, 1805875
Figure 1. Schematic illustration of photoacoustic imaging (PAI) contrast
agents and their biomedical applications.
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2. Inorganic Contrast Agents
2.1. Metallic Nanomaterials
Localized surface plasmon resonance (LSPR) is the plasmonic
resonant oscillation of the free conduction electrons at the
interface between positive and negative permittivity metallic
nanomaterial illuminated by incident light. Metallic nano-
materials possess excellent light absorption and exceptional
photothermal conversion ability due to the LSPR effect. Thus,
metallic nanomaterials are employed in PA imaging via excel-
lent light absorption property and cancer treatment through the
conversion of plasmon resonance into heat. Given the above
properties, metallic nanomaterials are also effective as contrast
agents for PA imaging as well as imaging-guided photothermal
therapy (PTT). Herein, we will further review three types of
metallic nanomaterials, namely: (1) gold nanocrystals and
(2) their assemblies, and (3) transition-metal chalcogenides/
MXene-based nanomaterials.
2.1.1. Gold Nanocrystals
Gold nanoparticles (AuNPs) have long been generally employed
as PA-imaging contrast agents due to the LSPR effect, which
allows their adjustable and excellent optical absorption.[28,49–55]
In addition, AuNPs can attain high photothermal conversion
effect upon laser illumination[56,57] and are highly biocompat-
ible, have good chemical inertness, excellent physiochemical
properties, and a high extinction coefficient.[58,59] AuNPs have
been synthesized as nanorods,[60–66] nanoprisms,[67,68] nanoc-
ages,[53,69–74] nanospheres,[75–78] nanostars,[79–83] nanodisks,[84–86]
bipyramids and rhombic dodecahedra,[87] nanoplates,[51,88,89]
nanoshells,[90–93] nanotripods,[94] and nanowreaths.[95]
When the particle size, interparticle distance, and mor-
phological characteristics of AuNPs are changed, the rela-
tive range of absorbed and scattered light can be adjusted,
thereby facilitating PA-imaging contrast. For example, the
optical absorption of gold nanospheres (AuNSp; Figure 2A)
and blood are both at ≈520 nm,[96] making it difficult to dif-
ferentiate between the PA signals of AuNSp and blood. Fortu-
nately, the LSPR peaks can be adjusted to the NIR region by
regulating the structure, size, and sharpness of AuNSp. For
example, Li and co-workers developed poly(ethylene glycol)-
coated (PEGylated) hollow AuNSp of 40–50 nm in size, with
a tunable absorption peak at 800 nm.[77] Importantly, the PA
signal of PEGylated hollow AuNSp is much stronger than that
of blood.
Gold nanorods (AuNRs) (Figure 2B) possess a cylinder-
shaped structure that affects the absorbance band, wherein
absorbance shifts further toward the NIR region with the
increase in particle aspect (length to width) ratio. Therefore,
due to their simple synthesis and adjustable NIR absorption
behavior, AuNRs play an important role in the field of PA con-
trast agents.[60,97] For example, Gambhir’s group synthesized
AuNRs with higher aspect ratios to achieve an increased PA
signal;[60] compared with AuNRs with an aspect ratio of 2.4 and
2.9, those with the aspect ratio of 3.5 exhibited the strongest ex
vivo and in vivo PA imaging performance. Additionally, AuNRs
can be easily encapsulated in silica NP to form silica-coated
AuNPs, facilitating cellular uptake and increasing the PA inten-
sity of AuNRs.[98]
Furthermore, gold-based hybrid bimetallic nanorods are
useful contrast agents for PA imaging as well as therapeutic
agents for bacterial infections. Au/Ag hybrid nanoagents pro-
duced by coating AuNRs with Ag showed a decreased PA signal
compared with the uncoated counterparts.[99] Interestingly, Ag-
coated AuNRs were shown to be stable under ambient condi-
tions, yet the Ag shell can be etched through the addition of
a ferricyanide solution. The PA intensity is simultaneously
enhanced as the Ag+ is etched, with the localized release of Ag+
being monitored by the PA signal.
Gold nanoprisms (AuNPrs) (Figure 2C) are anisotropic and
display an LSPR band in the NIR region, with potential as con-
trast agents for PA imaging. Bao et al. successfully prepared
PEGylated AuNPrs with excellent biocompatibility and an LSPR
band mainly localized at 830 nm, a suitable wavelength for
PA contrast agents.[100] The wavelength was further redshifted
by conjugating a cyclic Arg-Gly-Asp (cRGD) peptide onto the
PEGylated AuNPrs, leading to an LSPR peak at 980 nm; these
AuNPrs were confirmed to be highly efficient PA contrast
agents for tumor imaging.[67]
Gold nanocages (AuNCs) (Figure 2D) are cubic nanoparti-
cles (NPs) with a hollow nanostructure and an absorption band
ranged from 600 to 1200 nm, which can serve as excellent PA
contrast agents for biomedical applications.[70] For example, Tao
and co-workers developed AuNCs-based nanoagents to target
LNs, with the procedure being monitored in real time by PA
imaging.[69] Furthermore, AuNCs were prepared through an
ultrafast technique using a microwave-oven heating method,
Adv. Mater. 2019, 31, 1805875
Table 1. PA contrast agents and their bioapplications.
PA contrast
agents
Metallic nanomaterials Gold nanocrystals, gold-nanocrystal assemblies, Ag nanocrystals,
Pd nanosheets, copper neodecanoate NPs
Transition-metal chalcogenides/MXene-based nanomaterials WS2, TiS2, Ag2S, CuS, CuInS/ZnS, Ti3C2, Nb2C, TaC, MoSe2, CoS2, ReS2, Bi2S3, VS2
Carbon-based nanomaterials SWCNT-cRGD, Au-coated SWCNTs, CNTR@AuNPs, rGO-AuNR, rGO-AuNRVe
Other inorganic imaging agents Fe3O4, MoOx, Te, B, BP, Fe@gamma-Fe2O3@TiO2, Cu-Ag2S, MnOx/Ti3C2, CuS@Cu2S@Au
Small organic molecules Porphyrin, melanin, cyanine-based dye, perylene-diimide, porphysomes
Semiconducting polymer nanoparticles semiconducting polymers and oligomers
Bioapplications Biosensing Metal ions, pH, ROS, RNS, Enzymes, temperature, hypoxia
Bioimaging Tumors, LNs, vasculature, brain function
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and they were also used in the diagnosis and treatment of
ocular diseases by PA imaging.[101]
Gold nanostars (AuNSt) (Figure 2E), with a star-shaped
nanoconformation, have plasmon bands that are tunable into
the NIR region. The plasmon resonance wavelength of AuNSt
correlates with the branch aspect ratio, and the band intensity
increases with increasing number of branches, the length of
the branches, and the overall star size.[102] Therefore, AuNSt
are another kind of PA contrast agents. For example, spiky
Fe3O4@Au nanostars with preeminent biocompatibility, pre-
pared through a seed-mediated growth method, were applied in
multimodal MRI/Raman/PA imaging-guided PTT and photo-
dynamic therapy.[79]
Gold-based nanoplates (Figure 2F) are 2D nanomaterials
with a tunable LSPR in the NIR region, and they can also be
explored as PA-imaging agents. For example, Zheng and co-
workers fabricated PEGylated core–shell Pd@Au nanoplates
through a seeded growth approach.[51] The PEGylated Pd@
Au nanoplates exhibited outstanding stability and high tumor
uptake efficiency, as well as a high PA signal in the tumor.
Therefore, the nanoplates are excellent PA-imaging contrast
agents. The use of gold nanodisks (Figure 2G) in PA imaging
is rarely reported; however, 2D nanodisks can also be consid-
ered as nanoplates in a broader sense. Lee and co-workers
synthesized 2D gold nanodisks through a physical synthesis
method.[84] The stacked Au nanodisks possessed intrinsic
optical merits in a whole range of resonant wavelengths and a
superior light-response ability, and could therefore be employed
as sensitive contrast agents for PA imaging.
The LSPR frequency of gold nanoshells (AuNSh) can be
easily tuned through tailoring their size or shell thickness,
with thinner shells leading to a redshift.[103] A tunable charac-
teristic peak wavelength is therefore highly advantageous for
PA imaging. Chen and co-workers prepared branched nano-
porous AuNSh (BAuNSP) through a one-step, seedless method
(Figure 2H).[90] The LSPR peak wavelength of BAuNSP was fur-
ther redshifted to the NIR region compared with AuNSh due
to intense plasmon coupling in the shell nanopores and the
surface plasmon between the outer and inner shells, with great
potential for PA imaging and biomedical applications. Unsur-
prisingly, an aqueous BAuNSP solution showed a stronger
PA signal than an aqueous AuNSh solution with the same
optical density (OD). In addition, the accumulation behavior of
BAuNSP in the tumor was monitored by PA imaging.
Adv. Mater. 2019, 31, 1805875
Figure 2. SEM and TEM images of gold nanocrystals of various categories: A) nanospheres, B) nanorods, C) nanoprisms, D) nanocages, E) nanostars,
F) nanoplates, G) nanodisks, H) nanoshells, I,J) nanotripods, K) bipyramids, and L) rhombic dodecahedrons. (A) Reproduced with permission.[77]
Copyright 2010, Elsevier. (B) Reproduced with permission.[60] Copyright 2012, American Chemical Society. (C) Reproduced with permission.[67] Copy-
right 2016, Springer. (D) Reproduced with permission.[69] Copyright 2017, Elsevier. (E) Reproduced with permission.[79] Copyright 2018, Wiley-VCH.
(F) Reproduced with permission.[51] Copyright 2014, Wiley-VCH. (G) Reproduced with permission.[84] Copyright 2017, American Chemical Society.
(H) Reproduced with permission.[90] Copyright 2017, American Chemical Society. (I,J) Reproduced with permission.[94] Copyright 2014, American
Chemical Society. (K,L) Reproduced with permission.[87] Copyright 2014, American Chemical Society.
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Anisotropic hybrid gold NPs have shown outstanding optical
and physical properties compared with their isotropic struc-
tural counterparts. As representative anisotropic nanomaterials,
AuNRs and AuNCs have shown great promise as PA-imaging
contrast agents; however, the size of the particles is relatively
large (≈50 nm), which hinders their penetration into the tumor
site and seriously impedes their potential application for tar-
geted tumor imaging.[14,72,94,104] Cheng et al. synthesized Au
tripods (Figure 2I,J), with particle size less than 20 nm, a rig-
orous controlled morphology, excellent size distribution, and
strong visible and NIR absorptions, thereby showing great
advantages as PA-imaging contrast agents.[94] Furthermore,
cRGD peptide-functionalized Au-tripods exhibited remarkably
integrin-targeted enhancement of PA imaging effects in vitro
and in vivo.
2.1.2. Gold-Nanocrystal Assembly
Plasmonic coupling between gold nanocrystals induces an
intense electromagnetic field, improving their optical proper-
ties and photothermal conversion efficiency. Therefore, plas-
monic assemblies show outstanding interparticle plasmonic
coupling ability resulting in redshift of LSPR absorption band
into the NIR region.[105,106] Bai et al. reported a contrast agent
composed of hollow AuNSp cores and superparamagnetic iron
oxide (Fe3O4) NPs satellites, with enhanced NIR absorption
and magnetic properties.[107] The plasmon resonance peaks for
hollow AuNSp were observed at around 800 nm, with a redshift
to 830 nm following assembly with Fe3O4 NPs.
In recent years, plasmonic nanocrystal-based assemblies
have become a significant research focus. Self-assembly offers
a feasible approach to integrate discrete NPs into functional
components with the potential to meet the needs of large-
scale material fabrication for biomedical applications.[108,109]
For example, Duan and Song et al. synthesized gold nanovesi-
cles of amphiphilic AuNPs grafted with mixed hydrophilic and
hydrophobic polymers (Figure 3A).[110–112] In these studies, the
amphiphilic AuNPs were assembled into vesicles through a
self-assembly film rehydration method. Closely packed AuNP
films were formed via the slow evaporation of chloroform (a
common organic solvent), which provided an advantageous
state of energy for the hydrophilic and hydrophobic homopoly-
mers, such that the separated thin films could be rolled to form
vesicles after rehydration. The shell layer of the as-prepared
vesicles was shown to be a monolayer array composed of tightly
bonded AuNPs (Figure 3B,C). Figure 3A illustrates the fabri-
cation process, showing the hydrophobic brushes collapse to
form the vesicle shell and the hydrophilic brushes rearrange in
conformation; furthermore, the AuNPs are embedded within
the shell. In further work, Chen and co-workers developed bio-
degradable plasmonic gold nanovesicles of AuNPs coated with
block copolymer of PEG-PCL for PA imaging.[113] This tech-
nique achieved dense packing of AuNPs in the vesicular shell,
leading to enhanced plasmonic coupling properties between
adjacent AuNPs and inducing an enhanced NIR absorption
suitable for PA imaging.
It is well known that gold has good biocompatibility, yet
AuNPs exert size-dependent biotoxicity. It was reported that
AuNPs with a core size of 8–37 nm can cause serious disease
in animals, yet AuNPs with size smaller than 8 nm do not.[114]
Thus, the self-assembly of AuNPs with smaller size (less than
8 nm in diameter) would be of great practical significance.
Deng et al. synthesized gold nanomicelles (AuNMs) via the
self-assembly of comb-like amphiphilic polymers and AuNPs of
6 nm in size,[115] which was further employed as nanoplatform
to load the anticancer drug doxorubicin (DOX) (Figure 3D).
The AuNMs (Figure 3E) exhibited excellent biocompatibility
and no potential toxicity to multiple cell types, such as murine
fibroblasts (L929) cells, MCF-7 cells, and human umbilical vein
endothelial cells (HUVECs), and have the potential to be uti-
lized as a highly effective PA contrast agent. Additionally, the
wavelength of densely packed AuNMs with short AuNP chain
assemblies showed a remarkable redshift compared to the indi-
vidual AuNPs and AuNP chains, which is good for biomedical
imaging (Figure 3F).
Despite the great potential of discrete AuNRs as PA-imaging
contrast agents as described in Section 2.1.1, AuNRs have an
inherent defect, wherein those with a length of over 40 nm
have a slow clearance rate from the human body. Ideally, to
address this, sub-100 nm plasmonic assemblies consisting
of biocompatible substances and smaller AuNRs, with out-
standing tumor accumulation and rapid clearance after treat-
ment need to be developed. Chen and co-workers synthesized
small AuNR vesicles, ≈60 nm in size, assembled through
PEG- and poly(lactic-co-glycolic acid) (PLGA)-coated ultrasmall
AuNRs (dimension: ≈8 nm in length, 2 nm in width) via an
emulsion approach (Figure 3G).[63] The biodegradable AuNR@
PEG/PLGA vesicles were hydrolyzed to form small, hydro-
philic, PEG-coated AuNRs (AuNR@PEG) (Figure 3H), which
are stable under physiological conditions and have a rapid
clearance rate. In addition, the absorption peak of the vesicles
can be adjusted in the range of 800–1050 nm by increasing the
nanovesicle size. Compared with single AuNRs, strong inter-
particle plasmon coupling between the AuNR vesicles resulted
in an amplified PA signal (Figure 3I), with the PA intensity of
the AuNR vesicle being an order of magnitude higher than that
of AuNRs when treated with an 808 nm laser. The plasmon
peak wavelength can also be tailored by changing the interpar-
ticle distance of AuNPs.[116] Thus, in order to further improve
PA-imaging performance, the interparticle spacing within
the nanovesicles must be carefully adjusted to increase their
absorption wavelength in the NIR window. To address this, Nie
and co-workers proposed a hierarchical self-assembly method
for the synthesis of AuNP chain vesicles with an enhancement
of NIR absorption and PA contrast (Figure 3J),[117] wherein
the AuNP strings and networks are clearly embedded within
the vesicular membranes. The obtained vesicles had a hollow
structure and were composed of a monolayer of AuNP strings
(Figure 3K). The small interparticle distance (≈0.8 nm) within
each string of AuNP chain nanovesicles led to enhanced NIR
absorption caused by the plasmonic coupling effect between
contiguous AuNPs;[116] therefore, the chain nanovesicles pos-
sess a stronger maximum peak wavelength (780 nm) than
that of nonchain nanovesicles (620 nm) (Figure 3J,L). For PA
imaging in vivo, the chain vesicle group exhibited an eight-
fold increase in PA intensity compared to the control group
(without PA contrast agents), whereas only a minor increase
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Adv. Mater. 2019, 31, 1805875
Figure 3. A) Proposed mechanism of the preparation of amphiphilic Au nanovesicles via a self-assembly approach. B) TEM and C) SEM images of Au
nanovesicle. D) Schematic illustration of the preparation of DOX@gold nanomicelles. E) TEM of Au nanomicelles. F) UV–vis–NIR absorbance spectra
of three different forms of Au nanostructures. G) Proposed mechanism of the assembly of small Au nanorod (AuNR) vesicles through an oil-in-water
emulsion approach. H) SEM image of AuNR@PEG/PLGA vesicles (inset: high-magnification TEM and SEM images). I) PA images of two different
forms of AuNR. J) Schematic illustration of the preparation of chain and nonchain gold vesicles by self-assembly. K) SEM images of chain gold vesi-
cles. L) UV–vis spectra of nonchain gold vesicles (green and black), individual Au nanoparticles (red), and chain gold vesicles (blue). M) Proposed
mechanism of the preparation of Janus Au-Fe3O4 nanovesicles. N) SEM images of double-layered vesicle with an Fe3O4 outer shell. O) PA imaging
of four different forms of Janus nanostructures. (A) Reproduced with permission.[110] Copyright 2011, American Chemical Society. (B, C) Reproduced
with permission.[111] Copyright 2012, American Chemical Society. (D–F) Reproduced with permission.[115] Copyright 2015, Wiley-VCH. (G–I) Reproduced
with permission.[63] Copyright 2015, Wiley-VCH. (J–L) Reproduced with permission.[117] Copyright 2015, Wiley-VCH. (M–O) Reproduced with
permission.[118] Copyright 2017, Wiley-VCH.
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in PA-imaging signal was tested for the nonchain nanovesicle
group.
The self-assembly of nanomaterials is an interdisciplinary
subject involving the recomposition of ordered structure and
the surface modification of materials. It is at the frontier of
chemistry and material science and the cradle of new func-
tional materials. Nanoparticle assemblies possess magnetic,
electronic, and optical properties that vary considerably from
those of the corresponding single NPs. For example, Chen
and co-workers reported a double-layer plasmonic–magnetic
nanovesicle assembly that was prepared using different hydro-
philic polymer brushes functionalized onto the Au and Fe3O4
NP surfaces, respectively, forming Janus amphiphilic Au-
Fe3O4 NPs.[118] The location of the Fe3O4 and Au NPs within
the vesicular shell could be easily exchanged by adjusting the
amphiphilicity of the conjugated polymer brushes (Figure 3M).
Subsequently, the double-layered vesicle with an Fe3O4 NP
outer shell (DL-Ve2) opposite to the Au NP outer shell double-
layered vesicle (DL-Ve1) was prepared accordingly by varying
the amphiphilicity of Au or Fe3O4 NPs (Figure 3N). In addi-
tion, the DL-Ve2 vesicles displayed a distinct increase in mag-
netic and optical properties because of the enhanced plasmonic
coup ling effect between the Au NPs and magnetic dipole inter-
actions of Fe3O4 in the double-layered vesicle. Specifically, the
PA intensity of DL-Ve2 was 5- and 2.2-fold higher than that of a
monolayer vesicle and DL-Ve1, respectively, at the same OD785
(Figure 3O).
Apart from Au nanocrystals, other metal nanomaterials such
as Ag nanocrystals,[119–121] Pd nanosheets,[122–125] and copper
neodecanoate NPs[126] have also been explored to serve as con-
trast agents for PA imaging.
2.1.3. Transition-Metal Chalcogenides/MXene-Based
Nanomaterials
In addition to Au nanocrystals and their assemblies, transition-
metal chalcogenides/MXene-based nanomaterials have also
been widely used as PA-imaging agents.[127–137] For example,
Cheng et al. designed PEGylated tungsten disulfide (WS2-PEG)
(Figure 4A) that could act as a PA-imaging contrast agent of
tumors, as well as being a highly effective photothermal agent
due to its excellent NIR absorbance.[138] TiS2 (a transition-metal
dichalcogenide) nanosheets (Figure 4B) exhibited high physi-
ological stability, negligible toxicity, and high absorbance inten-
sity in the NIR window. TiS2 nanosheets have been used as a
PTT agent to guide tumor ablation with PA imaging in vivo,
with excellent therapeutic effect being observed in a mouse
tumor model.[139] Zhao and co-workers reported a nanoagent
with excellent targeting capability and PA contrast using
folic-acid-modified Pluronic F127, encapsulated in oil-soluble
Ag2S quantum dots (Figure 4C).[140] The nanoagent has been
employed as an excellent PA-imaging agent of HeLa tumor
cells, which have a high expression of the folate receptor. CuS
NPs have also been extensively used as PA contrast agents
(Figure 4D).[133,141–143] For example, Yang et al. designed a CuS-
based PA agent (CuS-peptide-BHQ3) (CPQ)) for in vivo matrix-
metalloproteinase sensing.[144] As a combination, two different
Adv. Mater. 2019, 31, 1805875
Figure 4. A) AFM image of WS2-PEG nanosheets. B–F) TEM images of TiS2, PF127-FA@Ag2S, CuS, CuInS/ZnS quantum dots, and Ti3C2@mMSNs.
(A) Reproduced with permission.[138] Copyright 2013, Wiley-VCH. (B) Reproduced with permission.[139] Copyright 2015, The Royal Society of Chemi-
stry. (C) Reproduced with permission.[140] Copyright 2018, IOP Science. (D) Reproduced with permission.[144] Copyright 2014, Ivyspring International
Publisher. (E) Reproduced with permission.[145] Copyright 2016, American Chemical Society. (F) Reproduced with permission.[146] Copyright 2018,
Wiley-VCH.
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transition-metal chalcogenides can also serve as PA-imaging
contrast agents; for example, Liang and co-workers developed
a multifunctional theranostic contrast agent using CuInS/
ZnS quantum dots (Figure 4E), which have good therapeutic
potential.[145]
Transition-metal MXene-based nanomaterials have also
received increasing attention as contrast agents for PA imaging
recently. For example, Yang and co-workers designed a type of
2D MXene-based nanoagent, Ti3C2@mMSNs (Figure 4F), con-
sisting of Ti3C2 MXene nanoparticles coated with a thin shell of
mesoporous silica.[146] An enhanced contrast agent was further
developed using this system by grafting with a cRGD sequence,
Ti3C2@mMSNs-cRGD, providing sensitive imaging-guided
and real-time monitoring of tumors. Shi and co-workers fab-
ricated a 2D Nb2C MXene to serve as a PA-imaging contrast
and phototherapeutic agent, which could be used in tumor
photothermal ablation.[147] Following surface functionalization
with poly(vinylpyrrolidone) (PVP), the as-prepared Nb2C-PVP
nanoagent showed enzyme-responsive biodegradability and
excellent biocompatibility to myeloperoxidase, as well as insig-
nificant phototoxicity and superb physiological stability.
2.2. Carbon-Based Nanomaterials
Two main categories of carbon-based nanomaterials, namely,
carbon nanotubes (CNTs)[29,30,148–151] and graphene-based nano-
materials,[31,32,52,152–159] have been extensively investigated as
contrast agents. Both categories have a distinct absorption in
the NIR window. Despite their lower molar-extinction coef-
ficient compared to gold nanocrystals, carbon-based nano-
materials are promising for PA imaging due to their ease of
fabrication and functionalization. Nonplasmonic single-walled
CNTs (SWCNTs) have a wide-band absorption, including
the NIR window, providing an enhanced PA signal.[160] How-
ever, they have no specific peak in the wide-band absorption
spectrum, which impedes their application in absorption-
wavelength-dependent PA imaging. Fortunately, the PA intensity
could be further improved by integrating plasmonic metal
nanomaterials or small molecules into carbon-based nano-
materials.[160–164] For example, de la Zerda et al. developed cRGD-
functionalized SWCNTs (SWCNT-cRGD) that were used in
the PA imaging of tumors, exhibiting an eight times higher
of the PA signal of the tumor section compared with plain
SWCNTs.[160] The PA signal of the SWCNT-cRGD was then
further increased through coating ICG dye onto the surface
of SWCNTs;[165] the SWCNT-ICG exhibited a 20-fold higher
optical absorbance at 780 nm compared with plain SWCNTs
and was bound to live animal molecular targets while main-
taining a high PA contrast. A further study coating SWCNTs
with either QSY21 (an optical dye and quencher) or ICG dye
showed a 17- and 20-fold increase in the particles’ absorption
and an over 100-fold stronger PA intensity compared with plain
SWCNTs.[161] In another example, Chen and co-workers used
hyaluronic acid-5
β
-cholanic acid conjugated with folic acid to
modify hydrophobic SWCNT, achieving high tumor-uptake effi-
ciency of the SWCNT. PA imaging was further used to trace the
circulation and tumor uptake of the functionalized SWCNT in
vivo.[166]
Noble-metal NP-coated SWCNTs possess an increased
NIR absorption, enhanced biocompatibility, and excellent PA-
imaging capability.[167–171] For example, Kim et al. developed Au-
coated (4–8 nm layer) SWCNTs (GNTs) with a size of 1.5–2 nm
(Figure 5A);[170] the absorbance intensity of the GNTs was over
85 times higher than that of SWCNTs in the NIR window at
the same concentration. Furthermore, lymphatic endothelial
hyaluronan receptor-1 (LYVE-1)-antibody-conjugated GNTs
have been employed in dual-mode PA and photothermal
imaging of lymphatic endothelial receptors (Figure 5B). In
another example, Chen and co-workers prepared a class of con-
trast agent that was based on CNT rings (CNTRs) coated with
AuNPs (CNTR@AuNPs) by growing AuNPs on the surface of
CNTRs (Figure 5C).[169] Due to the plasmonic coupling of the
AuNPs, the LSPR peak of the CNTR@AuNPs (Figure 5D) red-
shifted with the increase of AuNP size (Figure 5E). In addition,
compared with AuNP-coated non-ring-CNTs (CNT@AuNPs)
and whole Au-nanoshell-coated CNTRs (CNTR@AuNS), the
CNTR@AuNPs had significantly higher photothermal conver-
sion efficiency. The PA amplitude of CNTR@AuNPs was also
remarkably higher than that of CNTRs, CNTR@AuNSs, and
CNT@AuNPs (Figure 5F).
Graphene-based nanomaterials are another commonly used
class of carbon-based nanomaterial for PA imaging,[159,172,173]
extensively studied in the biomedical field because of their
unique chemical and physical properties.[174] Compared with
CNTs, graphene-based nanomaterials, especially reduced gra-
phene oxide (rGO), possess a larger surface area and better
dispersibility in most biological conditions. Recently, rGO-
coated AuNPs were reported to have an enhanced PA signal,
wherein the plasmonic AuNPs can act as a local nanoantenna
to increase the optical absorption efficiency of rGO. The inter-
action of plasmonic AuNPs and rGO under laser illumination
leads to the enhanced photocurrent of rGO, thus improving
its photothermal properties; such systems are promising PA
contrast agents.[169,175] Lim and co-workers designed a PA
contrast agent consisting of rGO-coated AuNRs (rGO-AuNR)
with strong NIR absorption, good photothermal stability, and
enhanced PA amplitudes[176] (Figure 5G–I). The rGO layer
provides thermal conductivity, leading to highly efficient heat
transfer. Thus, the light-absorbing properties of rGO can be
further enhanced by AuNRs. Chen and co-workers designed
a hybrid rGO-loaded AuNR vesicle (rGO-AuNRVe) through a
double-emulsion technique to integrate PEGylated rGO into
AuNR vesicles of amphiphilic small AuNRs grafted with PEG
and PLGA, for continuous drug release and increased photo-
thermal and PA effects[177] (Figure 5J,K). Compared with the
mixture of AuNRVe and rGO, the rGO-AuNRVe showed a
stronger PA intensity of the same OD808 value (Figure 5L), with
the PA intensity of the mixture being ≈2.5-fold lower than that
of the rGO-AuNRVe.
The above examples show that the assembly of AuNPs not
only gives rise to the redshift of their maximum absorption
band from the visible region to the NIR window by shortening
the interparticle space, but also enhances the photothermal
conversion capability due to the intense plasmonic coupling
prosperity between adjacent AuNPs. A series of carbon-based
nanomaterials of graphene, CNT, and their assemblies with
AuNPs were also developed and functionalized to investigate
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their optical properties.[178] The obtained assembled nanostruc-
tures exhibit dual enhanced photothermal conversion charac-
teristics of optically triggered acoustics and thermal treatment.
Therefore, AuNP assemblies and hybrid carbon-based nano-
materials can serve as promising nanoagents for sensitive in
vivo PA imaging.
2.3. Other Inorganic Imaging Agents
In addition to the abovementioned nanomaterials, researchers
have also reported various other nanomaterial-based PA-
imaging contrast agents, such as tellurium nanosheets,[179]
boron nanosheets,[180] black-phosphorus nanosheets,[181]
black-phosphorus quantum dots,[182] tantalum carbide
nanosheets,[183] molybdenum selenide,[184] cobalt sulfide
nanosheets,[185] rhenium disulfide nanosheets,[186] bismuth-
sulfide-based NPs,[187,188] and vanadium disulfide nanostruc-
tures,[189] as well as nanohybrids such as Fe@gamma-Fe2O3@
TiO2 nanocomposites,[190] Cu-Ag2S NPs,[191] tantalum carbide
(Ta4C3)-based composite nanosheets,[192] Ti3C2-based compos-
ites (MnOx/Ti3C2),[193] and CuS@Cu2S@Au nanohybrids.[194]
For example, Chen and co-workers developed a highly versa-
tile Fe3O4@polydopamine core–shell nanocomposite system
with an Fe3O4 core and a thin polydopamine shell, which can
be utilized for intracellular mRNA sensing and dual PA and
MRI-imaging-guided PTT.[195] Thawani et al.[196] fabricated an
indocyanine green (ICG)-coated superparamagnetic iron oxide
Adv. Mater. 2019, 31, 1805875
Figure 5. A,B) Diagrams of Au carbon nanotube (CNT) facilitating PA and photothermal diagnostics and treatment. C) Proposed mechanism of
preparation of CNT ring Au nanoparticles (CNTR@AuNPs). D) TEM and elemental mapping of CNTR@AuNP. E) UV–vis–NIR spectra of CNTR and
different types of CNTR@AuNP. F) Hybrid ultrasound and PA images. G) Proposed mechanism of preparation and application of reduced graphene
oxide Au nanorods (rGO-AuNRs). H,I) PA images and PA intensity of AuNRs, graphene oxide-AuNRs, and rGO-AuNRs. J) Schematic drawing of AuNR
vesicles loaded with rGO. K) SEM of rGO-AuNR vesicles. L) PA images of mixture of rGO and AuNR vesicles, and rGO-AuNR vesicles with various OD808
values. (A,B) Reproduced with permission.[170] Copyright 2009, Macmillan Publishers Limited. (C–F) Reproduced with permission.[169] Copyright 2016,
American Chemical Society. (G–I) Reproduced with permission.[176] Copyright 2015, American Chemical Society. (J–L) Reproduced with permission.[177]
Copyright 2015, American Chemical Society.
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NP cluster, which was employed for PA-imaging-guided brain-
tumor surgery in mice. In another example, Liu and co-workers
designed MoOx-PEG nanosheets, which showed strong NIR
absorbance[197] and a pH-dependent degradation behavior
in acidic environment, and they decomposed under a physi-
ological environment. In addition, MoOx-PEG is a strong PA-
imaging contrast, and therefore its degradation in vivo can be
monitored with PA imaging.
3. Organic Contrast Agents
3.1. Small Organic Molecules
Organic molecular PA contrast agents, including por-
phyrin,[198–200] melanin,[201–203] cyanine-based dyes,[204,205] and
perylene-diimide (PDI),[206–215] have been widely applied in PA
imaging due to their excellent biodegradability and biocompat-
ibility. In 2011, Zheng and co-workers developed porphysomes
by combining porphyrin with phospholipids and integrating
porphyrin–phospholipids into nanovesicles via a self-assembly
approach.[216] Porphysomes are composed of dense porphyrin
bilayers, which produce a strong self-quenching effect through
intermolecular interactions, resulting in strong nonradia-
tive heat and thus enhanced PA signals. Further, porphyrin–
lipid complexes possess excellent metal-ion-chelating ability,
adjustable NIR absorption, and remarkable biodegradability
(Figure 6A). Subsequently, they developed porphyrin-shell
microbubbles as a dual-modality US and PA contrast agent.[217]
In 2015, the Zheng group further developed trimodality con-
trast agents for US, PA, and fluorescence imaging, denoted as
porphyrin microbubbles (Figure 6B), including a bacteriochlo-
rophyll–lipid shell and encapsulated perfluorocarbon gas.[218]
Porphyrin microbubbles burst into smaller NPs with analo-
gous optical properties upon sonication, which can accumu-
late in the tumor region and thus improve the imaging quality.
In addition, Zemp and co-workers developed porphyrin-
containing nanodroplets with a size of ≈200 nm and excellent
optical absorption, offering remarkable PA contrast as assessed
in tumor or chicken embryos.[219]
Melanin is a common natural pigment with extensive NIR
absorption, superb chelating performance, and excellent sta-
bility under physiological conditions, with applications in PA
imaging. For example, melanin-based NPs of ≈4.5 nm were
synthesized by Fan et al. and used as a PA agent.[24] Melanin-
based NPs have an outstanding chelating effect with metal
ions, including Fe3+ and/or 64Cu2+, and can be used in multi-
modal imaging (MRI/PA/PET) of tumors (Figure 6C).
Dye-based nanomaterials have been extensively investigated
as PA-imaging contrast agents because of their low toxicity,
good biodistribution, and easy clearance. Heptamethine cya-
nine, composed of two aromatic nitrogen-containing hetero-
cycles and linked by a heptamethine chain, was the first NIR
dye to be used in PA imaging.[220] ICG, which has a maximum
absorption wavelength at 780 nm and low quantum yield, is a
widely used dye approved for clinical application by the U.S.
Food and Drug Administration (FDA). However, ICG has the
disadvantages of poor light stability and degradation in water,
which severely hinder its application in the biomedical field.
Therefore, various studies have focused on the encapsulation
of the dye into biocompatible polymers or other materials to
form stabilized NPs.[221] For example, Sailor and co-workers
found that the intensity of the PA contrast could be improved
by 17 times when using mesoporous silica NPs to encapsulate
ICG; the effect was ascribed to the weak thermal conductivity of
the mesoporous silica coating protecting the ICG from thermal
or photolytic degradation.[221] Huang and co-workers designed
a PA contrast agent composed of a hydrophobic MeHg+-
responsive NIR cyanine dye (hCy7) and liposomes (LP-hCy7;
Figure 6D).[204] LP-hCy7 has two separated NIR absorbance
peaks, and the PA signals of LP-hCy7 at 860 and 690 nm are,
respectively, enhanced and reduced when MeHg+ reacts with
hCy7 through the Hg-promoted cyclization method (Figure 6E).
Therefore, LP-hCy7 can act as a ratiometric PA-imaging agent
for the detection of MeHg+. Ratiometric imaging can provide
a feasible method for relative quantification of biometric sub-
stances both in vitro and in vivo with lower influence from
environmental factors that affect PA signals. However, single-
wavelength contrast agents, with one intensity-dependent PA
signal readout, lead to inaccurate imaging and sensing results
because diverse analyte-independent factors can affect their
absolute PA-signal intensity.
Furthermore, the combination of two NIR dye types leads
to greatly enhanced stability and specific new functions. Liu
and co-workers developed a chemically crosslinked albumin–
dye nanocomplex (C-HSA-BOPx-IR825) contrast agent, which
is composed of a built-in pH indicator of the pH-responsive
dye benzo[a]phenoxazine (BPOx), an encapsulated reference
of the pH-inert dye IR825, and human serum albumin (HSA)
(Figure 6F).[222] The C-HSA-BOPx-IR825 NP was employed to
test the pH in the tumor region by both ratiometric PA and
fluorescence imaging. Other NIR dyes, including naphthalocya-
nines,[223] phthalocyanine,[224] croconine,[225] squaraine,[226] and
Prussian blue,[227,228] can also serve as PA contrast agents.
3.2. Semiconducting Polymer Nanoparticles
SPNs are composed entirely of organic components, including
semiconducting polymers (SP) and oligomers. SPNs have
superb optical properties, such as a large absorption coefficient,
adjustable optical absorption, controllable size, and high photo-
stability, and can therefore act as contrast agents for biomedical
imaging. PDI (Figure 6G), as a widely used semiconducting
polymer, has received considerable attention in PA imaging
due to its strong NIR-light-absorption ability and excellent bio-
compatibility. Moreover, PDI possesses very high photothermal
stability and photothermal conversion efficiency, and is easily
modified.[206,210,212,229] Cheng and co-workers successfully devel-
oped an excellent contrast agent of PDI-based NIR-absorptive
organic NPs for PA imaging in the tumor region of the tumor-
bearing mice.[206] Fan and co-workers rationally designed an
efficient PA contrast agent consisting of amphiphilic PDI
derivatives and cRGD-modified NIR-absorptive organic semi-
conducting NPs through a self-assembly method,[229] which
could be used to selectively light up early thrombus in living
mice (Figure 6H). Recently, Cheng and co-workers developed
photosensitizer (PS)-loaded PDI PA activating nanodroplets
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(PS-PDI-PAnD) consisting of a PDI shell with long alky chains
and a liquid perfluoropentane core.[212] The photosensitizer
ZnF16Pc showed excellent compatibility at the interlayer
of the core–shell nanostructure (Figure 6I,J). As shown by
transmission electron microscopy (TEM), the as-prepared
PS-PDI-PAnDs possessed a uniformly distributed core–shell
Adv. Mater. 2019, 31, 1805875
Figure 6. A) Schematic illustration of porphyrin microbubbles (pMBs) and conversion process of pMBs to porphyrin nanoparticles (pNPs). B) Light
microscopy image of pMBs. C) Multimodality imaging of the melanin-based NPs. D) Chemical structural formula of cyanine dye hCy7 and hCy7′.
E) Proposed mechanism of ratiometric PA imaging of MeHg+. F) Proposed mechanism of the preparation process of C-HSA-BPOx-IR825. G) Chemical
structural formula of perylene-diimide (PDI). H) Proposed mechanism of the synthesis of cRGD-PDI NPs. I) Photosensitizer (PS)-loaded PDI PA acti-
vating nanodroplets PS-PDI-PAnD for multimodal-imaging-guided photothermal and photodynamic therapy. J) Structure of the PS-PDI-PAnDs. K) TEM
image of PS-PDI-PAnDs. (A,B) Reproduced with permission.[218] Copyright 2015, Macmillan Publishers Limited. (C) Reproduced with permission.[24]
Copyright 2014, American Chemical Society. (D,E) Reproduced with permission.[204] Copyright 2017, Wiley-VCH. (F) Reproduced with permission.[222]
Copyright 2015, Wiley-VCH. (G,H) Reproduced with permission.[229] Copyright 2017, American Chemical Society. (I–K) Reproduced with permission.[212]
Copyright 2018, American Chemical Society.
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nanostructure (Figure 6K), and these biocompatible PS-PDI-
PAnDs can serve as an excellent PA-imaging contrast agent. In
addition, Chen and co-workers recently reported another PDI-
based contrast agent that can detect the ROS level in the tumor
by PA imaging.[230] In addition, chlorin dimers,[231] polypyr-
role,[232,233] polylysine,[234] smart organic NPs,[235] natural humic-
acid-based nanoagents,[236] and tannic-acid-based assemblies[237]
have also been explored as contrast agents for PA imaging.
It has been recently reported that SPNs can effectively con-
vert a photon’s energy into acoustic waves, allowing the devel-
opment of responsive PA-imaging probes.[35,38,39,238–248] In
order to study the PA properties of different semiconducting
polymers, Pu et al. systematically studied and compared the
structures and properties of diketopyrrolopyrrole (DPP)-
based SPNs (SPN2-4) and poly(cyclopentadithiophene-alt-
benzothiadiazole)-based SPN (SPN1) (Figure 7A).[249] A series
of DPP-based copolymers integrated into PEGylated SPNs were
synthesized via a nanoprecipitation method (Figure 7A). The
different backbone structures of individual SPNs led to varia-
tions in their electron donor–acceptor properties and thus in
their PA intensities; for example, SPN4 showed the highest
PA signal due to its corresponding structural unit having the
strongest electron-donating ability (Figure 7B). Therefore, the
PA intensity and photothermal conversion efficiency of SPNs
are closely related to the electron donor–acceptor property of the
corresponding DPP structural units. Moreover, the fabrication
Adv. Mater. 2019, 31, 1805875
Figure 7. A) Schematic of fabrication of semiconducting polymer nanoparticles (SPNs) by nanoprecipitation. B) PA images of SPNs in solution. C) Sche-
matic of synthesis of SPN1 through a nanoprecipitation or self-assembly approach of semiconducting amphiphilic polymers into NPs. D,E) Chemical
structural formula of the semiconducting oligomer amphiphile and NIR775 as well as the preparation of a PA nanoprobe through a self-assembly
approach, and its sensing mechanism. F) Preparation method of DPPV, chemical structural formula of DPPT and PLGA-PEG, and proposed mechanism
of the synthesis of SPNs. G) Mechanism of SPNs biodegradation. (A,B) Reproduced with permission.[249] Copyright 2015, Wiley-VCH. (C) Reproduced
with permission.[254] Copyright 2017, Wiley-VCH. (D,E) Reproduced with permission.[255] Copyright 2017, American Chemical Society. (F,G) Reproduced
with permission.[257] Copyright 2018, American Chemical Society.
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of SPNs through a nanoprecipitation method usually leads
to the dissociation of NPs, since SPNs prepared by nanopre-
cipitation, encapsulating the SP within an amphiphilic block
copolymer, will produce binary micelles, which easily undergo
dissociation.[240,250,251] Furthermore, in the presence of proteins
or other substances in vivo, amphiphilic copolymers easily leak
from the NPs, resulting in alteration of the optical properties
and poor biodistribution.[252,253] Pu and co-workers reported a
synthetic method to prepare structurally stable SPNs through
the grafting of hydrophilic PEG onto the SP backbone.[254]
Thus, the semiconducting amphiphilic polymer, which has NIR
absorption capacity, could self-assemble into homogeneous
NPs (Figure 7C). The results showed the excellent stability of
these semiconducting amphiphilic polymers prepared by the
self-assembly method, superior to that of SPN1 prepared via
the nanoprecipitation approach. Moreover, the PA intensity
in tumors in mice, which were injected with semiconducting
amphiphilic polymers, which possessed a nondissociable nano-
structure and superhigh PEG density, was three times stronger
than that of the original PA signal of the tumor.
The combination of SPNs and dyes leads to a series of supe-
rior properties. Pu and co-workers designed a degradable and
activatable PA contrast agent composed of a degradable nano-
carrier semiconducting oligomer (SO) amphiphile and the
ROS-inert dye NIR775 via a self-assembly method,[255] which
can be used for in vivo imaging of ClO− (Figure 7D). NIR775
remained intact while the semiconducting oligomer amphi-
phile degraded, which was caused by ClO−, giving rise to a rati-
ometric PA signal (Figure 7E). Nevertheless, despite their great
potential in PA imaging, biodegradable contrast agents for use
in PA-imaging-guided PTT are rare. Although biodegradable
polymers such as polyamides and polyesters are readily avail-
able,[256] simply introducing these hydrolyzable units (esters,
carbonates, amides, etc.) into the SP backbone will inevitably
hinder the electron delocalization, thus affecting the optical
properties of the SPNs.[257] Recently, the same group designed
optically active polymer NPs with enhanced biodegradability
and elevated PTT capability by integrating a vinylene bond into
the SP backbone.[257] In this design, a biodegradable semicon-
ducting polymer, poly{2,2′-[(2,5-bis(2-hexyldecyl)-3,6-dioxo-
2,3,5,6-tetrahydropyrrolo[3,4-c]pyrrole-1,4-diyl)-dithiophene]-
5,5′-diyl-alt-vinylene} (DPPV), was synthesized and converted
to water-soluble NPs (SPNV) by combining the enzyme oxida-
tion of the ethylene bonds with polymer chemistry (Figure 7F).
Compared with its counterpart, SPN without any vinylene
bonds (SPNT), the presence of a vinylene bond in the SPNV
backbone significantly improved the mass absorption coef-
ficient (1.3-fold) and photothermal conversion efficiency
(2.4-fold). In addition, SPNs can decompose into small fragments
in a biological environment rich in oxide species (Figure 7G),
leading to their efficient degradation.
4. Nonlinear PA-Imaging Contrast Agents
The abovementioned studies refer to linear PA imaging; in
recent years, the application of multiple laser-pulse irradia-
tion to achieve nonlinear signal enhancement has attracted
increasing research interest. Nonlinear PA imaging involves
continuous excitation of biological tissue by employing a dual-
pulse laser with a short time delay,[258] which can provide even
more significant contrast and resolution than the commonly
studied linear PA imaging by reversibly switching the absorp-
tion property,[259] or enhancing the thermally related Gru-
neisen parameter (thermal expansion coefficient).[260–266] Some
preliminary work about the contrast agents for nonlinear PA
imaging has been reported recently.[267,268] For example, Gao
et al. designed a contrast agent including two NIR dyes of
IR-820 and IR-825 for nonlinear PA imaging.[267] Zheng and
co-workers reported a contrast agent of zinc-tetra(4-pyridyl)-
porphyrin-encapsulated AuNRs for both nonlinear and linear
PA-imaging contrast enhancement.[268] Compared with linear
PA imaging, the nonlinear PA imaging showed about 12-fold
contrast improvements in vitro and 4-fold in vivo.
5. Biomedical Applications
In recent years, PA imaging has been increasingly used in
the biomedical field. PA imaging can effectively image the
structure and function of biological tissue, providing essential
information to study its morphological structure, physio logical
characteristics, pathological characteristics, and metabolic func-
tion, especially suitable in the early sensing and treatment
of cancer. Currently, PA imaging is utilized to bioimaging of
lymph nodes, vasculature, tumors, and brain function. In par-
allel to bioimaging, PA imaging is employed in the biosensing
of metal ions, pH, ROS/RNS generation in vivo, enzymes, tem-
perature, and blood oxygen-content detection.
5.1. Sensing of Metal Ions
PA imaging has been researched for sensing of heavy-metal
ions, including copper (Cu2+),[269] methylmercury (MeHg+),[204]
mercury(II),[270] calcium (Ca2+),[271,272] lithium (Li+),[273] and
silver (Ag+).[99] For example, Chan and co-workers developed
two acoustogenic PA probes (APC-1 and APC-2) for the sensing
of Cu2+.[269] The APCs contain a Cu2+-responsive 2-picolinic
ester unit, which coordinates Cu2+ and induces ester-bond
hydrolysis. APC-2 shows two absorption peaks, at 767 and
697 nm; in the absence of Cu2+, the 2-picolinic ester unit
remains unchanged and the signal at 697 nm is stronger than
that of at 767 nm, leading to small PA767nm to PA697nm inten-
sity ratio. Following hydrolysis in the presence of Cu2+, the
absorption peak at 697 nm will reduce in intensity, while that at
767 nm will be enhanced; thus, the resulting PA767nm/PA697nm
intensity ratio will be increased (Figure 8A). Normalization of
the PA767nm to PA697nm led to a ratiometric PA turn-on response
of 100.5 and 91.3 times for 10 and 1 equivalent of Cu2+, respec-
tively (Figure 8B).
MeHg+ is a powerful neurotoxin, damaging the human
nervous system and brain. Therefore, there is a need to develop
an efficient approach for MeHg+ sensing. Huang and co-
workers designed a PA contrast agent (LP-hCy7) for MeHg+
sensing (Figure 6E).[204] In the presence of MeHg+, the MeHg+-
responsive NIR cyanine dye hCy7 is converted to hCy7′, and the
absorbance signals of the contrast agent at 860 and 690 nm are
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enhanced and reduced, respectively, leading to an increase in
the ratiometric PA intensity. The absorption signals of LP-hCy7
at 860 and 690 nm were directly and inversely proportional to
the amount of MeHg+, respectively, with the ratiometric PA
intensity (PA860 to PA690) being significantly enhanced in
the presence of MeHg+ (Figure 8C,D). Therefore, LP-hCy7 can
be used to monitor the presence of MeHg+ by ratiometric PA
imaging.
Ca2+ affects almost all aspects of cellular life and it is
therefore of major importance to accurately sense Ca2+ sig-
nals. Recently, Westmeyer and co-workers developed a cell-
permeable, highly selective, and sensitive PA imaging probe to
sense Ca2+ content.[271] Using this probe, micromolar concentra-
tions of Ca2+ led to a major blueshift in absorbance, causing a
decrease in PA intensity. Cash et al. designed a PA sensor con-
sisting of a lithium ionophore,[273] where a Li+-selective crown
ether ionophore and a chromoionophore were used to analyze
Li+ concentrations in vivo.
Bimetallic nanoagents combine the inherent properties of
monometallic elements, as well as exhibiting unique proper-
ties superior to those of corresponding monometallic nanoag-
ents, thus providing a platform for the development of contrast
agents with excellent selectivity, sensitivity, and stability. Ag+ is
a well-known antibacterial agent, and AgNPs can serve as a res-
ervoir of Ag+ for the targeted treatment of bacterial infections.
Kim et al. developed Au/Ag hybrid NPs through the coating
of AuNRs with Ag (Au/AgNRs).[99] The Au/AgNRs were inert
under ambient conditions, yet upon the addition of a ferricya-
nide solution, the Ag shell was oxidatively etched and Ag+ was
released, thus recovering the PA contrast. Simultaneously, the
PA signal provided noninvasive monitoring of the localized
release of Ag+, with the PA signal switching on and off with
the Ag deposition and oxidation cycle on AuNRs (Figure 8E).
Furthermore, the released Ag+ showed an intense bactericidal
efficacy in vivo. Moreover, the PA signal in mice treated with
Au/AgNRs with successive addition of Ag etchant was signifi-
cantly enhanced (Figure 8F,G). The recovered PA signal sug-
gested the localized release of Ag from Au/AgNRs and could
potentially offer further critical feedback on infection diagnosis.
5.2. pH Sensing
The regulation of pH plays a major role in managing homeo-
stasis processes in mammalian tissues. Moreover, the charge
state of macromolecules and proteins is also closely related
to the pH, and pH variations will induce a series of patholo-
gies, including inflammation, chronic cancer, ischemia, renal
disease, and intrauterine disorders.[274–276] Therefore, pH
sensing has practical significance in the design of biocompat-
ible contrast agents to noninvasively monitor the acidity of
the cancer microenvironment for better disease treatment and
prognosis. Previous studies have reported preliminary pH-
sensing methods using PA imaging.[222,277–286] For example,
Liu and co-workers successfully fabricated an albumin-based
contrast agent composed of a pH-sensitive dye, BPOx, and a
pH-inert NIR dye, IR825, for real-time ratiometric PA imaging
of tumor pH (C-HAS-BOPx-IR825) (Figure 6F).[222] When the
pH was lowered, the PA signal intensity at 680 nm was shown to
increase significantly, yet, at 825 nm there was negligible change,
thus providing a ratiometric PA imaging probe. The same
group subsequently designed an albumin–croconine dye contrast
Adv. Mater. 2019, 31, 1805875
Figure 8. A) Schematic illustration of the ratiometric PA sensing of Cu2+. B) Ratiometric PA signal of APC-2 treated with Cu2+ for 90 min. C) Absorb-
ance intensity of LP-hCy7 following reaction with different concentrations of MeHg+. D) Ratios of PA860/PA690. E) Schematic illustration of AuNRs, Au/
AgNRs, and etched Au/AgNRs. F) In vivo PA imaging of the Au/AgNRs after and before Ag etching. G) PA spectrum of tissue, implanted Au/AgNRs,
and Au/AgNRs after Ag etching. (A,B) Reproduced with permission.[269] Copyright 2015, American Chemical Society. (C,D) Reproduced with permis-
sion.[204] Copyright 2017, Wiley-VCH. (E,G) Reproduced with permission.[99] Copyright 2018, American Chemical Society.
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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agent for PA imaging of tumor pH.[277] In the another study,
Pu and co-workers developed a smart PA nanoprobe (SONs)
consisting of an inert PA matrix with a SO and a pH-indicating
boron-dipyrromethene (BODIPY) dye.[278] The BODIPY dye,
which contains hydroxyl groups, underwent an efficient proto-
nation–deprotonation process in the acidic tumor environment,
thus changing the absorption intensity and PA intensity of the
SONs at 750 nm. Following a decrease in pH, the PA inten-
sity at 750 nm was considerably reduced, and that at 680 nm
remained intact (Figure 9A). Therefore, the PA signal ratio
(PA680nm/PA750nm) can be used to sense pH in vivo. In a HeLa
tumor model, the PA ratiometric intensity of SON remarkably
increased at 6 h postinjection compared to that before treat-
ment (Figure 9B).
Because of the intrinsic background of biological tissues,
none of the abovementioned studies have demonstrated quan-
titative pH sensing of cancer in vivo. Lee et al. designed a
quad-wavelength PA-imaging strategy to address this issue[276]
(Figure 9C). Thus, the dual-wavelength ratiometric PA imaging
results showed that the concentrations of SNARF-PAAm NPs
and hemoglobin have a great influence on the detection of
pH, and therefore the ratio of the dual-laser wavelengths is not
sufficient for pH quantification. A so-called “quad-wavelength
ratiometric PA imaging method,” which is independent of
blood and SNARF-PAAm NP concentration, was proposed to
overcome the limitations of dual-wavelength ratiometric PA
imaging (Figure 9D), with pH sensing remaining undisturbed
by blood and SNARF-PAA NP concentration (Figure 9E). In
vivo tumor experiments using quad-wavelength ratiometric
PA imaging showed that pH levels can be quantitatively moni-
tored, with the largest ratio emerging at 75 min postinjection
(Figure 9F). Furthermore, the pH at the peripheral region
(6.97) was higher than that in center of the tumor (pH 6.72),
consistent with the pathological tumor mechanism (Figure 9G).
5.3. Sensing of ROS
ROS, including superoxide (O2˙−), hydrogen peroxide (H2O2),
peroxyl radical (ROO˙), hydroxyl (HO˙), singlet oxygen (1O2),
hypochlorous acid/hypochlorite (HOCl/−OCl), and so on, are
generated by either exogenous or endogenous sources (mito-
chondria, inflammation, metabolic process, etc.)[287,288] and
play a major role in managing many biological phenomena.[289]
A high concentration of ROS is closely related to various
pathological environments, including angiocardiopathy,[290]
Adv. Mater. 2019, 31, 1805875
Figure 9. A) Proposed mechanism of doping-induced photoacoustic (PA) enhancement and pH sensing. B) Ratiometric PA images (ΔPA680/ΔPA750)
of HeLa tumor before and 6 h after injection of a semiconducting oligomer nanoprobe. C) Absorption spectrum of SNARF-PAA nanoparticles (NPs)
of different pH, deoxygenated hemoglobin (Hb), and oxygenated hemoglobin (HbO2). D) Measured ratiometric PA intensity of 576 nm/565 nm,
584 nm/565 nm, and 600 nm/565 nm at different pH values. E) Quantitative pH images of SNARF-PAA NPs of different concentrations at different pH
values. F) Quantitative PA images for pH of SNARF-PAA NPs postinjection. G) A close-up PA image of tumor pH shown in (F) (75 min). (A,B) Repro-
duced with permission.[278] Copyright 2016, Wiley-VCH. (C-G) Reproduced with permission.[276] Copyright 2017, Springer Nature Limited.
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atheromatosis,[291] pneumopathy,[292,293] arthronosos,[294,295]
neurodegeneration,[296] and tumors or cancer.[297] Therefore,
real-time PA imaging of ROS in vivo can offer essential infor-
mation for the diagnosis and treatment of these diseases. Rao
and co-workers developed a ratiometric PA probe consisting of
poly(cyclopentadithiophene-alt-benzothiadiazole), with absorp-
tion at 700 nm, and a cyanine dye IR775S, with absorption at
820 and 735 nm, for the effective sensing of ROS in vivo.[238]
IR775S was rapidly decomposed by ONOO− and ClO−, leading
to a sharp decline in the peak at 820 nm while that at 700 nm
remained intact; thus, the probe detected ROS levels by ratio-
metric (PA700nm/PA820nm) PA imaging. ClO− levels are related
to various diseases and cancer; therefore, Pu and co-workers[255]
similarly designed a smart PA imaging probe for the in vivo
sensing of ClO− (Figure 7D). The contrast agent has two sepa-
rated absorption peaks at 780 and 680 nm, and the PA signal
intensity at 780 nm unchanged while that at 680 nm was gradu-
ally reduced by the addition of ClO− (Figure 7E). Thus, the ClO−
level could be sensed through the variation of ratiometric PA
intensity (PA780nm/PA680nm).
H2O2 is a vital species in many physiological processes, such
as immune response, cell growth, and senescence, as well as
in diseases that lead to an imbalance in H2O2.[298–301] There-
fore, the sensitive and precise sensing of H2O2 is of remarkable
clinical significance not only for cancer treatment but also
for the better understanding of pathogeny. Recently, Liu and
co-workers developed a H2O2-responsive contrast agent, called
Lip@HRP&ABTS, by simultaneously integrating horseradish
peroxidase (HRP) and 2,2′-azino-bis(3-ethylbenzothiazoline-
6-sulfonic acid) (ABTS) into the liposomal NPs. ABTS reacts
with H2O2 to generate its green, showing strong NIR absorb-
ance (Figure 10A).[302] In vitro experiments showed Lipo@
HRP&ABTS to be highly specific and sensitive to H2O2
(Figure 10B). An in vivo inflammatory disease and bacterial
infection model assay proved that Lipo@HRP&ABTS success-
fully detected H2O2 levels in vivo by PA imaging (Figure 10C).
More importantly, Lipo@HRP&ABTS was also sensitive to the
endogenous H2O2 response in the tumor microenvironment.
In vivo PA imaging in an LN metastasis model, tumor model,
and orthotopic brain glioma model (Figure 10D) was used to
specifically image the tumor region according to the difference
in H2O2 content by the Lipo@HRP&ABTS probe.
More recently, Chen and co-workers designed a PDI-based
contrast agent (PDI-IR790s-Fe/Pt) with two absorption peaks at
790 and 680 nm, through a self-assembly approach.[230] In the
tumor microenvironment, cisplatin was shown to be released
in the presence of reductase, inducing the transformation of
oxygen to superoxide free radicals, and resulting in the genera-
tion of H2O2 (Figure 10E). Fe3+ further catalyzed H2O2 to pro-
duce •OH based on the Fenton reaction. With increasing •OH
content, the absorption intensity at 680 nm was stable; however,
that at 790 nm gradually declined (Figure 10F), thus showing
that the PDI-IR790s-Fe/Pt can function as a ratiometric PA-
imaging contrast agent to sense ROS levels. Furthermore, in
vivo tumor ratiometric PA imaging experiments showed that
the PA signal intensity at 680 nm was enhanced; however, the
peak at 790 nm remained practically unchanged (Figure 10G).
The corresponding ratiometric PA signals (ΔPA680/ΔPA790) in
the tumor were quantitatively calculated (Figure 10H), showing
that PDI-IR790s-Fe/Pt NPs function as an excellent ratiometric
PA contrast agent to visualize ROS in vivo.
5.4. Sensing of RNS
RNS, including nitric oxide (NO) and its higher oxides, such as
nitrogen dioxide radicals (NO2
•), peroxynitrite (ONOO−), and
nitrate (NO3−), are another type of oxidative stress-related species
to cell signaling during multifarious pathological and physiolog-
ical processes.[288,303] ONOO− leads to the damage of various bio-
molecules, including proteins, lipids, DNA, carbohydrates, and
thiols, by facilitating oxidation reactions; as a result, it leads to
various pathological diseases, such as inflammation and cancer,
as well as cardiovascular and neurodegenerative diseases.[288]
The real-time sensing of ONOO− in tumors is important for the
study of the tumor etiology and select treatment methods.[304,305]
Pu and co-workers designed a smart PA contrast agent with
strong selective sensing of ONOO− and enhanced pH inert-
ness, which was applied to visualize and monitor ONOO− levels
in tumors of living mice via ratiometric PA imaging.[246] More
recently, Chan and co-workers designed a set of acoustogenic
probes for nitric oxide, termed APNOs, to sense NO in vivo[306]
(Figure 11A). APNO-5 was shown to have the best performance,
with a high stability, outstanding selectivity, excellent biocompat-
ibility, and specific response to NO. APNO-5, with a maxi mum
absorption band at 764 nm, was shown to react rapidly with
NO to produce N-nitroso products (tAPNO-5), which have an
absorption peak at 673 nm (Figure 11B,C). About 18.6-fold
higher ratiometric PA signal response was observed when
APNO-5 and tAPNO-5 were selectively illuminated by a laser at
770 and 680 nm, respectively (Figure 11D). When APNO-5 was
converted to tAPNO-5, the PA intensity at 680 nm was enhanced
whereas that at 770 nm was reduced (Figure 11E). Furthermore,
APNO-5 was used in the detection of NO in an inflammation
model (Figure 11F), with clear accumulation of the contrast
agent being observed at the injection site. Compared to the
saline control experiment, the PA was enhanced by 1.9-fold at
680 nm, and the PA680nm/PA770nm ratiometric turn-on response
relative increased by 1.3 times, respectively (Figure 11G).
Recently, Chan and co-workers designed NIR photo activatable
NO donors that employed a direct PA readout to endow non-
invasive sensing of analyte release.[307]
5.5. Sensing of Enzymes
Abnormal enzyme activity and the pathology of various diseases
are strongly intertwined. Due to the major role of enzymes in
many biological and physiological processes, the precise sensing
of enzyme activity has been a focus of attention in recent
years.[144,308–311] For example, Liu and co-workers designed a
smart PA contrast agent (CPQ) for the sensing of cancer-related
matrix metalloproteinases (MMPs).[144] CPQ has two specific
absorption peaks at 930 and 680 nm, corresponding to absorb-
ance of CuS and BHQ3, respectively. In the tumor microen-
vironment in which MMPs exist, MMP-sensitive peptides are
cut and BHQ3 is released from CuS NPs. The former is rapidly
removed from the tumor as a small molecule, while the latter
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remains in the tumor. Therefore, the PA intensity at 680 nm
will be swiftly decreased, while that at 930 nm will remain intact
(Figure 12A). In vivo detection of MMPs using PA imaging
showed no obvious change in PA intensity at 680 nm during the
first 2 h, while a dramatic decrease was observed at 6 and 24 h
after the CPQ contrast agent was injected due to the time-lag in
the MMP-induced cleavage of CPQ and the removal of released
BHQ3 from the tumor. However, the PA intensity at both
Adv. Mater. 2019, 31, 1805875
Figure 10. A) Proposed mechanism of the preparation and application of Lipo@HRP&ABTS. B) Absorbance of Lipo@HRP&ABTS or Lipo&ABTS
at 800 nm after incubation with different kinds of reactive oxygen species (ROS). C) Photoacoustic (PA) signals of mouse inflammation model with
injection of different contrast agents. D) In vivo PA images of tumor-bearing mice. E) Schematic illustration of PDI-based nanoprobes and generation
process of ROS in vivo as well as their ratiometric PA imaging. F) UV–vis spectra of PDI-IR790s NPs with increasing •OH concentration. G) PA images
of U87MG tumor of PDI-IR790s-Fe/Pt NPs postinjection. H) The ratiometric PA intensity in the tumor at different time points post PDI-IR790s-Fe/Pt
NP injection. (A–D) Reproduced with permission.[302] Copyright 2017, National Academy of Sciences. (E–H) Reproduced with permission.[230] Copyright
2018, Wiley-VCH.
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930 and 680 nm remained largely unchanged when employing
MMP inhibitor-III, which inhibits MMP enzyme activity in
vivo (Figure 12B). In addition, the PA signal ratio results were
consistent with the imaging results (Figure 12C). The above phe-
nomenon proves that the CPQ contrast agent can be employed
to sense MMP enzyme activity by PA imaging. In another
study, Gambhir and co-workers reported a furan-sensitive
oligomerizable PA contrast agent, which was accumulated at
the target site of enzyme activity during proteolysis and pro-
vided a responsive PA signal.[310] Thus, the PA imaging tech-
nique can be used to sense the activity of furfural and furan-like
enzymes in cells and tumors. Recently, Lu and co-workers
developed a DNA-aptamer-based PA-imaging contrast agent
with a DNA chain and an NIR fluorophore/quencher pair with
a contact-quenching effect.[311] Contact quenching was inhibited
when binding of thrombin induced the release of DNA strands
with the quenching agent, thus changing the PA signal ratio of
780 nm/725 nm (Figure 12D). For in vitro assay upon thrombin
being injected into serum, the PA intensity at 725 nm was
shown to gradually decline, while that at 780 nm only changed
slightly with the increase in thrombin concentration; thus, the
PA780nm/PA725nm ratio also increased (Figure 12E), suggesting
that the PA contrast agent could be employed in complex body
fluids. In an in vivo experiment in living mice, the PA intensities
at 725 and 780 nm were remarkably enhanced after injection of
the DNA-based contrast agent. Due to the dissociation of the
DNA-aptamer-based PA contrast agent following activation by
thrombin, the PA signal of thrombin-treated mice at 725 nm
was much weaker than that of mice treated with phosphate
buffered saline (PBS) at 45 min postinjection (Figure 12F,G);
in addition, the PA780nm/PA725nm ratio of untreated and PBS-
treated mice was lower than that of thrombin-treated mice. The
above results suggest that exogenous thrombin could activate
the DNA-aptamer-based PA contrast agent in living mice, indi-
cating its potential for advanced biomedical imaging in vivo.
5.6. Sensing of Temperature
The delivery of contrast agents can be directly observed by
PA imaging while visualizing the temperature distribu-
tion in vivo, thereby guiding and confirming the therapeutic
effect of NP-mediated PTT.[312] Furthermore, the PA signal
varies with change in temperature, yet techniques for the
sensitive and quantitative measurement of temperature vari-
ation remain to be developed. For instance, Zheng and co-
workers studied a stimuli-responsive PA contrast agent
with J-aggregating NPs (JNPs) consisting of dipalmitoyl-
phosphatidylcholine, 1,2-dipalmitoyl-sn-glycero-3-phos-
phoethanolamine-N-[methoxy(polyethyleneglycol)-2000],
Adv. Mater. 2019, 31, 1805875
Figure 11. A) Chemical structural formula of acoustogenic probe(s) for nitric oxide (APNO) (red) and corresponding product upon selective illumina-
tion of APNO (tAPNO) (blue), as well as their schematic illustration for sensing mechanisms. B) Absorbance spectra of APNO and tAPNO. C) APNO-5
fluorescence turn-on after 1 h treatment with various metal ions (red), carbonyl (green), ROS (blue), or RNS (purple) species. D,E) Photoacoustic (PA)
spectra and PA images of APNO-5 and tAPNO-5. F) PA images for APNO-5 in a murine lipopolysaccharide-induced inflammation model with endog-
enous NO and saline treatment. G) Ratiometric imaging (PA680/PA770) responding to endogenously produced NO in a murine lipopolysaccharide-
induced inflammation model. (A–G) Reproduced with permission.[306] Copyright 2018, American Chemical Society.
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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and Bchl-lipid (bacteriopheophorbide a-lipid), which were
employed to sense the variation of temperature.[313] The color
of the sample varied from dark brown to bright pink, with a
decrease in absorption of the contrast agent at 824 nm and an
increase at 750 nm with increasing temperature (Figure 13A).
The repeated heating–cooling cycles gave rise to an analogous
periodic variation of PA signals, suggesting that the temper-
ature-sensing ability is reversible on heating–cooling cycles
(Figure 13B). Based on the thermochromic characteristics of
the above system, the contrast agent was successfully employed
to noninvasively sense localized temperature variation in vivo
and to monitor the thermal treatment of tumors (Figure 13C).
Emelianov and co-workers designed NP-loaded poly(n-
isopropylacrylamide) (PNIPAM) nanogels to fabricate two
stimuli-responsive PA contrast agents, namely PNIPAM-AuNR
(Figure 13D) and PNIPAM-CuS respectively.[314] The diameter
of PNIPAM is known to decrease rapidly with the temperature
surpassing its critical temperature (32 °C) and to expand and
recover its initial diameter with a subsequent decrease in tem-
perature. This occurs due to the reversible phase transition of
the hydrophobic structure of PNIPAM chain (Figure 13E). The
PA signal of PNIPAM-CuS increased significantly with the rise
in temperature, and PA signal of PNIPAM-CuS was higher than
that of pure CuS (Figure 13F). Furthermore, the CuS instantly
heated the PNIPAM cage when a continuous-wave (CW) laser
was switched on, resulting in a significant increase in the PA
signal in the PNIPAM-CuS region, with a periodic repeated
increasing pattern upon laser irradiation or lack thereof
(Figure 13G). The PA signal was correspondingly observed to
increase over the first 30 s of laser irradiation (Figure 13H),
while PA signal decreased over the following 30 s during which
the laser radiation was turned off. In a subsequent experiment,
Adv. Mater. 2019, 31, 1805875
Figure 12. A) Proposed mechanism of the matrix metalloproteinases (MMPs) activating CuS-peptide-BHQ3 (CPQ) contrast agent. B) Photoacoustic
(PA) imaging of tumors in mice in vivo. C) Ratiometric PA signal of the CPQ and CPQ+MMPI-III groups. D) Schematic illustration of PA imaging of
functional DNA probes. E) PA imaging of thrombin and corresponding PA ratios. F) PA images of mice before and after injection with the probes and
phosphate buffered saline controls. G) PA images of mice before and after injection of the probes with thrombin. (A–C) Reproduced with permis-
sion.[144] Copyright 2014, Ivyspring. (D–G) Reproduced with permission.[311] Copyright 2017, American Chemical Society.
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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the contrast agent poly(n-isopropylacrylamide-acrylamide)-
AuNR (PNIPAM-AM-AuNR), which has a higher critical tem-
perature than the normal physiological temperature of mice,
was employed to perform in vivo imaging. The vast majority
of PNIPAM-AM-AuNR was removed from the blood vessels
(Figure 13I) and accumulated in the tumor at 24 h postinjec-
tion. Comparing the PA images of the CW laser off and on,
an enhancement of the PA signal was recorded only in the
tumor region where PNIPAM-AM-AuNR was accumulated
(Figure 13J,K). Furthermore, the PNIPAM-AM-AuNR contrast
Adv. Mater. 2019, 31, 1805875
Figure 13. A) Color photographs and phase transition of J-aggregating NPs with change of temperature. B) Variation of photoacoustic (PA) signal
at 824 and 750 nm according to change in temperature. C) PA images of J-aggregating NP in tumors postinjection. D) Schematic illustration of the
preparation of PNIPAM-AuNR. E) The diameters of PNIPAM above and below the critical temperature. F) PA intensity of the region with PNIPAM-CuS
or CuS with the continuous-wave (CW) laser off or on. G) PA intensity following multicycles of CW laser off and on. H) PA signals recorded in a full
cycle. I) Ultrasound image of a tumor. J) PA intensity of the tumor at 24 h postinjection. K) The PA intensity of tumor and blood vessels with the CW
laser on. L) Dynamic contrast-enhanced PA image of PNIPAM-AM-AuNR. (A–C) Reproduced with permission.[313] Copyright 2014, American Chemical
Society. (D–L) Reproduced with permission.[314] Copyright 2017, Springer Nature Limited.
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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agent showed an over fivefold PA contrast enhancement in
vivo when employing dynamic-contrast-enhanced PA imaging
(Figure 13L).[314] Dynamic-contrast-enhanced PA imaging is a
new imaging processing approach able to suppress background
signals to further improve PA contrast.
5.7. Sensing of Hypoxia
A lack of oxygen supply leads to hypoxia, which damages
physiological function and is the pathological feature of many
diseases, including cancer and ischemia.[315–318] Therefore,
sensing of hypoxia could guide the therapeutic regimen and
could be used as a predictor of patient prognosis.[319–322] Chan
and co-workers developed a hypoxia-responsive PA-imaging
contrast agent with a N-oxide trigger (HyP-1), which can be
reduced in conditions without oxygen, while the reduction of
Hyp-1 (absorption at 670 nm) produces a different spectral
product (Red-Hyp-1; absorption at 760 nm) easily identified
by PA imaging (Figure 14A).[319] HyP-1 has a high selectivity
for hypoxic activation in vivo. For in vitro tests, the PA inten-
sity under hypoxic condition was shown to be fourfold higher
Adv. Mater. 2019, 31, 1805875
Figure 14. A) Chemical structural formula of HyP-1 and red-HyP-1 and sensing mechanism for hypoxia. B) PA intensity of hypoxic or normoxic condi-
tions. C) PA images at 770 nm of the control and tumor-bearing mice before and after injection of HyP-1. D) Time-dependent enhancement of PA
intensity of control and tumor-bearing mice. E) Time-dependent enhancement of PA intensity of control and ischemic limbs. F) Sensing mechanism
of rHyPs for hypoxia. G) PA images of rHyP-1 solutions after incubation at hypoxic and normoxic conditions. H) 3D reconstruction (left) of a 4T1
tumor with rHyP-1 postinjection, and depth distribution shown in 2D maximum intensity projections (right). I) Ratiometric PA intensity of rHyP-1 corresponding
to (H). (A–E) Reproduced with permission.[319] Copyright 2017, Springer Nature Limited. (F–I) Reproduced with permission.[320] Copyright 2018,
American Chemical Society.
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than that under normoxic conditions when irradiated using
a 770 nm laser (Figure 14B). For in vivo tests, the PA signal
of the hypoxic tumor region increased gradually and reached
maximum at 3 h when the Red-Hyp-1 is highly accumulated;
conversely, no obvious increase was observed in the control
group (Figure 14C,D). In addition, the PA signal from the
ischemic increased by 3.1 times over that of the control group
(Figure 14E), suggesting that the HyP-1 contrast agent can be
employed in hypoxia sensing in multiple disease models. On
this basis, Knox et al. developed a hypoxia-responsive contrast
agent, rHyP-1, with a high and low PA signal ratio for hypoxia
and normoxia, respectively (Figure 14F).[320] In vitro PA imaging
experiments of rHyP-1 showed the PA820nm/PA770nm ratio of
the hypoxic condition to be 2-fold that under normoxic condi-
tion (Figure 14G). Significantly, the rHyP-1 PA contrast agent
not only can sense hypoxia within the intratumor, but also can
estimate the area of contrast agent activation in tumors. Fur-
thermore, in an in vivo tumor model, the largest hypoxic region
and location of rHyP-1 activation was determined through
3D reconstruction ratiometric PA imaging (Figure 14H,I). In
addition, the sensing of H2S[323,324] and protein interactions
in vivo[325] could also be performed through PA imaging.
5.8. Imaging of LNs
Metastases, rather than the primary tumor, the cause of most
cancer patients, with cancer cells often damaging local LNs
before metastasizing to other organs.[326] Therefore, imaging
of LNs is an essential technique to study tumor staging and
prognosis. To date, PA-imaging technology has been widely
employed in real-time LN mapping.[89,126,327–331] In 2013,
Emelianov and co-workers[89] developed silica-coated Au nano-
plates (SPNs) as a PA contrast agent for sentinel LN (SLN)
imaging. The SPNs exhibited a strong, persistent PA signal that
could be rapidly transferred to the SLN and gradually spread
throughout most nodes. Later, Pu et al. used a stable contrast
agent, SPN1, to map the LNs in mice.[238] Briefly, after SPN1
was injected intravenously into healthy mice for 24 h, an
amplified PA signal was observed in the brachial, inguinal,
and superficial cervical LNs. In the another study, Liu and
o-workers designed a type of conjugated-oligomer-based NPs
(N4) as a PA-imaging contrast agent for the real-time imaging
of the SLN.[330] In vivo experiments by injecting an N4 contrast
agent into the left forepaw pad of mouse showed a negligible
PA contrast in the SLN prior to injection (Figure 15A), with
a maximum signal at 10 min postinjection (Figure 15B), fol-
lowed by a gradual decline at 20 min postinjection (Figure 15C)
and still detectable at 90 min postinjection (Figure 15D). The
3D PA SLN imaging corresponding to the different time
points (Figure 15E,F) showed the same results. These results
suggested that the N4 contrast agent possessed the merits of
excellent biocompatibility, photostability, and rapid body clear-
ance, therefore, inhibiting cancer metastasis at SLNs through
PA-imaging-guided PTT. Recently, Emelianov and co-workers
combined CuS NPs and laser-activated perfluorocarbon nano-
droplets as a contrast agent in the NIR absorption window at
1064 nm for hyperpermeable LN vasculature imaging by both
PA and US.[142] The CuS NPs were used as a photoabsorber
to initiate the vaporization of perfluorocarbon nanodroplets,
leading to phase-change and a subsequent enhanced PA signal,
generating a gaseous perfluorocarbon microbubble to increase
the US contrast signal (Figure 15G). In another example, Chen
and co-workers studied the size-dependent PA imaging of
lymphatic system after local administration of PDI NPs, con-
cluding that NPs of 100 nm in size led to the best distinction
in sciatic LNs from popliteal LNs (Figure 15H),[210] because
it takes ≈1 h for the NPs of 100 nm in size to migrate from
popliteal LNs to sciatic LNs; the 1 h interval is long enough for
surgeons to make pathological analysis and to determine the
following surgery.
5.9. Imaging of Vasculature In Vitro and In Vivo
PA imaging has also been employed to evaluate the treatment
efficacy of vasculature-related diseases such as atherosclerosis
and thrombus.[207,332–341] For example, Fan and co-workers
prepared cRGD-PDI NPs that bind glycoprotein IIb/IIIa
(GPIIb/IIIa), which can specifically highlight early thrombus
by PA imaging. The PA signal was shown to be enhanced in
early thrombus, which expresses a high level of GPIIb/IIIa,
but not in older thrombus, with a low level of GPIIb/IIIa
(Figure 16A–C). In addition, the effects of thrombolysis could
be monitored in real time using cRGD-PDI NPs. PA imaging
showed an irregular margin in the vessel surrounding the high-
lighted thrombus; however, when the thrombolytic agent was
injected, the margin was gradually smoothed out and eventually
regained the appearance of a normal vessel (Figure 16C). Lee
and co-workers reported a PA contrast agent and theranostic
nanoagent (T-FBM) offering an enhanced PA signal via H2O2-
triggered CO2-bubble production that is suitable in the treat-
ment of H2O2-associated vascular diseases through the release
of anti-inflammatory agents and antioxidants (Figure 16D).[339]
In an in vivo mouse model of FeCl3-induced arterial throm-
bosis (Figure 16E), T-FBM NPs showed a stronger ratiometric
(thrombus/normal tissue) PA signal than that of the control
nanoagent T-FPLGA (Figure 16F,H), proving the good targeting
ability of T-FBM NPs to thrombus. More importantly, T-FBM
NPs reacted with endogenous H2O2, increasing the PA signals
of thrombus, without the end of external laser radiation.
5.10. Brain Imaging
PA imaging has also been widely used in brain
imaging.[129,206,342–349] For example, Sailor and co-workers devel-
oped an effective PA contrast agent, Ca-pSiNP-ICG, in which
ICG was encapsulated in porous silicon NPs via a calcium sili-
cate precipitation method for ex vivo mouse-brain imaging.[221]
Compared with the free ICG or PBS controls, which had
weak and nonexistent PA signals, respectively, the Ca-pSiNP-
ICG injected into the brain showed an enhanced PA signal
(Figure 17A). In another study, Nie and co-workers employed
modified Prussian blue NP-labeled bone mesenchymal stem
cells to monitor traumatic brain injury (TBI) and its rehabilita-
tion by PA imaging (Figure 17B).[350] Following craniocerebral
injury in mice, the process of natural recovery in the TBI region
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takes half a month (Figure 17C,D); interestingly, rehabilitation
time with intravenously injected bone mesenchymal stem
cells in mice was reduced to ≈5 d (Figure 17E). Furthermore,
the removal rate of blood clots without the stem cell injection
was ≈15 d, which was reduced to 160 h to return to normal
tissue levels following stem cell injection (Figure 17F). The
above pheno menon proved that PA imaging can be employed
not only observe brain damage and recovery but also to trace
stem cells within the pathological region. In recent years,
more examples have demonstrated the feasibility for brain PA
imaging.[351–354]
6. Conclusions and Outlook
PA-imaging technology has the advantages of safety, high reso-
lution, and real-time imaging, and can offer vital information on
biological tissue structure, function, meta bolism, and genetic
variation. Furthermore, it has been shown to have important
applications in various biomedical fields, including: (1) in-depth
study of cardiovascular disease, (2) drug monitoring, (3) tumor
imaging, (4) gene expression, (5) stem cells and immune
system, and (6) sensing and early diagnosis of disease.
PA contrast agents are signal contrast intensifiers and sig-
nificantly improve the PA-imaging ability and quality, including
resolution and contrast, through the alteration of the PA charac-
teristics of local tissue. Over the last few years, a variety of con-
trast agents have been explored for PA imaging. Here, we have
summarized and reviewed the various types of contrast agents,
including both inorganic and organic contrast agents, as well
as their applications in biomedicine. The use of PA imaging
and specific contrast agents in the biosensing of metal ions,
pH, ROS, RNS, enzymes, temperature, and hypoxia, as well as
in the bioimaging of tumor, LNs, vasculature, and brain func-
tion are also elaborated. Through the further development of
biomedicine and interventional therapies, the application of PA
contrast agents will become ever more extensive. To date, the
study of PA contrast agents focuses on two main aspects; first,
Figure 15. A) In vivo photoacoustic (PA) imaging of sentinel lymph nodes (SLN) before and B–D) after the injection of N4 contrast agent for 10, 20,
and 90 min. E,F) 3D PA images before and after injection of N4 contrast agent for 10 min. G) PA and ultrasound (US) images of the LN preinjec-
tion (top), postinjection, and upon starting illumination (middle) and terminal irradiation (bottom). H) The overlaid US and PA images that exhibit
size-dependent uptake in sciatic LNs (red arrows) and popliteal LNs (white arrows) at various time points postinjection. (A–F) Reproduced with
permission.[330] Copyright 2016, Wiley-VCH. (G) Reproduced with permission.[142] Copyright 2017, American Chemical Society. (H) Reproduced with
permission.[210] Copyright 2017, American Chemical Society.
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the modification of existing PA imaging materials by chemical
modification or their combination with other functionalized
materials to form new multifunctional systems, and second,
on the development of new and efficient PA contrast agents to
overcome the shortcomings of traditional contrast agents whilst
simultaneously achieving more efficient PA imaging.
Although there have been various reports focusing on PA
contrast agents in recent years, the study of contrast agents
remains at the laboratory stage. Although different types of con-
trast agent possess respective merits, most nanomaterials used
in PA imaging exhibit various issues, such as relatively poor
biocompatibility, the requirement of large doses of nanoagents,
poor targeting effect, suboptimal tissue biodistribution, lack
of proper evaluation of pharmacokinetics, and difficulty to
be accurately quantified, among others (Table 2). Therefore, there
remains a long path in the study of PA contrast agents. Future
Figure 16. A) Proposed mechanism of cRGD-PDI nanoparticles (NPs) to highlight early thrombus via PA imaging. B) Change of PA signal in the
thrombus of various experimental conditions with injection time. C) Differentiation between early and old thrombus and applications of monitoring
thrombolysis through PA imaging. D) Proposed mechanism of T-FBM nanoagent for thrombus-specific therapeutics. E) Schematic illustration of
carotid artery injury model treated with FeCl3 in a mouse model. F) Ratiometric PA intensity of thrombus/normal tissue at different time points.
G) Time course of carotid artery PA imaging. (A–C) Reproduced with permission.[229] Copyright 2017, American Chemical Society. (D–G) Reproduced
with permission.[339] Copyright 2018, American Chemical Society.
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Figure 17. A) Comparison of the effects of contrast agent on mouse brain photoacoustic (PA) imaging. B) Monitoring of in vivo brain injury by modified
Prussian-blue-labeled bone mesenchymal stem cells via PA imaging. C) PA imaging of mice brain at various time points postinjury. D) The area varia-
tion in blood clot in the injured region at different time points. E) Recovery process of mouse brains of different groups at various time points. F) The
change in blood clot area in the injured region as a function of time. (A) Reproduced with permission.[221] Copyright 2018, Wiley-VCH. (B–F) Reproduced
with permission.[350] Copyright 2018, Wiley-VCH.
Table 2. The merits and drawbacks of different types of PA-imaging contrast agents.
Classification Merits Drawbacks
Metallic nanomaterials Adjustable physiochemical and biochemical properties;
Carrying cargoes and good biocompatibility
Poor biodegradability;
Accurate control of size
Carbon-based nanomaterials Excellent photothermal stability;
Carrying cargoes
Poor biodegradability;
Difficult to remove from the body
Transition-metal chalcogenides/MXene-based
nanomaterials
Excellent photothermal stability;
High photothermal conversion efficiency and drug-loading
content
Poor biodegradability;
Need to do surface modification
Small organic molecules Good biocompatibility;
Low toxicity;
Fast clearance
Poor aqueous solubility;
Short circulation time in vivo
Semiconducting polymer nanoparticles Superb optical properties;
Large absorption coefficient;
High photostability;
Controllable size
Unbeknown biodegradation behaviors;
Poor aqueous solubility
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work should focus on the development of highly efficient,
stable, low-cost, functionalized, and novel contrast agents, con-
sidering the following two aspects: (1) optimization of optical
properties, including molar absorption coefficient and NIR
absorption wavelength, and (2) optimization of biological char-
acteristics, including immunogenicity, toxicity, and particle
size. Thus, the design and synthesis of biomaterials with excel-
lent optical and biological properties will become a focus of
attention in the field of bioimaging. Through extensive and sys-
tematic research in biomaterials, the structure and properties
of nanomaterials are now more deeply understood. With this
knowledge and the help of high-quality imaging techniques,
the PA-imaging technology and PA contrast agents will be rap-
idly developed and widely applied.
Acknowledgements
This work was supported by the National Natural Science Foundation
of China (Nos. U1505221, 21635002, 21874024, and 21475026), the
Program for Changjiang Scholars and Innovative Research Team
in University (No. IRT15R11), the Health-Education joint research
project of Fujian Province (No. KJ2016-2-23), Minjiang Scholars of
Fujian Province, and the Intramural Research Program (IRP) of the
NIBIB, NIH.
Conflict of Interest
The authors declare no conflict of interest.
Keywords
bioimaging, biomedical application, biosensing, contrast agents,
photoacoustic imaging
Received: September 10, 2018
Revised: October 10, 2018
Published online: December 17, 2018
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