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Communication J-aggregates of Cyanine Dye for NIR-II In-vivo
Dynamic Vascular Imaging Beyond 1500 nm
Caixia Sun, Benhao Li, Mengyao Zhao, Shangfeng Wang, Zuhai Lei, Lingfei Lu, Hongxin Zhang,
Lishuai Feng, Chaoran Dou, Dongrui Yin, Huixiong Xu, Yingsheng Cheng, and Fan Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b10043 • Publication Date (Web): 20 Nov 2019
Downloaded from pubs.acs.org on November 20, 2019
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J-aggregates of Cyanine Dye for NIR-II In-vivo Dynamic
Vascular Imaging Beyond 1500 nm
Caixia Sun†,#, Benhao Li†,#, Mengyao Zhao†, Shangfeng Wang†, Zuhai Lei†, Lingfei Lu†, Hongxin
Zhang†, Lishuai Feng‡, Chaoran Dou‡, Dongrui Yin†, Huixiong Xu§, Yingsheng Cheng‡, Fan Zhang*,†
†Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Shanghai Key Laboratory of
Molecular Catalysis and Innovative Materials and iChem, Fudan University, Shanghai 200433, P. R. China.
‡Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, P. R. China.
§Department of Medical Ultrasound, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai
200072, China.
Supporting Information Placeholder
ABSTRACT: Light in the second near-infrared window,
especially beyond 1500 nm, shows enhanced tissue transparency
for high-resolution in-vivo optical bio-imaging due to decreased
tissue scattering, absorption and auto-fluorescence. Despite some
inorganic luminescent nanoparticles have been developed to
improve the bio-imaging around 1500 nm, it is still a great
challenge to synthesize organic molecules with the absorption and
emission toward this region. Here, we present J-aggregates with
1360 nm absorption and 1370 nm emission formed by self-
assembly of amphiphilic cyanine dye FD-1080 and 1,2-
dimyristoyl-sn-glycero-3-phosphocholine. Molecular dynamics
simulations were further employed to illustrate the self-assembly
process. Superior spatial resolution and high signal-to-background
ratio of J-aggregates were demonstrated for non-invasive brain
and hindlimb vasculature bio-imaging beyond 1500 nm. The
efficacy evaluation of the clinically used hypotensor is
successfully achieved by high-resolution in-vivo dynamic vascular
imaging with J-aggregates.
Accurate biomedical imaging methods are crucial for diagnosis
and prognosis of diseases. Among them, fluorescence imaging
exhibits superior properties in terms of high sensitivity, high
temporal resolution and fast feedback, but is limited to low tissue
penetration depth.1-8 Recently, developments in fluorescence
imaging in the second near-infrared window (NIR-II; 1000-1700
nm) have received considerable attention due to the reduced bio-
tissue photon scattering, absorption and diminished auto-
fluorescence compared with visible to traditional first near-
infrared window regions.9-15 Especially, region beyond 1500 nm
provides the lowest photon scattering according to the Mie theory,
which presents that photon scattering in bio-tissue is in inverse
ratio of the wavelength λ (reduced scattering coefficient μs’∝λ-α,
α = 0.2-4 for different tissues).16 In addition, little tissue auto-
fluorescence induced by laser excitation could be detected beyond
1500 nm.17,18 Thus, region of 1500-1700 nm shows a promising
potential for bio-imaging, motivating the development of a series
of emitters, including rare-earth nanoparticles,19,20 single-walled
carbon nanotubes,21 and quantum dots,22 for resolving fine-scale
anatomical structures in-vivo. Owing to unknown long-term
cytotoxicity concerns of above inorganic nanomaterials, it is
necessary to design long wavelength organic fluorophores to
facilitate clinical translation.23-25 However, it is difficult to
synthesize organic molecules only by structure changing to extend
the absorption and emission beyond 1300 nm window.
J-aggregates are fascinating fluorescent probes formed by
highly ordered assembled organic dyes.26,27 The transition dipole
moments of individual molecules are slip-stacked alignment
(Figure S1).28 Photophysical properties of J-aggregates are
dramatically different from that of monomers, such as
bathochromic-shifted absorption/emission wavelengths, enhanced
absorption coefficients and small Stokes shift.29 J-aggregates have
played important role as sensors and materials for optoelectronic
devices,30 biomedical applications.31-34
Herein, we successfully developed a novel type of NIR-II probe,
FD-1080 J-aggregates, based on the self-assembly of FD-1080
cyanine dyes and 1,2-dimyristoyl-sn-glycero-3-phosphocholine
(DMPC) with absorption and emission beyond 1300 nm (Figure
1a). The FD-1080 J-aggregates exhibited high hydrophility and
stability in physiological conditions. Molecular dynamics
simulations were further employed to illustrate the interaction
between DMPC and FD-1080 during the formation process of J-
aggregates. The superior imaging ability beyond 1500 nm was
acquired both in-vitro and in-vivo. Furthermore, we performed
beyond 1500 nm optical imaging of FD-1080 J-aggregates to
monitor the in-vivo dynamic changing of carotid artery in
hypertensive rat after the administration of clinically used Isoket
hypotensor. This is a novel way to evaluate the efficacy of
hypotensor by monitoring the width of the carotid artery changing
in real time through NIR-II imaging.
FD-1080 cyanine dyes was synthesized by a four-step reaction
(Figure S2).35 FD-1080 J-aggregates were obtained by self-
assembly of FD-1080 and DMPC via film dispersion method.36
The maximal absorption and emission of FD-1080 J-aggregates
were 1360 nm and 1370 nm, respectively, which had
bathochromic-shifted about 300 nm compared to FD-1080
monomer (Figure 1b). Circular dichroic (CD) signal of J-
aggregates showed a negative Cotton effect at maxima of ~ 1360
nm, while no CD signal could be detected for monomer (Figure
1c). FD-1080 monomer emission decays mono-exponentially,
yielding a lifetime of 312 ps. The J-aggregates have shortened
fluorescence lifetimes of 172 ps (Figure 1d).
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Figure 1. a) The structure of FD-1080 and DMPC. b) Normalized
absorption (solid lines) and emission (dashed line) of FD-1080 monomer
and J-aggregates. c) CD spectra of monomer and J-aggregates. d)
Fluorescence decay profiles of monomer and J-aggregates. e) TEM
images, DLS results insert, molecular dynamics simulation (red frame)
and schematic diagram of J-aggregates. (The molar ratio of FD-1080 to
DMPC is 1:20)
Meanwhile, the J-aggregates showed high molar extinction
coefficients (εmax) of ~0.5×105 M-1cm-1, small Stokes shifts of 10
nm, and quantum yield of 0.0545% (Figure S3 and Table S1).
Transmission electron microscope (TEM) image showed the
uniform and monodispersed J-aggregates with the size of 110 ±
10 nm, which was consistent with the hydrodynamic diameters of
100 nm measured by dynamic light scattering (DLS) (Figure 1e,
Figure S4).
To explore the synthesis of J-aggregates, the polarity of solvent
was firstly adjusted. Methanol was chosen as the good solvent of
FD-1080 to ensure the monomer state. When the volume fraction
of water was progressively increased in the methanol/water
solution, the monomer absorption peak gradually decreased while
the H-aggregates absorption peak (820 nm) concomitantly
increased, suggesting that J-aggregates could not form only by
changing the polarity of solvent (Figure S5). The J-aggregation
absorption/emission peaks at 1360/1370 nm could be observed in
the presence of DMPC (Figure S6). Furthermore, to track the
formation process of the J-aggregates, we studied the morphology
with different molar ratio of FD-1080/DMPC. As shown in the
TEM images, there were not vesicular or tubular like bilayer
structures observed during the self-assembly of FD-1080 in the
presence of phospholipid. In fact, they tended to form
nanoparticles with various sizes (Figure S7). Then, we also
studied the optical spectra of solutions with FD-1080/DMPC
molar ratio from 1:2000 to 1:6.67. Absorption peaks at 1012 nm
(monomer) and 820 nm (H-aggregates) were observed with ratio
of 1:2000 and 1:1000. When the ratio reached 1:20, only a strong
absorption peak at 1360 nm could be detected, indicating J-
aggregates could be formed with the increase of dye content.
Meanwhile, with the increase of ratio from 1:2000 to 1:6.67, the
fluorescence intensity of the monomer at 1080 nm was decreased,
while that of J-aggregates at 1370 nm was enhanced gradually ，
and the fluorescence intensity at ratio of 1:20 reached its peak
value (Figure S8). These results illustrated that DMPC played an
essential role in the formation process of the J-aggregates, and the
optimum of FD-1080/DMPC molar ratio is 1:20.
Furthermore, the stability of J-aggregates toward biological
environment was investigated. Absorption, emission spectra and
size of J-aggregates remained unchanged in neutral phosphate
buffered solution (PBS), saline, and blood within one week
(Figure S9, S10), indicating that the J-aggregates have good
structural stability. Moreover, the chemical stability of J-
aggregates was also assessed. No apparent absorption and
emission spectral change for J-aggregates were observed in
neutral PBS upon addition of glutathione, cysteine, and hydrogen
peroxide at 37 °C for 6 h (Figure S11). From the absorption
spectra of J-aggregates from -196 to 100 °C (Figure S12), J-
aggregates remained unchanged, indicating that the J-aggregates
have good stability at varied temperature. In addition, J-
aggregates exhibit superior photostability in different
physiological conditions under the continuous 1064 nm laser
irradiation for 2 h (Figure S13).
In addition, to understand the FD-1080 self-assembly with or
without DMPC in water, molecular dynamics simulation was
further carried out with the Groningen Machine37-38. We built two
simulation systems, i.e., pure FD-1080 and FD-1080/DMPC
mixture (Figure S14). For FD-1080/DMPC, the solutes combine
together to form J-aggregates (Figure S15), in which the
hydrophilic heads of DMPC and heads of FD-1080 exposed in the
solvent whereas the hydrophobic tails of DMPC and tails of FD-
1080 buried in the core. Meanwhile, FD-1080 has amphiphilic
structure, this character compelled the heads of FD-1080 being in
one side when J-aggregates formed. Also, local binding details
were further illustrated that the electrostatic attraction (~ -12.7
kJ/mol) between hydrophilic FD-1080 and DMPC heads
enhanced the J-aggregates formation. The steric hindrance and
electrostatic repulsion between neighboring sulphonic groups of
FD-1080 heads (~ 9.4 kJ/mol) caused the slipping within adjacent
FD-1080 (Figure 2a-b).
Figure 2. The molecular dynamics simulation of FD-1080 with or without
DMPC side a) and top b) views. c) Packing diagram of FD-1080 J-
aggregates. d) The side views of FD-1080 H-aggregates formed in pure
water without DMPC. (Orange sticks: hydrocarbon chains, yellow sticks:
sulfur atoms, red sticks: oxygen atoms, blue spheres: nitrogen atoms).
Furthermore, the assembly of four FD-1080 molecules was shown
in Figure 2c. It is notable that the neighboring FD-1080 molecules
showed clear slipping with the distance of ~2.9 Å. The
intermolecular distance was about 4.0 Å, which confirmed its π-π
stacking character.39 Meanwhile, the slip angle was calculated to
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be 46.5°, which was smaller than the critical value of 54.7º,
illustrating the formation of J-aggregates.40 However, in pure
water, the FD-1080 molecules formed H-aggregates, which were
almost aligned vertically to the line joining their centers through a
“head-to-head” arrangement via intermolecular forces like π-π
interactions (Figure 2d). Taken together, these results indicated
that the FD-1080 J-aggregates were formed by DMPC induction.
To investigate the bio-imaging performance of J-aggregates in
NIR-II window, in-vitro images were acquired by varied filters.
1064 nm laser was chosen for in-vivo imaging due to the lower
photothermal effect and tissue absorption (Figure S16-S18).
When capillary tubes filled with FD-1080 J-aggregates were
immersed in 1% Intralipid solution at increased phantom depth,
the sharp tube edges for 1400-1500 nm and beyond 1500 nm
exhibited a clearer image even at a 6 mm immersion depth
compared to 1300-1400 nm group (Figure 3a).
Figure 3. a) Fluorescence images of J-aggregates immersed at varied
depths in 1% Intralipid. b) FWHM of J-aggregates at penetration depth in
varied imaging windows. c) Images of brain and hindlimb vessels
achieved by J-aggregates in varied regions. The fluorescence intensity
profiles (solid line) and Gaussian fit (dashed line) along the red-dashed
line in brain d) and hindlimb e) vessels.
The spatial resolution was evaluated through the full width at
half-maximum (FWHM) of capillary tubes, and negligible
FWHM enhancement of beyond 1500 nm group could be
observed along with the increased penetration depth (Figure 3b,
and Figure S19). Meanwhile, the bioimaging signals beyond 1500
nm were from J-aggregates rather than FD-1080 monomer, which
were illustrated via in-vitro and in-vivo bioimaging results (Figure
S20). The low cytotoxicity of the J-aggregates was evaluated in
human umbilical vein endothelial cells (Figure S21). Then, we
further performed in-vivo bioimaging of hindlimb and cerebral
vasculature with J-aggregates. The signal-to-background (SBR)
and FWHM of beyond 1500 nm group (5.56) was 1.2-fold higher
than that of 1400-1500 nm group (4.55), and almost 3.3-fold
higher than that of 1300-1400 nm group (1.67). Besides, the
FWHM of the cerebral vessels at the same position were
measured as 468 μm (beyond 1500 nm), 482 μm (1400-1500 nm),
and 502 μm (1300-1400 nm), respectively (Figure 3c, d).
Similarly, higher spatial resolution and SBR were obtained in
hindlimb vessels bioimaging (Figure 3c, e), illustrating the
superior bioimaging performance achieved by J-aggregates
beyond 1500 nm window, which is consistent with previous
reports.41-43
Hypertension is one of the leading risk factor for
cardiovascular disease.44 Measuring arterial blood pressure is the
primary means of diagnosing and evaluating the severity of
hypertension in clinical.45 At present, Isoket is an ideal
antihypertensive agent for treating hypertension emergencies,
owing to its fast and precise effect to reduce blood-pressure.46
However, the dynamic process of vascular width changing is still
difficult to realize for evaluating the treatment efficiency in real-
time. Herein, we successfully realized the continuously dynamic
imaging of the carotid artery width beyond 1500 nm window
(Video S1) after intravenous injection (i.v.) of J-aggregates and
hypotensor into the spontaneously hypertensive rats. By
measuring the FWHM of the cross-sectional intensity profiles of
the features, blood width of carotid artery was observed to expand
from 370 μm to 680 μm within 240 s (Figure 4b, c).
Figure 4. a) Schematic illustration of the hypotensive process. b) The
dynamic bioimaging of carotid artery after administration of Isoket
beyond 1500 nm window achieved by J-aggregates. c) FWHM of carotid
artery as a function of time after administration of antihypertensive agent
Isoket. d) Systolic blood pressure (SBP) of carotid artery as a function of
time after administration of Isoket.
Meanwhile, clinically used blood pressure monitor was hired to
calibrate the dynamic change of the blood pressure of
hypertensive rats after injection of the hypotensor. The systolic
blood pressure dropped from 180 mmHg to 134 mmHg within
280 s (Figure 4d and Figure S22), indicating that the carotid artery
width gradually increased with the decrease of blood pressure
after administration of Isoket. To the best of our knowledge, this
is the first time to evaluate the efficacy of hypotensor by
monitoring the blood vessels width changing in real time through
NIR-II imaging.
In summary, we employed biocompatible DMPC lipid and FD-
1080 to form J-aggregates for in-vivo bioimaging beyond 1500
nm. Meanwhile, molecular dynamics simulations were further
employed to illustrate self-assembly process of FD-1080 in the
presence of DMPC. FD-1080 J-aggregates ensured bio-imaging
with higher signal-to-background ratio and spatial resolution in
NIR-II optical window to monitor dynamic vascular changing
during hypotensive process in rat. Our study provides a novel
route for the preparation of NIR-II J-aggregates, which may be
extended to other NIR molecular dye to form J-aggregates and
achieve superior bio-imaging in longer wavelength.
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ASSOCIATED CONTENT
Supporting Information
This Supporting Information is available as a PDF free of charge
on the ACS Publications website.
All experimental procedures, Figure S1-S20, Table S1 (PDF)
Video S1: Continuously dynamic imaging of the carotid artery
width beyond 1500 nm window after intravenous injection (i.v.)
of J-aggregates and hypotensor into the spontaneously
hypertensive rats. (MP4)
AUTHOR INFORMATION
Corresponding Author
zhang_fan@fudan.edu.cn;
Author Contributions
# Caixia Sun, and Benhao Li contributed equally to this work.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The work was supported by the National Key R&D Program of
China (2017YFA0207303), National Natural Science Foundation
of China (NSFC, 21725502), and Key Basic Research Program
and Intergovernmental International Cooperation Project of
Science and Technology Commission of Shanghai Municipality
(17JC1400100, 19490713100). The authors appreciate the help
from Prof. Ruhong Zhou of Soochow University for the molecular
dynamics simulations supporting.
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