Novel aza-BODIPY based small molecular NIR-II fluorophores for: In vivo imaging

Article abstract of DOI:10.1039/c9cc03378e

The development of new NIR-II fluorophores, particularly those with facile syntheses, high fluorescence quantum yields, and stable and tunable photophysical properties, is challenging. Herein, we report a new class of small molecular NIR-II fluorophores based on aza-dipyrromethene boron difluoride (aza-BODIPY) dyes. We demonstrate promising photophysical properties of these dyes, such as large Stokes shift, superior photostability, and good fluorescence brightness as nanoparticles in aqueous solution. Because of these properties and high resolution and deep penetration NIR-II imaging ability, the aza-BODIPY based dyes show great potential as NIR-II imaging agents.

Full text of DOI:10.1039/c9cc03378e

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DOI: 10.1039/C9CC03378E
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Novel Aza-BODIPY based Small Molecular NIR-II Fluorophores for
in vivo Imaging
a,†
b,†
a,†
a
a
b
a,
Lei Bai, Pengfei Sun, Yi Liu, Hang Zhang, Wenbo Hu, Wansu Zhang, Zhipeng Liu, * Quli
Received 00th January 20xx,
Accepted 00th January 20xx
b,
a,
a,b,c
Fan, * Lin Li * and Wei Huang
DOI: 10.1039/x0xx00000x
The development of new NIR-II fluorophores, particularly those (Figure 1 and Table S1). One type is based on polymethines. By
with facile syntheses, high fluorescence quantum yields, and stable increasing the conjugation length and heterocycle substitutions,
and tunable photophysical properties, is challenging. Herein, we dyes such as Flav7, IR1048, IR1061, IR26, and FD-1080 have shown
2
1-23
report a new class of small molecular NIR-II fluorophores based on NIR-II emission and good in vivo imaging ability.
aza-dipyrromethene boron difluoride (aza-BODIPY) dyes. We NIR-II fluorophores is based on
demonstrate promising photophysical properties of these dyes, ]bis([1,2,5]thiadiazole) (BBTD) with a donor-acceptor-donor (D-A-D)
Another type of
benzo[1,2-c:4,5-c0
2
4-26
such as large Stokes shift, superior photostability, and good structure.
By rational tuning of the electron donating ability of
fluorescent brightness as nanoparticles in aqueous solution. the donor and incorporation of substitutes with good water
Because of these properties and high resolution and deep solubility, Dai and other groups have reported several BBTD-based
2
4
penetration NIR-II imaging ability, aza-BODIPY based dyes show NIR-II fluorophores, such as CH1055. Although these reported NIR-
great potential as NIR-II imaging agents.
II fluorophores exhibit good photophysical properties, which
facilitate their application in biological imaging, novel NIR-II
fluorophores especially with facile syntheses, high fluorescence
quantum yields ( ), and stable and tunable photophysical
f
properties are still needed.
Biological imaging in the second near-infrared (NIR-II, 1000-1700
nm) window has gained considerable research attention in recent
years because of its advantages such as deep tissue penetration, high
signal-to-background ratio (SBR), and high maximum permissible
1
,2
exposure to lasers. To achieve NIR-II imaging, the highly tunable
electronic structures of various inorganic nanomaterials were
investigated, leading to the development of materials such as
transition-metal sulfide/oxide semiconductors, single-walled carbon
3
4,5
nanotubes (SWNTs), quantum dots (QDs),
and noble and
6
-12
semimetal nanoparticles (NPs). In addition, a few organic polymer
nanomaterials with narrow bandgap were also developed.12
However, applications for both inorganic and organic polymer
nanomaterials for clinical use are limited because of their unknown
1
3-20
long-term toxicity and excretion time.
Hence, small molecular
and biocompatible NIR-II organic fluorescent dyes are desirable for
clinical applications. Unfortunately, the design and synthesis of small
molecular organic NIR-II fluorophores are challenging. To date, only
two types of small molecular NIR-II fluorophores have been reported
a. Key Laboratory of Flexible Electronics (KLOFE) & Institute of Advanced Materials
(IAM), Nanjing Tech University (NanjingTech), Nanjing 211816, China.
iamlli@njtech.edu.cn; iamzpliu@njtech.edu.cn.
b.
Key Laboratory for Organic Electronics and Information Displays & Institute of
Advanced Materials (IAM), Nanjing University of Posts & Telecommunications,
Nanjing 210023, China. iamqlfan@njupt.edu.cn.
Shaanxi Institute of Flexible Electronics (SIFE), Northwestern Polytechnical
University, 127 West Youyi Road, Xi'an 710072, China.
c.
Figure 1. Fluorescence maxima of selected NIR-II dyes and chemical structures of
polymethines, BBTDs, NJ960, NJ1030, and NJ1060.
†
These authors contributed equally.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
Commercially available aza-dipyrromethene boron difluoride (aza-
BODIPY) dyes exhibiting favorable NIR-I photophysical properties
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have been investigated for their applications in biological and (Figure 2a). The most exciting result was that the emVisieswioAnrtimcleaOxnimlinae
materials sciences.27,28 Due to the strong electron-withdrawing (em) centered at 960, 1030, and 1060 nm for NJ960, NJ1030, and
nature of borane difluoride azadipyrromethene’s center, NJ1060, respectively, successfully reached the NIR-II region (Figure
incorporating electron-donating groups will form a D-A structure and 2b).
DOI: 10.1039/C9CC03378E
2
9-32
result in red-shifted absorption and emission.
For example,
O’Shea’s group reported that the introduction of the dimethylamino Table 1. Emission related energy gaps (eV) and oscillator strengths (f), configurations of
the low-lying excited states of NJ960, NJ1030, and NJ1060 calculated by TD-
group into the phenyl ring at the 3,5-positions resulted in the distinct
DFT/B3LYP/6-31G(d), based on the optimized S
solvent in the calculations).
1
state geometries (Water was used as a
red-shift of absorption and emission maxima from 650 and 672 nm
3
1
to 799 and 823 nm in chloroform solution, respectively. Although
the NIR-I absorption and emission properties of aza-BODIPY can be
easily achieved via facile synthetic derivatization, it is surprising that
no aza-BODIPYs with NIR-II emission have been reported. In our
efforts to develop new small molecular NIR-II fluorophores, we
explored molecular engineering on the classical aza-BODIPY unit to
red-shift its emission from the NIR-I to the NIR-II window. A new
family of NIR-II fluorophores based on aza-BODIPY (NJ960, NJ1030,
and NJ1060) resulted (Figure 1).
TDDFT/B3LYP/6-31G(d)
E [eV]
 [nm] f[b]
Electronic
transition
Dye
Orbitals
coefficient)
[
a]
[
c]
(
NJ960
S
0
→ S
1
1.3624 910
1.4149 876
1.2654 980
[b]
0.7328 H–L (0.70727)
0.7157 H–L (0.70681)
0.7298 H–L (0.70927)
[c]
NJ1030
NJ1060
S
S
0
→S
→S
1
0
1
[
a]
Only S
1
state was considered. Oscillator strength. MOs involved in the transitions.
H = HOMO; L = LUMO.
The photophysical properties of these new NIR-II dyes were also
investigated in organic solvents having different polarities. As shown
in Figure S4 and Table S3, the fluorescence spectra of NJ960, NJ1030,
and NJ1060 reach further into the NIR-II region as the solvent polarity
increases. For example, NJ960, NJ1030, and NJ1060 exhibited em in
DMSO at 989, 1036, 1070 nm, respectively, which were 65, 80, and
NJ960, NJ1030, and NJ1060 with a D-A-D’ structure were designed
by incorporating strong electron-donating groups (D), such as 4-(N,
N-dimethylamino)phenyl
for
NJ960,
1-ethyl-1,2,3,4-
tetrahydroquinolinyl for NJ1030, and 4-julolidinyl for NJ1060, into
the 3, 5-positions of aza-BODIPY. In addition, 4-anisoly groups were
introduced into the 1, 2-positions of aza-BODIPY to act as electron-
donating groups (D’) and potential functional groups. With the help
of the strong D to A intramolecular charge transfer (ICT) effect, a
large emission red-shift from NIR-I to NIR-II for aza-BODIPY is
8
1 nm red-shifted relative to those observed in o-dichlorobenzene.
Based on the Lippert-Mataga plot, the Stokes shift from 123 to 171
nm for NJ960, 124 to 182 nm for NJ1030, and 133 to 187 nm for
NJ1060 versus the polarity increment demonstrated the ICT nature
of NJ960, NJ1030, and NJ1060. The NIR-II emission of NJ960, NJ1030,
and NJ1060 in both organic solvents and aqueous solutions showed
the rationality of the molecular design.
2
7-32
expected compared with that of classical aza-BODIPYs.
Theoretical calculations were performed to support this prediction.
Using time-dependent density functional theory (TD-DFT),
calculations based on the optimized ground state in water w/o DMSO
(20%) were done. Two main allowed electronic transitions from the
highest occupied molecular orbital (HOMO) to the lowest
unoccupied molecular orbital (LUMO) and from HOMO-1 to LUMO
were observed for NJ960, NJ1030, and NJ1060 in the NIR-I region
(
(
773 and 641 nm, 796 and 646 nm, and 823 and 666 nm, respectively)
Figure S1-3 and Table S2). The red-shift of the absorption maximum
of 773, 796, and 823 nm for NJ960, NJ1030, and NJ1060, can be
ascribed to the increasing electron-donating ability of 4-(N, N-
dimethylamino)phenyl, 1-ethyl-1, 2, 3, 4-tetrahydroquinolinyl, and 4-
julolidinyl, respectively. The geometries of NJ1060, NJ1030, and
NJ1060 NPs in the singlet excited state (S
water and the excitations based on the S
TD-DFT calculations indicated an emissive S
1
) were further perfected in
geometry calculated. The
. The calculated emission
1
1
maxima for NJ960, NJ1030, and NJ1060 were 910, 876, and 980 nm,
respectively, indicating the potential NIR-II emission of NJ960, Figure 2. (a) Normalized absorption. (b) Emission spectra of NJ960, NJ1030, and
-5
-1
NJ1060 in PBS solution (10 mol L ). (c) Normalized emission decay of NJ960,
NJ1030, and NJ1060 (Figure S1-3 and Table 1). In light of these results, NJ1030, NJ1060, and IR1061 at their emission maxima under laser irradiation (808
2
nm, 100 mW/cm , 60 min) for different irradiation times. (d) NIR-II fluorescent
NJ960, NJ1030, and NJ1060 were facile synthesized using the images and related emission intensities of NJ960, NJ1030, NJ1060, and IR1061 in
PBS solution at an equivalent absorbance of OD 0.1 at 808 nm.
classical aza-BODIPY synthesis (the synthetic routes are depicted in
1
Scheme S1) strategy. All the compounds were characterized by H,
NJ960, NJ1030, and NJ1060 showed relatively high 
solutions. The calculated  for NJ960, NJ1030, and NJ1060 were
.16%, 0.2%, and 1.0%, respectively (reference dye IR 26,  = 0.1%),
f
in aqueous
1
3
C NMR, and HRMS.
f
The photophysical properties of NJ960, NJ1030, and NJ1060 were
investigated in PBS solution (pH = 7.4) containing 20% DMSO as a co-
solvent. As expected, NJ960, NJ1030, and NJ1060 showed their
0
f
which were slightly higher than those reported for NIR-II
fluorophores such as CH1055 and FD-1080 (Table S1). Furthermore,
the relative photostability and fluorescent brightness of NJ960,
NJ1030, and NJ1060 were investigated in PBS solutions containing
-
1
major absorption bands in the NIR-I region, i.e., 651 (ε = 55000 mol
-1
-1
-1
cm ) and 799 nm (ε = 40000 mol cm ) for NJ960, 668 (ε = 38000
mol cm ) and 830 nm (ε = 26000 mol cm ) for NJ1030, and 672 (ε
17000 mol cm ) and 910 nm (ε = 170000 mol cm ) for NJ1060
-1
-1
-1
-1
2
0% DMSO as a co-solvent. For comparison, 10 M concentrations
-1
-1
-1
-1
=
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were tested with IR1061 tested. After continuous laser irradiation II imaging applications in living systems.
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DOI: 10.1039/C9CC03378E
2
(808 nm, 100 mW/cm ) for 60 min, the emission intensity of NJ960,
NIR-II imaging in mice was performed with NJ1060 NPs. NJ1060
NJ1030, and NJ1060 remained almost unchanged, while the NPs (c = 0.696 mg/mL, 150 μL) were intravenously injected into mice
emission of IR1061 decayed rapidly from 100% to 65% (Figure 2c). (n = 3) through the tail vein, then the mice were anesthetized for 5
Moreover, the average emission intensity of the imaged vials was min before imaging. After irradiating with laser (808 nm), the
2
46, 236, and 252 for NJ960, NJ1030, and NJ1060, respectively, vasculature of the mouse could be clearly visualized from the
which was higher than the 172 for IR1061 (Figure 2d). These results surrounding background tissue via NIR-II fluorescence (Figures 4a
show the superior photostability and good fluorescent brightness of and 4c). For example, according to the full width at half maximum of
NJ960, NJ1030, and NJ1060.
the emission intensity profiles across the red line of interest, the
Encouraged by the above results, we next investigated the in vivo emission intensities of the hind limb and brain blood vessel resolved
NIR-II imaging ability of NJ1060 combined with these novel NIR-II by imaging were estimated to be 0.52 and 0.60 mm (Figure 4b and
dyes. However, due to its low water solubility, NJ1060 molecules 4d), respectively, which is consistent with previously reported
4
-12
aggregate in water without DMSO as a co-solvent, which means values. A comparative imaging experiment was also carried out by
NJ1060 cannot be used directly for in vivo imaging. Hence, NJ1060 using the FDA-approved NIR-I dye indocyanine green (ICG, em = 835
NPs were prepared for in vivo NIR-II imaging by using sonication to nm) and classical NIR-II dye IR1061 (em = 1100 nm) as imaging agents.
encapsulate them into a Pluronic F-127 matrix. NJ1060 NPs, thus, can Unfortunately, only the dim fluorescence of both ICG and IR1061
be homogeneously dispersed in aqueous solutions. NJ1060 NPs could be observed in whole mice at the same imaging conditions as
showed spherical morphology with a diameter of ～45 nm, which our experiments, and the vasculature of mice could not be
was characterized by transmission electron microscopy (TEM) distinguished at all (Figures S7 & S8). These results clearly show the
(Figure 3a inset). The average diameter of NJ1060 NPs was measured deep penetration and high-resolution imaging ability of the NJ1060
to be ～90 nm by a dynamic light scattering (DLS) experiment with a NPs.
low polydispersity index (PDI) of 0.137 (Figure 3a). The smaller
We next investigated the tumor imaging ability of the NJ1060
diameter observed using TEM was possibly due to shrinking during NPs (Figure 4e). After intravenous injection of the NJ1060 NPs
TEM sample preparation. Most importantly, NJ1060 NPs showed a through the tail vein into mice (n = 3) with 4T1 tumors at the left
maximum absorption at 858 nm and an intense emission peak at shoulder, relatively strong fluorescence was observed in the
1
062 nm, which is consistent with the abs (910 nm) and em (1060 vasculature and abdomen region. When time was increased to 3 h,
nm) of molecular NJ1060 observed in PBS solution (Figure 3b).
the fluorescence signal in the vasculature was reduced accompanied
by fluorescence enhancement in the abdomen region. In addition, a
weak fluorescence was observed in the tumor. When time was
further increased to 6 and 8 h, besides the strong fluorescence in the
abdomen, distinct fluorescence enhancement was observed in the
tumor, and the SBR increased from 4.9 (1 h) to 23 (8 h), then
stabilized at ～30 (24 h) (Figures 4g & S9). This result was attributed
to the accumulation of the NJ1060 NPs through the enhanced
permeability and retention (EPR) effect. Furthermore, ex-vivo bio-
distribution studies showed a high fluorescence intensity in the liver,
spleen, and tumor (Figure 4f), demonstrating the preferential
accumulation of NJ1060 NPs in the liver and spleen. These imaging
results highlight the great potential for in vivo NIR-II imaging of
NJ1060 NPs.
In conclusion, we have developed a new class of small molecular
NIR-II dyes (NJ960, NJ1030, and NJ1060) based on the classical aza-
BODIPY dye. These dyes were rationally designed under the guidance
of theoretical calculations then facile synthesized via classical aza-
BODIPY synthetic methods. These new aza-BODIPY dyes exhibited
NIR-II fluorescence emission with a large Stokes shift, good quantum
yield/fluorescent brightness/photostability in aqueous solution, in
spite of their low water solubility. The in vivo NIR-II imaging results
demonstrated the high resolution and deep penetration imaging
ability of these dyes with NPs. Considering these results, we can
predict that new generations of aza-BODIPY based NIR-II dyes can be
developed via rational tuning of the NJ1060 structure. Our future
work will focus on the construction of analogues/fluorogenic probes
of these new dyes with good water solubility, higher quantum yields,
and tunable NIR-II emission wavelengths. We will then investigate
their potential uses in clinical applications.
Figure 3. (a) Particle size distribution of NJ1060 NPs measured by dynamic light
scattering with a mean diameter of 90 nm and a PDI of 0.137. Inset: TEM images
of NJ1060 NPs. (b) Normalized absorption and emission spectra of NJ1060 NPs in
PBS solution. (c) NIR-II images of NJ1060 NPs at different depths (0, 1, 2, 4, 6, 8,
and 10 mm). ex = 808 nm. (d) SBR ratio of NJ1060 NPs at different depths.
Before the study of the in vivo imaging of NJ1060 NPs, the NIR-II
imaging depth was investigated by imaging a capillary tube filled with
NJ1060 NPs solution within biological tissue (chicken meat) at
various depths (Figures 3c and S5). As the depth of imaging increased
from 0 to 10 mm, the SBR decreased linearly from 14.1 (0 mm), 10.6
(2 mm), 9.77 (4 mm), 7.0 (6 mm), and 2.68 (8 mm) to 1.2 (10 mm)
(Figure 3d). These results show that NIR-II imaging depths for NJ1060
NPs can reach up to ~8 mm, which is higher than that of other NIR-I
3
imaging agents (~0.2 mm). Moreover, in vitro cytotoxicity studies
via standard XTT analysis showed that no cytotoxicity of NJ1060 NPs
was observed even in concentrations up to 400 μg/mL (Figure S6). All
these results suggest that NJ1060 NPs are applicable for in vivo NIR-
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DOI: 10.1039/C9CC03378E
Figure 4. NIR-II images of the mouse hind limb (a) and brain (c) vasculature. The emission intensity profiles of the red line of interest in figure a (b) and figure c (d). (e)
The NIR-II images of the 4T1 tumor at different times after tail-vein injection of NJ1060 NPs under an 808-nm laser excitation. (f) The ex-vivo biodistribution of NJ1060
NPs in the liver, spleen, kidney, and tumor at 4 h under an 808-nm laser excitation. (g) SBR ratios of the tumor at different times.
1
3 G. Hong, J. T. Robinson, Y. Zhang, S. Diao and A. L. Antaris,
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Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (81672508, 21674048, 21574064
and 21501085), the Jiangsu Provincial Foundation for
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