Red-Light-Mediated Photoredox Catalysis Enables Self-Reporting Nitric Oxide Release for Efficient Antibacterial Treatment

Article abstract of DOI:10.1002/anie.202107155

Nitric oxide (NO) serves as a key regulator of many physiological processes and as a potent therapeutic agent. The local delivery of NO is important to achieve target therapeutic outcomes due to the toxicity of NO at high concentrations. Although light stimulus represents a non-invasive tool with spatiotemporal precision to mediate NO release, many photoresponsive NO-releasing molecules can only respond to ultraviolet (UV) or near-UV visible light with low penetration and high phototoxicity. We report that coumarin-based NO donors with maximal absorbances at 328 nm can be activated under (deep) red-light (630 or 700 nm) irradiation in the presence of palladium(II) tetraphenyltetrabenzoporphyrin, enabling stoichiometric and self-reporting NO release with a photolysis quantum yield of 8 % via photoredox catalysis. This NO-releasing platform with ciprofloxacin loading can eradicate Pseudomonas aeruginosa biofilm in vitro and treat cutaneous abscesses in vivo.

Full text of DOI:10.1002/anie.202107155

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How to cite:
International Edition: doi.org/10.1002/anie.202107155
German Edition: doi.org/10.1002/ange.202107155
Photoredox Catalysis
Red-Light-Mediated Photoredox Catalysis Enables Self-Reporting
Nitric Oxide Release for Efficient Antibacterial Treatment
Zhiqiang Shen, Shaoqiu Zheng, Shiyan Xiao,* Ruan Shen, Shiyong Liu,* and Jinming Hu*
Abstract: Nitric oxide (NO) serves as a key regulator of many
physiological processes and as a potent therapeutic agent. The
local delivery of NO is important to achieve target therapeutic
outcomes due to the toxicity of NO at high concentrations.
Although light stimulus represents a non-invasive tool with
spatiotemporal precision to mediate NO release, many photo-
responsive NO-releasing molecules can only respond to ultra-
violet (UV) or near-UV visible light with low penetration and
high phototoxicity. We report that coumarin-based NO donors
with maximal absorbances at 328 nm can be activated under
(deep) red-light (630 or 700 nm) irradiation in the presence of
palladium(II) tetraphenyltetrabenzoporphyrin, enabling stoi-
chiometric and self-reporting NO release with a photolysis
quantum yield of 8% via photoredox catalysis. This NO-
releasing platform with ciprofloxacin loading can eradicate
Pseudomonas aeruginosa biofilm in vitro and treat cutaneous
abscesses in vivo.
increasing attention.[9] Of these, light irradiation represents
a non-invasive means to regulate the NO release with
advantages such as spatiotemporal control and tunable
irradiation wavelengths/intensities.[10] However, conventional
photoresponsive NORMs (photoNORMs) were primarily
activated under ultraviolet (UV) or near-UV visible light,
which was unfavorable for biomedical applications due to the
inherent phototoxicity and limited tissue penetrations.[11]
To develop photoNORMs responsive to the photother-
apeutic window (600–950 nm), two main approaches have
been applied: (1) the introduction of chromophores with red
or near-infrared (NIR)-absorbing capacity;[12] (2) the use of
upconversion nanoparticles or two-photon absorption tech-
nique.[13] However, the former strategy generally led to
decreased NO loading contents and water dispersity in
biological fluids. The latter approach had to be operated at
high excitation powers that typically surpassed the photo-
damage threshold of normal tissues.[14] To date, it remains
a great challenge to develop photoNORMs with high NO
loading contents that can release NO under the photother-
apeutic window in biological fluids.
Herein, we report that the excited photosensitizers such as
palladium(II) tetraphenyltetrabenzoporphyrin (PdTPTBP)
derivatives can activate coumarin-based photoNORMs con-
taining N-nitrosoamine moieties (CouN(NO)-R) under red-
light irradiation (up to 700 nm), exhibiting self-reporting NO
release with a remarkable fluorescence turn-on (Scheme 1a).
To demonstrate the potential biomedical applications, NO-
releasing micelles were fabricated through the incorporation
of PdTPTBP and CouN(NO)-R derivatives into micelle cores,
showing red-light-triggered NO release in biological fluids
and excellent antibiofilm activity in vitro. Moreover, the NO-
releasing micelles could efficiently treat Pseudomonas aeru-
ginosa (P. aeruginosa) infections in a cutaneous abscess
model, synergistically eradicating bacterial pathogens and
boosting wound healing.
Introduction
Nitric oxide (NO), a diatom radical, has been recognized
as the first gaseous signaling molecule, playing critical roles in
many physiological and pathological processes.[1] The excel-
lent contributions from Meyerhoff,[2] Handa,[3] Schoenfisch,[4]
Reynolds,[5] and others[6] have revealed that NO could be used
as a therapeutic agent as well, showing benefits in the
treatment of cancers, bacterial infections, inflammatory dis-
eases, and so on. Nevertheless, the systemic toxicity of NO at
high concentrations necessitates local NO delivery to achieve
target therapeutic outcomes.[7] To this end, NO-releasing
molecules (NORMs) have been developed, including
N-diazeniumdiolates, S-nitrosothiols, nitrate compounds, fu-
roxans, metal nitrosyls, etc.[8] Notably, many NORMs suffered
from spontaneous NO release, short half-lives, and (or) poor
pharmacokinetics, impeding their biomedical applications. To
circumvent this problem, the development of NORMs that
can be selectively activated under specific stimuli has received
Results and Discussion
[*] Z. Shen, S. Zheng, Prof. Dr. S. Xiao, R. Shen, Prof. Dr. S. Liu,
Prof. Dr. J. Hu
Synthesis of coumarin-based NO donors. It is well-
documented that N-nitrosoamine derivatives can release
NO under light irradiation, and the excitation wavelengths
could be switched by appending chromophores.[15] To date,
both UV and visible light have been employed to activate
N-nitrosoamine donors (Supporting Information, Figure S1).
To facilitate the biomedical applications of these photo-
responsive NO donors, the development of red or NIR light-
responsive NO donors is of increasing interest due to
increased tissue penetration and decreased phototoxicity.[12b]
CAS Key Laboratory of Soft Matter Chemistry
Hefei National Laboratory for Physical Science at the Microscale
Department of Polymer Science and Engineering
University of Science and Technology of China
Hefei 230026, Anhui (China)
E-mail: xiaosy@ustc.edu.cn
sliu@ustc.edu.cn
jmhu@ustc.edu.cn
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202107155.
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responsive nature of CouN(NO)-R derivatives. Upon screen-
ing specific photosensitizers, we unexpectedly found that
a mixture of CouN(NO)-NO2 (50 mM) and PdTPTBP (5 mM)
showed a concurrent absorbance decrease at 328 nm and
increase at 358 nm (Figure 1b), respectively, under mild red-
light irradiation (630 nm, 30 mWcmꢁ2; this irradiation con-
dition was used throughout this work). Note that the Soret
and Q-bands of PdTPTBP were at 442 and 628 nm, respec-
tively (Figure 1a). By sharp contrast, the control experiments
revealed no absorbance changes without PdTPTBP, light
irradiation, or CouN(NO)-NO2 under otherwise identical
conditions (Figure S9). Interestingly, we noticed that the
absorbance spectra of CouN(NO)-NO2 and PdTPTBP mix-
ture after 630 nm light irradiation agreed quite well with the
absorbance spectrum of CouN(H)-NO2 (Figure S10a), imply-
ing the release of NO under 630 nm light irradiation. Electron
paramagnetic resonance (EPR) spectra using 2-phenyl-
4,4,5,5-tetramethyl-imidazoline-1-oxyl 3-oxide (PTIO) as
the spin-trapping agent unequivocally revealed the release
of NO radical (Figure 1c),[18] whereas no spontaneous NO
release was observed without light irradiation or PdTPTBP, in
line with the UV-vis results (Figure S9).
Scheme 1. a) Illustration of red-light-triggered self-reporting NO
release from micellar nanoparticles containing both PdTPTBP photo-
sensitizer and NO-releasing CouN(NO)-R moieties within the cores.
b) Proposed mechanisms of the activation of CouN(NO)-R derivatives:
(I) direct photolysis of CouN(NO)-R derivatives under UV light;
(II) red-light-triggered NO release through photoredox catalysis.
However, the NO loading content, which was arbitrarily
defined as the NO weight percentage in the NO donor,
gradually decreased upon red-shifting the absorbance of the
donors (Figure S1), which was unfavorable for biomedical
applications.
In contrast to direct photolysis in the excited singlet state,
triplet sensitization provided an indirect activation of latent
acceptors through the triplet-triplet energy transfer (TTET)
process.[16] We managed to activate N-nitrosoamine deriva-
tives in the presence of suitable photosensitizers. To this end,
we chose 7-aminocoumarin derivatives as the NO-releasing
scaffold because of relatively high NO loading contents
( ꢀ 10 wt%) and the self-reporting NO release behavior.[17]
Starting from 7-amino-4-hydroxymethyl-coumarin, three cou-
marin-based NO donors (CouN(NO)-R; R = NO2, H, or
OCH3) were synthesized using similar protocols (Supporting
Information, Scheme S1). The chemical structures of three
NO donors were identified by 1H and 13C NMR spectroscopy
and high-resolution mass spectrometry (HR-MS; Figures S2–
S7).
Figure 1. a) UV-vis absorbance spectra of PdTPTBP (5 mM) and CouN-
(NO)-NO2 (50 mM) in DMSO. b) Evolution of UV-vis spectra of DMSO
solution of CouN(NO)-NO2 (50 mM) and PdTPTBP (5 mM) under
630 nm light irradiation (30 mWcmꢁ2). c) EPR spectra of CouN(NO)-
NO2 in the absence (black curve) and presence of PdTPTBP (5 mM)
without (red curve) and with (blue curve) 630 nm light irradiation for
2 min. In all cases, the concentrations of PTIO and CouN(NO)-NO2
were 20 and 50 mM, respectively. d) NO release profiles of DMSO
solution of CouN(NO)-NO2 (50 mM) and PdTPTBP (5 mM) mixture
with or without 630 nm irradiation (30 mWcmꢁ2). e) Stern–Volmer plot
of phosphorescence intensity quenching of PdTPTBP (10 mM) by
CouN(NO)-NO2 in Ar-saturated DMSO. f) Nanosecond time-resolved
transient absorption spectra (lex =630 nm) of PdTPTBP (10 mM) and
CouN(NO)-NO2 (10 mM) in Ar-saturated DMSO.
Red-light-triggered NO release from CouN(NO)-R in the
presence of PdTPTBP. CouN(NO)-NO2 had maximal ab-
sorbance at 328 nm but no evident absorbance above 450 nm
(Figure 1a). Under 365 nm light irradiation, photo-mediated
NO release was achieved (Figure S8), confirming the photo-
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It is challenging to monitor the NO release in real-time
due to the high reactivity of NO,[19] while the NO release
contents could be calculated by the absorbance changes due
to the quantitative conversion of CouN(NO)-NO2 to CouN-
(H)-NO2 (Figure S11). We found that the NO release
amounts reached a plateau after ꢀ50 min light irradiation
(Figure 1d), releasing NO in a stoichiometric manner with
a photolysis quantum yield of 8% (see Supporting Informa-
tion for details). Notably, both the NO-releasing amounts and
rates under 630 nm light irradiation were higher than that of
365 nm light irradiation, which was likely due to the side
reactions under UV light irradiation (Figure S8). Moreover,
the NO release profiles can be tuned by changing the
PdTPTBP concentrations, and an increased PdTPTBP con-
centration led to a faster NO-releasing rate (Supporting
Information, Figure S12, Table S1). Since CouN(NO)-NO2
itself cannot release NO under 630 nm light irradiation, it
was assumed that the red-light-triggered NO release was
ascribed to the indirect activation of CouN(NO)-NO2 in the
presence of PdTPTBP. To confirm this assumption, we
investigated the photoluminescence of PdTPTBP with vary-
ing amounts of CouN(NO)-NO2. Both the phosphoresce
intensities and lifetimes of PdTPTBP were drastically
quenched upon increasing the concentrations of CouN-
(NO)-NO2 donor (Figures 1e; Figure S13), demonstrating
that the excited PdTPTBP can be quenched by CouN(NO)-
NO2 through either an energy or electron transfer process.
could be operated in purely aqueous media. Notably, many
previous triplet sensitization systems can only be operated in
organic solvents or solid states and suffered from partial or
complete loss of efficiency in aqueous solutions.[20] Due to the
poor water-solubility of CouN(NO)-R and PdTPTBP deriv-
atives, we covalently incorporated both the NO-releasing
moieties and PdTPTBP into the cores of micellar nano-
particles. To this end, the hydroxyl groups of CouN(NO)-NO2
and CouN(H)-NO2 were functionalized with 2-isocyanato-
ethyl methacrylate with the formation of CouN(NO) and
CouN(H) monomers, respectively (Scheme S2a). In addition,
the PdTPTBP monomer was also synthesized (Scheme S2b).
The chemical structures of all monomers were characterized
by the combination of NMR, HR-MS, and high-performance
liquid chromatography (HPLC; Figures S19–S22). Interest-
ingly, the formation of CouN(NO) monomer did not com-
promise the NO release capacity, and the conversion of
CouN(NO) to CouN(H) with the release of NO in the
presence of PdTPTBP was confirmed by HR-MS analysis
(Figure S23). Although the carbamate linkage in the
4-position of coumarin derivatives can also be photo-activat-
ed,[21] only the N-nitrosoamine moieties were selectively
activated under the current circumstances (Figure S23). In
order to fabricate NO-releasing micelles, we used reversible
addition-fragmentation chain transfer (RAFT) polymeri-
zation to copolymerize PdTPTBP and CouN(NO) monomers
by taking advantage of the versatility in monomer compat-
ibility of RAFT polymerization. Besides conventional
poly(ethylene glycol)(PEG)-based macroRAFT agent, we
also prepared PGal homopolymer through the RAFT poly-
merization of galactose-based monomer (Gal), which was
known to specifically bind to Lectin A (LecA) in P.
aeruginosa (Scheme S2c, Figures S24 and S25).[22] With the
macroRAFT agents and monomers in hand, amphiphilic
block copolymers (PGalNP, PGalHP, PEGNP, and PGalN)
were then synthesized (Scheme 2; Scheme S3) and charac-
terized (Figures S26–S29, Table S4).
All the block copolymers self-assembled into micellar
nanoparticles in aqueous solutions with diameters of 50–
70 nm, and the exposure to 630 nm light irradiation did not
significantly affect the micellar sizes (Figure 2a,b; Fig-
ure S30). Moreover, all micellar nanoparticles had negative
zeta potentials of ꢁ8 to ꢁ12 mV, showing negligible changes
under irradiation (Figure S31). However, we observed con-
current absorbance decreases at 328 nm and increases at
358 nm of PGalNP micelles in the presence of sodium
ascorbate (Figure 2c). The changes of UV-vis spectra were
similar to that of the CouN(NO)-NO2 precursor in the
presence of PdTPTBP in DMSO (Figure 1b), indicating
photo-triggered NO release under 630 nm light irradiation.
Moreover, the NO-releasing profiles can be tuned by
irradiation intensities, and a higher irradiation intensity led
to a fast NO release (Figure S32). By sharp contrast, there was
no appreciable NO release without 630 nm light irradiation or
sodium ascorbate (Figure S33). Notably, the triple-state of
photosensitizers was readily quenched by oxygen, and sodium
ascorbate was used to scavenge the produced singlet oxygen
(Figure S34).[23] Moreover, we found that PEGNP micelles
with the same core but different coronas showed similar
Specifically, the Stern–Volmer constant (KSV
) and the
quenching rate constant (kq) was calculated to be 432.5 Mꢁ1
and 1.95 ꢀ 106 Mꢁ1 sꢁ1 (Figure 1e). This quenching process was
further corroborated by nanosecond transient absorption
spectra (Figure 1 f; Figure S14).
Having confirmed that it was possible to regulate the NO
release from CouN(NO)-NO2 by red-light irradiation, we
next sought to test whether CouN(NO)-H and CouN(NO)-
OCH3 could be activated under the same conditions.
Although there were no absorbance changes without
630 nm light irradiation, similar changes in UV-vis spectra
were observed for both CouN(NO)-H and CouN(NO)-OCH3
under 630 nm irradiation (Figure S15). Quantitative analysis
by comparing the absorption ratio changes (A358nm/A328nm
)
revealed that the NO-releasing rates were in the order of
CouN(NO)-NO2 > CouN(NO)-H > CouN(NO)-OCH3 (Fig-
ure S16, Table S2), revealing that the electronic effect played
a critical role on the NO-releasing rates. In addition to varying
NO donors, we also examined the NO-releasing behavior in
the presence of distinct photosensitizers. Using CouN(NO)-
NO2 as an example, the photo-mediated NO release could
also be established in the presence of 5,10,15,20-(tetraphe-
nyl)tetrabenzoporphyrin (H2TPTBP). Albeit slower, the use
of metal-free H2TPTBP rendered it possible to achieve the
NO release under 700 nm light irradiation (Figures S17 and
S18, Table S3), which was rather appealing for biomedical
applications due to the further increased tissue penetration
and decreased phototoxicity.
Red-light-triggered NO release from micellar nanoparti-
cles. After confirming red-light-triggered NO release in
organic solvents (i.e., DMSO), we attempted to investigate
whether the red-light-activatable NO-releasing platform
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regardless of with or without 630 nm light irradiation (Fig-
ure S36). These results not only precluded spontaneous NO
release but also demonstrated the critical role of PdTPTBP
for red-light-mediated NO release.
The NO release with the generation of CouN(H)-NO2
moieties within micellar cores led to the fluorescence turn-on,
exhibiting ꢀ 70-fold fluorescence increase (Figure 2d; Fig-
ure S37). The released NO content was calculated to be
ꢀ 70 mM at a PGalNP micelle concentration of 0.1 gLꢁ1 under
630 nm irradiation for 20 min (Figure 2e), corresponding to
ꢀ 78% of CouN(NO)-NO2 moieties within the micelle cores.
Moreover, although the NO release did not lead to the
micellar disassembly, we found that the encapsulated payload
such as ciprofloxacin (Cip) was released under 630 nm light
irradiation, enabling the corelease of NO and Cip (Figure 2 f;
Figure S38).
Red-light-triggered NO release for P. aeruginosa biofilm
dispersal. Considering the red-light-triggered NO release
from PGalNP micelles in aqueous solutions, subsequently, we
investigated the antibiofilm performance by using the local
NO release.[24] P. aeruginosa has been known as an oppor-
tunistic microbe, accounting for 10–20% of nosocomial
infections. Even worse, the formation of P. aeruginosa biofilm
renders it more resistant to conventional antibiotics and more
difficult to treat.[22] In vitro antibiofilm experiments revealed
that although Cip (10 mgmLꢁ1, identical to the Cip concen-
tration in Cip@PGalNP micelles of 0.2 gLꢁ1) cannot effi-
ciently eradicate the biofilm, NO-releasing micelles of
PEGNP, PGalNP, and Cip-loaded PGalNP (Cip@PGalNP)
led to 37.1%, 70.9%, and 96.7% decrease in the biofilm
biomass after 630 nm light irradiation for 30 min, as deter-
mined by the crystal violet staining (Figure 3a; Figure S39).
The bacterial viability was further analyzed by colony-
forming unit (CFU) assay, revealing that Cip@PGalNP
displayed the best antibiofilm performance as well (Fig-
ure 3b).
Scheme 2. Chemical structures of PGalNP, PGalHP, PEGNP, and
PGalN diblock copolymers.
To ascertain the cause of biofilm dispersal, we quantified
the nitrite concentrations within the biofilms by Griess
assay,[25] revealing the increased nitrite concentrations of
PEGNP, PGalNP, and Cip@PGalNP micelles after 630 nm
light irradiation (Figure 3c; Figure S40). This result suggested
that the red-light-triggered NO release from the micellar
nanoparticles resulted in biofilm dispersal. Interestingly,
PGalNP exhibited better antibiofilm performance than that
of PEGNP with similar NO loading contents yet different
coronas. The increased antibiofilm capacity was likely due to
the presence of galactose moieties, facilitating the penetration
of PGalNP micelles within the biofilm via binding to the
LecA of bacteria.[22] The increased biofilm penetration was
important to boost the NO release because of the increased
hypoxic condition within the interior of biofilms.[26] Indeed,
the increased NO release of PGalNP micelles was observed
(Figure 3c).
Figure 2. TEM images of PGalNP micelles a) before and b) after
630 nm irradiation for 30 min. Evolution of c) UV-vis spectra PGalNP
micelles (0.1 gLꢁ1) in the presence of sodium ascorbate (10 mM)
under 630 nm irradiation. d) Fluorescence intensity changes of PGalNP
micelles (0.1 gLꢁ1) in the presence of sodium ascorbate (10 mM)
under 630 nm irradiation. e) NO release profiles and f) Ciprofloxacin
(Cip) release profiles from Cip@PGalNP micelles under varying
conditions. Data are shown as mean ꢂ s.d. (n=3). In all cases, the
irradiation intensity was 30 mWcmꢁ2
.
Moreover, we used confocal laser scanning microscopy
(CLSM) to directly observe the NO-mediated biofilm dis-
persal (Scheme S4). Despite no evident biofilm dispersal
subjected to 630 nm light irradiation or Cip addition, we
observed decreased P. aeruginosa biofilms for PEGNP,
PGalNP, and Cip@PGalNP micelles under 630 nm light
NO-releasing performance (Figure S35), revealing that the
NO release process was not affected by the hydrophilic
corona. However, for PGalN micelles without the labeling of
PdTPTBP, no changes in UV-vis spectra were observed,
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conventional antibiotics, and it
is highly desirable to develop
new therapeutic agents for effi-
cient abscess treatment.[28] NO-
releasing nanoparticles have
previously been used for the
treatment of bacterial infec-
tions with the advantages of
no drug-resistance develop-
ment and accelerated wound
healing.[29] We subcutaneously
injected P. aeruginosa PAO1
microbes into mice to develop
skin abscesses.[26a] The bacterial
proliferation could be in-vivo-
monitored by the GFP fluores-
cence of PAO1 (Figure S42).
After 48 h of infection, cutane-
ous abscesses with evident der-
monecrosis and white lesions
(filled with fluid/pus) were
formed. The infected mice
were randomly divided into
five groups, receiving different
treatments including PBS, Cip,
PGalNP micelles with 630 nm
light irradiation, Cip@PGalNP
micelles without and with
630 nm light irradiation, re-
spectively. At predetermined
times, the abscesses were im-
aged, the bacterial burden in
the lesion tissues was counted,
and the lesion tissues were
evaluated by histological anal-
ysis (Figure 4a).
Figure 3. a) Bacterial biomass of P. aeruginosa biofilms by crystal violet staining and b) corresponding
bacterial viability after treatment with free Cip and PEGNP, PGalNP, and Cip@PGalNP micelles without
or with 630 nm light irradiation for 30 min, respectively. c) Quantification of nitrite concentrations by
Griess assay after treatment with free Cip and PEGNP, PGalNP, and Cip@PGalNP micelles without or
with 630 nm light irradiation for 30 min, respectively. Data are shown as mean ꢂ s.d. (n=3); p values
were calculated in comparison with the non-irradiated groups. **p<0.01; ***p<0.001; ****p<0.0001;
n.s., not significant. d) 3D CLSM images of P. aeruginosa biofilms stained with the LIVE/DEADꢁ BacLight
bacterial viability kit, which were treated with free Cip and PEGNP, PGalNP, and Cip@PGalNP micelles
without or with 630 nm light irradiation for 30 min (30 mWcmꢁ2), respectively. The green and red
channels were excited with a 488 nm laser and were collected at 500–545 nm (green) and 600–650 nm
(red), respectively. e) SEM images of P. aeruginosa biofilms treated with free Cip or PEGNP, PGalNP, and
Cip@PGalNP micelles without or with 630 nm light irradiation for 30 min (30 mWcmꢁ2), respectively. The
arrows indicate dead bacteria with disrupted membrane integrity. In all cases, the Cip and micelle
concentrations were 10 mgmLꢁ1 and 0.2 gLꢁ1, respectively.
The infected mice receiving
irradiation (Figure S41). Notably, the NO-mediated biofilm
dispersal was accompanied by the appearance of blue
fluorescence due to the in situ conversion of non-fluorescent
CouN(NO)-NO2 to fluorescent CouN(H)-NO2 moieties (Fig-
ure S37). More importantly, the red-light-triggered NO
release not only efficiently eradicated the biofilm but also
killed bacterial pathogens, as indicated by the LIVE/DEADꢁ
BacLight bacterial viability kit staining (Figure 3d). Cip@P-
GalNP micelles showed the best antibiofilm performance, as
evidenced by the significantly decreased green fluorescence
(living bacteria) and increased yellow and red fluorescence
(dead bacteria). Moreover, NO-mediated biofilm dispersal
was also confirmed by scanning electron microscopy (SEM)
analysis, revealing the efficient biofilm eradication and
disruption of bacterial membrane integrity under 630 nm
light irradiation (Figure 3e).[27]
PBS and Cip treatments showed negligible changes in the
abscess areas throughout the therapeutic procedure. How-
ever, PGalNP micelles with 630 nm light irradiation efficient-
ly accelerated the lesion healing, and the corelease of Cip and
NO from Cip@PGalNP micelles further augmented the
therapeutic outcomes (Figure 4b,c). By striking contrast,
Cip@PGalNP micelles without 630 nm irradiation did not
show evident therapeutic benefits compared with the PBS
control, indicating that the red-light-triggered corelease of
NO and Cip played a critical role in the antibacterial effect.
To prove the NO release in vivo under 630 nm light irradi-
ation, we used a NO-specific fluorescence probe (i.e., RhBP,
Figure S43) to detect the NO release.[30] The formation of
highly emissive rhodamine B was observed for PGalNP
micelle in the presence of RhBP probe with 630 nm light
irradiation, whereas control experiments using either PGalNP
micelles with RhBP without irradiation, PGalHP micelles
without NO-releasing capacity with or without 630 nm light
irradiation, or PGalNP micelles without RhBP probe with or
without 630 nm light irradiation revealed no detectable
emission of RhB (Figure S43). This result potently revealed
that red-light-triggered NO release from PGalNP micelles
Treatment of P. aeruginosa infection in a cutaneous
abscess model. After in vitro screening of the antibiofilm and
antibacterial performance of NO-releasing micelles, we chose
PGalNP micelles with better antibacterial activity to further
explore the anti-infection applications in vivo. Cutaneous
abscess infections are very common and difficult to treat with
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Figure 4. a) Experimental timeline of in vivo treatment of bacterial infection in a cutaneous abscess model. b) Representative images of the
abscess during the treatment process and c) quantitative analysis of the infected areas receiving different treatments. **p<0.01, ***p<0.001
compared with the PBS group. d) Photographs of bacterial colonies on the agar plates of the abscess tissues with varying treatments. e) Bacterial
colony-forming unit separated from abscess tissues with varying treatments. *p<0.05, ***p<0.001, ****p<0.0001, compared with the group
receiving Cip@PGalNP (+hv) treatment on day 7. f) Changes of body weights of P. aeruginosa biofilm-infected mice after different treatments.
*p<0.05. g) Histological and immunofluorescence analysis on days 3, 5, and 7 of the mice infected with P. aeruginosa receiving varying
treatments (the black arrows indicate collagen deposition and white triangles suggest re-epithelialization). Scale bar: 100 mm. In all cases, the Cip
and micelle concentrations were 10 mgmLꢁ1 and 0.2 gLꢁ1, respectively.
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could be in situ detected by RhBP probe. Therefore, the red-
light-triggered NO release can be achieved in physiological
conditions, representing a feasible approach to locally deliver
NO.
Quantitative analysis by CFU assay of the abscess tissues
after various treatments revealed that the least bacterial
burden of Cip@PGalNP-treated group under 630 nm light
irradiation (Figure 4d,e). Moreover, the Cip@PGalNP-treat-
ed group resulted in the recovery of body weights (Figure 4 f).
Histological and immunofluorescence analyses revealed that
the red-light-mediated NO release from Cip@PGalNP mi-
celles markedly decreased the in-
nism.[16a] However, we found that the PdTPTBP monomer
had a LUMO energy level of ꢁ2.61 eV, which was higher than
CouN(NO)-NO2 (ꢁ3.14 eV). This higher LUMO energy level
provided a driving force for the electron transfer (ET) from
PdTPTBP to CouN(NO)-NO2 upon excitation. By contrast,
the LUMO energy levels of CouN(NO)-H (ꢁ2.57 eV) and
CouN(NO)-OCH3 (ꢁ2.44 eV) were higher than that of
PdTPTBP, indicating unfavorable ET from PdTPTBP (Fig-
ure 5a). The above result led to the postulation that the NO
release from CouN(NO)-R was activated through a photo-
induced electron transfer (PeT) process.
filtration of inflammatory cells,
boosted collagen deposition in the
wound areas, and facilitated re-
epithelialization, in line with the
physiological effects of NO in ac-
celerating lesion healing (Fig-
ure 4g).[31] Importantly, we found
that PGalNP micelles exhibited
negligible toxicity toward normal
mammalian cells such as L929 cells
(Figure S44). In addition, PGalNP
and PGalHP micelles showed neg-
ligible hemolysis behavior (Fig-
ure S45). Hence, the NO-releasing
PGalNP could be potentially used
as a novel antibiofilm and antibac-
terial agent with low toxicity to-
ward normal cells.
Study on NO-releasing mecha-
nism. PdTPTBP photosensitizer
was overwhelmingly used as a trip-
let energy donor in triplet-triplet
annihilation upconversion (TTA-
UC) due to the relatively high
triplet energy level.[21b,23,32] We first
hypothesized that the activation of
CouN(NO)-R moieties in the pres-
ence of PdTPTBP through a TTET
process. As such, we calculated the
triplet energy of PdTPTBP and
CouN(NO)-R moieties. The triplet
energy (T1) of the PdTPTBP mo-
nomer was determined to be
ꢀ 1.55 eV according to the phos-
phorescence emission spectrum
(Figure S46). The T1 energy of
CouN(NO)-NO2, CouN(NO)-H,
and CouN(NO)-OCH3 were calcu-
lated to be 2.15, 2.17, and 2.23 eV,
respectively, using time-dependent
density
functional
theory
Figure 5. a) The relative energetic dispositions for the frontier orbitals (HOMO and LUMO) of
PdTPTBP monomer and CouN(NO)-R derivatives. b) Free energy profiles for the PeT process from
the triple excited state of [PdTPTBP]* ([D]*) to CouN(NO)-R (A(NO)) under red-light irradiation: red-
(TDDFT) at the level of B3LYP/
6–31 + G(d, p), which were much
higher than that of PdTPTBP
(> 0.6 eV), precluding the possibil-
ity of activation of CouN(NO)-R
moieties through a TTET mecha-
+
light-mediated electron transfer ([D]* + A(NO) ! [D]C + [A(NO)]Cꢁ), the subsequent NO release
([A(NO)]Cꢁ ! [A]ꢁ + CNO), the conversion of [A]ꢁ to [A]C through the ET from [A]ꢁ to [D]C+, and the
combination of [A]C and [CH] into AH. DFT calculations were performed at the B3LYP/6-31+G(d,p)
level.
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Angewandte
Research Articles
Chemie
To confirm the PeT mechanism, we measured the excited
redox potential of E1/2(PdTBTBPC /PdTPTBP*) using cyclic
Acknowledgements
+
voltammetry, which was determined to be ꢁ0.8 V (potential
vs. an Ag/AgCl electrode in DMF). The reduction potentials
of CouN(NO)-NO2, CouN(NO)-H, and CouN(NO)-OCH3
were calculated to be ꢁ0.74, ꢁ1.17, and ꢁ1.21 V, respectively
(Figure S47). As such, PdTBTBP could potentially reduce
CouN(NO)-NO2 at the excited state, whereas the reduction of
CouN(NO)-H and CouN(NO)-OCH3 was less effective, in
good agreement with the decreased NO-releasing rates
(Table S2). Moreover, we applied the Marcus theory[33] to
calculate the activation Gibbs free energy barrier of the ET
from [PdTPTBP]* to CouN(NO)-R moieties (Figure S48).
Remarkably, the energy barrier for the ET reaction between
[PdTPTBP]* and CouN(NO)-NO2 was as low as DG† =
1.61 kcalmolꢁ1, whereas much higher barriers were observed
for CouN(NO)-H and CouN(NO)-OCH3 (8.64 and
12.74 kcalmolꢁ1; Figure 5b).
The authors gratefully acknowledge the financial support of
the National Key R&D Program of China
(2020YFA0710700), the National Natural Scientific Founda-
tion of China (NNSFC) Projects (51690150, 51690154,
52073270, 51722307, and 22073090), and the Fundamental
Research
Funds
for
the
Central
Universities
(WK2060190102).
Conflict of Interest
The authors declare no conflict of interest.
Keywords: abscess · antibiofilm · bacterial infection ·
nitric oxide · self-reporting release
Building on the above results, we proposed the following
mechanism for NO release. Upon red-light excitation, the
excited PdTPTBP in its triplet state reduced CouN(NO)-R
moieties via ET with the formation of [CouN(NO)-R]Cꢁ.
Then, [CouN(NO)-R]Cꢁ species underwent spontaneously
release of NO radical with the formation of [CouN-R]ꢁ,
while [CouN-R]ꢁ was oxidized to [CouN-R]C after the
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Manuscript received: May 28, 2021
Revised manuscript received: June 22, 2021
Accepted manuscript online: July 1, 2021
Version of record online: && &&
,
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Research Articles
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Research Articles
Photoredox Catalysis
Red-light-mediated photoredox catalysis
for self-reporting nitric oxide release is
reported in the presence of palladium(II)
tetraphenyltetrabenzoporphyrin. The NO-
releasing platform eradicates Pseudomo-
nas aeruginosa biofilm in vitro and treats
bacterial infection in vivo.
Z. Shen, S. Zheng, S. Xiao,* R. Shen,
S. Liu,* J. Hu*
&&&& — &&&&
Red-Light-Mediated Photoredox Catalysis
Enables Self-Reporting Nitric Oxide
Release for Efficient Antibacterial
Treatment
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These are not the final page numbers!