Fluorescent and Biocompatible Ruthenium-Coordinated Oligo(p-phenylenevinylene) Nanocatalysts for Transfer Hydrogenation in the Mitochondria of Living Cells

Article abstract of DOI:10.1002/chem.201905448

It is challenging to design metal catalysts for in situ transformation of endogenous biomolecules with good performance inside living cells. Herein, we report a multifunctional metal catalyst, ruthenium-coordinated oligo(p-phenylenevinylene) (OPV-Ru), for intracellular catalysis of transfer hydrogenation of nicotinamide adenine dinucleotide (NAD⁺) to its reduced format (NADH). Owing to its amphiphilic characteristic, OPV-Ru possesses good self-assembly capability in water to form nanoparticles through hydrophobic interaction and π–π stacking, and numerous positive charges on the surface of nanoparticles displayed a strong electrostatic interaction with negatively charged substrate molecules, creating a local microenvironment for enhancing the catalysis efficiency in comparison to dispersed catalytic center molecule (TOF value was enhanced by about 15 fold). OPV-Ru could selectively accumulate in the mitochondria of living cells. Benefiting from its inherent fluorescence, the dynamic distribution in cells and uptake behavior of OPV-Ru could be visualized under fluorescence microscopy. This work represents the first demonstration of a multifunctional organometallic complex catalyzing natural hydrogenation transformation in specific subcellular compartments of living cells with excellent performance, fluorescent imaging ability, specific mitochondria targeting and good chemoselectivity with high catalysis efficiency.

Full text of DOI:10.1002/chem.201905448

A Journal of
Accepted Article
Title: Fluorescent and Biocompatible Ruthenium-Coordinated Oligo(p-
phenylenevinylene) Nanocatalyst for Transfer Hydrogenation in
Mitochondria of Living Cells
Authors: Shu Wang
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To be cited as: Chem. Eur. J. 10.1002/chem.201905448
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Fluorescent and Biocompatible Ruthenium-Coordinated Oligo(p-
phenylenevinylene) Nanocatalyst for Transfer Hydrogenation in
Mitochondria of Living Cells
Nan Daia,b, Hao Zhaoa,b, Ruilian Qia, Yanyan Chena, Fengting Lva, Libing Liua,b and Shu Wang a,b
*
Abstract: It is challenging to design metal catalysts for in situ
transformation of endogenous biomolecules with good performance
inside living cells. Herein, we report a multifunctional metal catalyst,
ruthenium-coordinated oligo(p-phenylenevinylene) (OPV-Ru), for
intracellular catalysis of transfer hydrogenation of nicotinamide
adenine dinucleotide (NAD+) to its reduced format (NADH). Owing to
its amphiphilic characteristic, OPV-Ru possesses good self-
assembly capability in water to form nanoparticles through
hydrophobic interaction and π-π stacking, and numerous positive
specific subcellular organelles with good intracellular catalysis
ability have been rarely reported. Considering that, it would be
appealing to design a fluorescent organelle-targeted metal
catalyst for intracellular catalysis.
charges on the surface of nanoparticles displayed
electrostatic interaction with negatively charged substrate molecules,
creating local microenvironment for enhancing the catalysis
a strong
a
efficiency in comparison to dispersed catalytic center molecule (TOF
value was enhanced by about 15 folds). OPV-Ru could selectively
accumulate in mitochondria of living cells. Benefiting from its
inherent fluorescence, the dynamic distribution in cells and uptake
behavior of OPV-Ru could be visualized under fluorescence
microscopy. This work represents the first demonstration to perform
a
multifunctional organometallic complex to catalyze natural
hydrogenation transformation in specific subcellular compartments of
living cells with excellent performance, including fluorescent imaging
ability, specific mitochondria targeting, good chemoselectivity and
high catalysis efficiency.
Synthetic metal catalysts, as an alternative to natural
enzymes, have been broadening the scope of intracellular
chemical transformations1-4. The design and synthesis of new
metal catalysts creates vast possibilities for their application in
biosystems, such as developing metal-based drugs, in situ
synthesizing fluorescent molecules and activating prodrugs5-7
.
Figure 1. a) Chemical structure of OPV-Ru. b) Synthesis route
However, due to the complexity of cellular environment, the
transformation mediated by metal catalysts inside living cells is
quite difficult from that in aqueous solution. It requires the metal
catalysts to possess many properties including good
biocompatibility, stability in physiological conditions, certain
water dispersibility as well as hydrophobicity for easy uptake by
cells, high activity, etc. Despite of these challenges, numerous
metal catalysts have been successfully developed for
of OPV-Ru.
As oligo(p-phenylenevinylene) (OPV) and its derivatives are
easy to assemble in water through π-π stacking and
hydrophobic interaction, it will contribute to amplifying the
function of functional groups through improving local
concentration14. Also due to their good biocompatibility, OPV
derivatives have been widely applied in biological field such as
imaging and cancer therapy15-16. In view of this, it is exciting to
know whether it is possible to enhance the catalytic activity
inside living cells by linking a metal active site to an OPV
backbone. In addition, OPV derivatives usually exhibit strong
fluorescence under visible light excitation, which will provide
advantages for studying the endocytosis mechanism of metal
catalyst and its dynamic distribution inside cells. Furthermore,
because of its significance in regulating cell functions,
mitochondrion was chosen as a certain place for intracellular
catalysis. Based on above considerations, herein, we design an
intracellular catalysis, including metal nanoparticles8-10
entrapped metal nanoparticles11 and metal complexes12-13
However, fluorescent traceable metal catalysts that can target
,
.
[a]
[b]
Prof. S. Wang, Dr. L. Liu, Dr. F. Lv, N. Dai, H. Zhao, Dr. R. Qi, Dr. Y.
Chen
Beijing National Laboratory for Molecular Sciences, Key Laboratory
of Organic Solids, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, P. R. China.
E-mail: wangshu@iccas.ac.cn
oligo(p-phenylenevinylene)-ruthenium
complex
(OPV-Ru),
Prof. S. Wang, Dr. L. Liu, N. Dai, H. Zhao
College of Chemistry, University of Chinese Academy of Sciences,
Beijing 100049, P. R. China
composed of OPV backbone, a mitochondria targeted group and
a catalytic activity center (Fig. 1a). The activity center is a
Noyori-type ruthenium transfer hydrogenation catalyst which
could catalyze the hydrogenation of C=O of aldehydes, ketones
and C=N of imines17-19. Benzyldiphenylphosphonium which is
similar to triphenylphosphonium (TPP) is utilized as the targeting
Supporting information for this article is given via a link at the end of
the document.
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Figure 2. a) Absorption and emission spectra. b) DLS analysis and zeta potential measurement, [OPV-Ru] = 100 μM. c) TEM image,
[OPV-Ru] = 100 μM. d) Solvent-dependent 1H NMR spectra, [OPV-Ru] = 200 μM. e) Schematic self-assembly of OPV-Ru in water.
group. TPP cation has been demonstrated numerously to be
capable of targeting mitochondria efficiently20. It is noted that
bioactive molecule nicotinamide adenine dinucleotide (NAD+) is
a crucial coenzyme in eukaryotic cells, which plays a critical role
in a variety of physiological activities including cell material
metabolism, energy synthesis and cell DNA repair21-22. The
interconversion between NAD+ and its reduced format (NADH)
regulates many metabolic pathways, including glycolysis, citric
acid cycle and oxidative phosphorylation23-24. Besides, the
NAD+/NADH ratio is also a symbol of redox state of mammalian
cell25. We therefore choose this natural transformation of NAD+
to NADH as a model reaction catalyzed by OPV-Ru.
the active ester of 3-(diphenylphosphino)propionic acid and then
with active benzyl bromide to produce a positively charged OPV-
+
+
PPh2 -NHBoc. After removing the protective group, OPV-PPh2 -
NH2 coordinated with ruthenium precursor to generate the target
metal complex OPV-Ru (Fig. 1b). Detailed synthetic procedures
and molecular characterizations are provided in Supporting
Information.
The photophysical properties of OPV-Ru were studied in
water. As shown in Fig. 2a, the OPV-Ru complex exhibits two
absorption peaks respectively at 320 nm and 380 nm, and an
emission maximum at 450 nm. The absolute fluorescence
quantum yield of OPV-Ru was measured to be 6.7% in water.
To study the aggregation of OPV-Ru in water, dynamic light
scattering (DLS), 1H nuclear magnetic resonance (NMR)
spectroscopy and transmission electron microscopy (TEM) were
employed. DLS measurement results showed that OPV-Ru
formed nanoparticles with an average diameter of 50.6  2.1 nm
and its zeta potential was +23.1  0.8 mV (Fig. 2b), which also
was confirmed by TEM image (Fig. 2c). Broad proton signals for
aromatic rings of OPV-Ru in water suggested that OPV-Ru
Fig. 1a shows the chemical structure of OPV-Ru. OPV
backbone with three benzene rings and a six-carbon alkyl chain
was designed for cell imaging and its hydrophobicity provides
driving
force
for
self-assembly
in
water.
Cationic
benzyldiphenylphosphonium group and ruthenium complex were
covalently linked to the end of the alkyl chain acting for
mitochondria targeting and catalysis, respectively. The positive
charge ensures a good water dispersibility of the catalyst. In
brief, monomer 1 reacted with styrene to get OPV-NHBoc, which
was deprotected to OPV-NH2 afterwards. OPV-NH2 reacted with
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Figure 3. a) Transfer hydrogenation of NAD+ to NADH catalyzed by OPV-Ru with HCOONa as hydrogen source. b) Influence of
OPV-Ru content on the conversion of NAD+, [NAD+] = 0.1 mM, [HCOONa] = 100 mM, in water, 37 oC. c) Effect of HCOONa
concentration on the conversion of NAD+, [NAD+] = 0.1 mM, [OPV-Ru] = 0.01 mM, in water, 37 oC. d) Plot of the TOF against
HCOONa concentration with a fitted Michaelis-Menten-type equation. e) Plot of the reciprocal of the TOF against HCOONa
concentration.
formed extensive aggregates. With increasing the ratio of d6-
DMSO, the broad peaks gradually sharpened and were shifted
downfield. For example, the signal of α proton was shifted from δ
= 7.714 to 7.907 ppm over the ratio of DMSO increasing from
50% to 100% (Fig. 2d). Solvent-dependent 1H NMR
spectroscopy further revealed that OPV-Ru aggregated in water
(Fig. 2e). Therefore, the self-assembly of OPV-Ru in water was
verified clearly. It is noted that, in comparison with OPV-Ru, Ts-
Ru lacks self-assembly capability as shown by its TEM, although
it exhibits a larger hydration particle size (164.4  5.3 nm) while
with much smaller zeta potential (+3.63  0.4 mV) (Fig. S1).
fixed concentration of HCOONa (Fig. 3b). With 5% OPV-Ru, the
NADH production yield reached 70% within 60 min. Upon
increasing OPV-Ru to 10%, more NADH was produced with
faster rate, reaching a yield of 93% within 45 min. Further
increment of OPV-Ru to 15% nearly completed the
transformation, giving a yield of 96% at 41 min. As HCOONa
served as
a hydrogen source, the effect of HCOONa
concentration on this reaction was also studied (Fig. 3c). With
increasing concentration of HCOONa from 5 mM to 100 mM,
both the production of NADH and reaction rate were improved,
which shows that HCOONa could accelerate this catalytic
process. Plot of the TOF versus HCOONa concentration
indicated a typical Michaelis–Menten behavior (Fig. 3d). From
the reciprocal of TOF versus HCOONa concentration, the
maximum turnover frequency (TOFmax) and Michaelis constant
(KM) were determined to be 11.91 h-1 and 6.3 mM, respectively
(Fig. 3e).
The catalytic activity of OPV-Ru in transforming NAD+ to
NADH with HCOONa as hydrogen source (Fig. 3a) in water was
firstly assessed by UV-visible spectroscopy. The catalysis
process was monitored with absorbance variation at 340 nm
assigned to NADH over NAD+. According to the standard curve
of NADH concentration versus its absorbance at 340 nm (Fig.
S2), the yield of NADH could be determined. Firstly, the effect of
OPV-Ru concentration on this reaction was investigated with a
To investigate the relationship between aggregation of OPV-
Ru and its catalytic efficiency, we compared OPV-Ru and
catalysis center (p-cymene)Ru(TsEn)Cl (Ts-Ru, Fig. 4a) on the
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Figure 4 a) Chemical structures of OPV-Ru aggregate and dispersed Ts-Ru. b) Transfer hydrogenation of NAD+ by OPV-Ru and Ts-
Ru in water at 37 oC. [NAD+] = 0.1 mM, [OPV-Ru] = 0.01 mM, [Ts-Ru] = 0.01 mM, [HCOONa] = 100 mM. c) TOF values of OPV-Ru
and Ts-Ru. d) ITC result, where observed enthalpy changes against NAD+/catalyst ratio by titrating 5 mM NAD+ into 0.2 mM OPV-Ru
or Ts-Ru in water.
transfer hydrogenation of NAD+, as Ts-Ru lacks self-assembly
capability (shown in Fig. S1). As shown in Fig. 4b, the transfer
hydrogenation catalyzed by OPV-Ru reached endpoint at about
45 min while Ts-Ru required more than 600 min under the same
condition. It is remarkable that OPV-Ru realized 55% yield within
10 min while Ts-Ru only reached a yield of 1.8%, which clearly
revealed the high catalytic efficiency of OPV-Ru. In addition,
calculated TOF value of OPV-Ru was 14.5 folds higher than that
of Ts-Ru (Fig. 4c). Since both OPV-Ru and Ts-Ru are positively
charged with a zeta potential of +23.1  0.8 mV and +3.63  0.4
mV, respectively, while NAD+ is negatively charged, we utilized
isothermal titration calorimetry (ITC) to verify the relationship of
catalyst activity and their interactions with NAD+. As shown in
Fig. 4d, the ITC results demonstrated that the interaction
between OPV-Ru and NAD+ was an exothermic process, and its
binding constant was measured to be 7.04 x 104 M-1 with a
binding ratio of 0.896. However, there was no obvious enthalpy
change in the titrating process of NAD+ to Ts-Ru. These results
showed that NAD+ preferred to bind to OPV-Ru nanoparticles
rather than dispersed Ts-Ru. Thus, OPV-Ru nanoparticles with
dense positive charges can bring substrates and catalytic
centers into closer proximity and provide
a
local
microenvironment for significantly enhancing the catalytic
efficiency.
Different types of substrate, including aldehyde, ketone,
imine, carboxylic acid and amide, were employed for the transfer
hydrogenation catalyzed by OPV-Ru, with HCOONa as
hydrogen source in D2O/d6-DMSO (v/v = 3 : 2) at 37 oC (Fig. 5a).
These reactions were all confirmed by 1H NMR spectra (Fig. S3).
OPV-Ru displayed a good activity in the reduction of C=O of
aromatic aldehyde S1 and C=N of aromatic imine S5 both with
100% yield, moderate activity in transforming C=O of aromatic
Figure 5. a) Scope of the OPV-Ru catalyzed transfer
hydrogenation. [Substrate] = 2 mM, [OPV-Ru] = 0.4 mM,
[HCOONa] = 50 mM, in D2O and d6-DMSO (3:2), 37 oC. 1H NMR
was employed to monitor the reaction and determine the yield. b)
Proposed mechanism for OPV-Ru catalyzed reduction of NAD+
in water with HCOONa as hydrogen source.
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Figure 6. a) Intracellular transfer hydrogenation of NAD+ to NADH catalyzed by OPV-Ru with HCOONa as hydrogen source. b)
Mitochondria targeting ability of OPV-Ru and its dynamic distribution in living cells. Colocalization of OPV-Ru and Mito-Tracker Red-
FM dye in A2780 cells after incubation for 1 h. c) Colocalization of OPV-Ru and Lyso-Tracker DND 99 in A2780 cells after incubation
for 24 hours. d) Intracellular NAD+ ratio variation after treatment of A2780 cells with fresh medium, HCOONa (2 mM), OPV-Ru (16 µM)
and HCOONa (2 mM) + OPV-Ru (16 µM) for 1 h, 2 h, 4 h, 12 h and 24 h, respectively. NAD+ ratio = [NAD+]/[total NAD+/NADH]. For
blue line: Δ NAD+ ratio = (NAD+ ratio in blank group) - (NAD+ ratio in OPV-Ru group); for red line: Δ NAD+ ratio = (NAD+ ratio in
o
HCOONa group) - (NAD+ ratio in HCOONa + OPV-Ru group). e) Influence of pH on the conversion of NAD+ at 37 C. [NAD+] = 0.1
mM, [HCOONa] = 100 mM, [OPV-Ru] = 0.01 mM.
ketone S2 with 64% yield, while no reactions were observed for
alkyl aldehyde S3, alkyl ketone S4, aromatic carboxylic acid S6
and aromatic amide S7. The chemoselectivity of OPV-Ru
indicated its good biocompatibility as biological systems are
mostly composed of amino acids and proteins. Based on
between OPV-Ru (1) and H2O and HCOONa via intermediates 2
and 3 to generate active species OPV-Ru-H (4). This active
intermediate reacted with NAD+ to form a hexatomic ring species
(5) following by the generation of NADH and the catalyst
returned to its original state. It is apparent that interaction
between OPV-Ru and substrate NAD+ is vital for the whole
catalytic process.
previous research on Noyori-type ruthenium catalysts,
a
possible mechanism for the transfer hydrogenation of NAD+ by
OPV-Ru was proposed (Fig. 5b). It mainly involved interactions
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After a series of characterization in aqueous solution, OPV-
Ru was introduced into living cells for biological application (Fig.
6a). We first investigated its ability in targeting mitochondria and
decreased by certain proportion (Fig. S7c). After 12 hours,
almost no change of NAD+ ratio could be monitored in the
experimental groups, compared to that of blank group (Fig. S7d),
which implied that intracellular NAD+ and NADH reached a state
of balance again. The comparison for OPV-Ru group and blank
group as well as that for HCOONa group and HCOONa/OPV-Ru
group are summarized (Fig. 6d), from which conditions and
rules of intracellular catalysis by OPV-Ru were clearly figured
out. It is noted that, 24 hours later, also no obvious NAD+ ratio
variation in experimental groups was detected (Fig. S7e), which
probably because this catalysis cannot proceed in lysosome.
This is confirmed by the pH-dependent catalysis behavior of
OPV-Ru. As shown in Fig. 6e, the reduction process cannot
occur at pH 4.1, which it is apparent that OPV-Ru cannot play its
catalytic role in lysosome, where environment is acidic.
A2780 human ovarian cancer cell was selected as
a
representative. MTT assay (Fig. S4) showed that OPV-Ru lower
than 16 µM had little effect on the growth of A2780 cells, which
verified a good biocompatibility of OPV-Ru. OPV-Ru could enter
A2780 cells within
1 hour and was mostly located in
mitochondria with a Pearson correlation coefficient of 0.85,
demonstrated by colocalizing OPV-Ru with the mitochondrion
tracker dye (Fig. 6b). After continuous incubation for 12 hours,
most OPV-Ru remained accumulated in mitochondria with a
Pearson correlation coefficient of 0.74 (Fig. S5a-b). Whereas
after incubation of 24 hours, the confocal images showed that
almost no OPV-Ru existed in mitochondria (Fig. S5c-d). Further
colocalization with lysosomal tracker dye demonstrated its wide
distribution in lysosomes (Fig. 6c). Through cell imaging, the
mitochondria targeting ability of OPV-Ru and its dynamic
distribution in cells were clearly revealed. To deeply investigate
the endocytosis mechanism of OPV-Ru, A2780 cells were
treated in different conditions including low temperature (4 oC),
dynasore, chlorpromazine (CPZ), sucrose and nystatin. Then
cells were photographed using confocal laser scanning
microscopy (CLSM) (Fig. S6a) and fluorescence intensity of
OPV-Ru in each image were analyzed quantitatively (Fig. S6b).
It was observed that the internalization of OPV-Ru was strongly
inhibited at 4 oC, which implied the endocytosis process was
energy-dependent. In addition, the uptake was completely
suppressed by dynasore, an inhibitor of dynamin, which is
essential for clathrin-dependent coated vesicle formation as well
as some clathrin-independent endocytosis pathways such as
caveolae-dependent pathway. However, the endocytosis was
scarcely suppressed by nystatin, which excluded a caveolae-
dependent endocytosis pathway. In addition, the fluorescence of
OPV-Ru was decreased to 19% and 59% in the presence of
sucrose and CPZ, respectively. Therefore, the internalization
was mostly dominated by clathrin-dependent endocytosis
pathway.
In summary, we designed and synthesized
a novel
amphiphilic conjugated oligomer-based Noyori-type ruthenium
complex OPV-Ru, which could self-assemble into nanoparticles
in water. With numerous positive charges accumulated on the
surface of OPV-Ru nanoparticles, it displayed
a strong
electrostatic interaction with negatively charged NAD+ molecules,
creating a local microenvironment for enhancing the catalytic
transfer hydrogenation of NAD+ to NADH. Benefiting from
inherent fluorescence of OPV-Ru, the dynamic distribution in
cells and uptake behavior of OPV-Ru could be traced under
fluorescence
microscopy.
With
a
cationic
benzyldiphenylphosphine group, OPV-Ru could selectively
accumulate in mitochondria of living cells. Importantly, OPV-Ru
displayed a remarkable activity in reducing intracellular NAD+
ratio. Overall, this work provides a new strategy for designing
multifunctional organometallic complex to work perfectly inside
living cells with excellent performance, including fluorescent
imaging ability, specific mitochondria targeting, good
chemoselectivity and high catalysis efficiency.
Acknowledgements
The catalytic activity of OPV-Ru in cells was investigated
through NAD+/NADH ratio assay kit, which can measure the
content of total NAD+/NADH as well as NAD+. Initially,
cytotoxicity of HCOONa was evaluated by MTT assay (Fig. S4b),
which showed that millimolar level of HCOONa was nontoxic to
cell growth. Four groups were set up for comparison, including
blank group, group treated with HCOONa, group treated with
OPV-Ru and group treated with HCOONa/OPV-Ru. After
incubation for 1, 2, 4, 12 and 24 hours, respectively, cells of the
four groups were respectively collected and treated for
measurement. At 1 hour, NAD+ ratio in blank group was found to
be 71% and OPV-Ru alone barely affected NAD+ ratio of cells.
While HCOONa/OPV-Ru decreased the ratio of NAD+ by 23%,
compared with that in HCOONa group (Fig. S7a). The results
demonstrated a high catalytic activity of OPV-Ru in converting
NAD+ to NADH intracellularly. After 2 hours, in comparison with
HCOONa group, NAD+ ratio in group of HCOONa/OPV-Ru was
reduced by 18% (Fig. S7b). It is worth mentioning that NAD+
ratio in OPV-Ru group was decreased by 11%, compared to that
of blank group. It is different from the transfer hydrogenation in
aqueous solution, which requires both OPV-Ru and HCOONa.
Probably endogenous reductants served as hydrogen source
here. Similarly, after 4 hours, intracellular NAD+ ratios in the
presence of OPV-Ru and HCOONa/OPV-Ru were both
The authors are grateful to the National Natural Science
Foundation of China (Nos. 21533012, 21661132006) and the
Strategic Priority Research Program of the Chinese Academy of
Sciences (XDA16020804).
Keywords: ruthenium catalyst • biocatalysis • intracellular
catalysis • transfer hydrogenation • mitochondria
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A multifunctional metal catalyst,
ruthenium-coordinated oligo(p-
phenylenevinylene) (OPV-Ru) is
developed for intracellular catalysis
of transfer hydrogenation reaction.
OPV-Ru self-assembles into
nanoparticles and subsequently
work perfectly inside living cells
with excellent performance,
including fluorescent imaging
ability, specific mitochondria
targeting, good chemoselectivity
and high catalysis efficiency.
Nan Dai, Hao Zhao, Ruilian Qi,
Yanyan Chen, Fengting Lv, Libing Liu
and Shu Wang
Page No. – Page No.
Fluorescent and Biocompatible
Ruthenium-Coordinated Oligo(p-
phenylenevinylene) Nanocatalyst
for Transfer Hydrogenation in
Mitochondria of Living Cells
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