A Biocompatible Heterogeneous MOF–Cu Catalyst for In Vivo Drug Synthesis in Targeted Subcellular Organelles

Article abstract of DOI:10.1002/anie.201901760

As a typical bioorthogonal reaction, the copper-catalyzed azide–alkyne cycloaddition (CuAAC) has been used for drug design and synthesis. However, for localized drug synthesis, it is important to be able to determine where the CuAAC reaction occurs in living cells. In this study, we constructed a heterogeneous copper catalyst on a metal–organic framework that could preferentially accumulate in the mitochondria of living cells. Our system enabled the localized synthesis of drugs through a site-specific CuAAC reaction in mitochondria with good biocompatibility. Importantly, the subcellular catalytic process for localized drug synthesis avoided the problems of the delivery and distribution of toxic molecules. In vivo tumor therapy experiments indicated that the localized synthesis of resveratrol-derived drugs led to greater antitumor efficacy and minimized side effects usually associated with drug delivery and distribution.

Full text of DOI:10.1002/anie.201901760

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Biocompatible Heterogeneous MOF-Cu Catalyst Used for In Vivo
Drug Synthesis at Targeted Subcellular Organelles
Authors: Xiaogang Qu, Faming Wang, Yan Zhang, Zhi Du, Jinsong
Ren, Zhengwei Liu, and Lu Zhang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201901760
Angew. Chem. 10.1002/ange.201901760
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10.1002/anie.201901760
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Biocompatible Heterogeneous MOF-Cu Catalyst Used for In Vivo
Drug Synthesis at Targeted Subcellular Organelles
Faming Wang, Yan Zhang, Zhengwei Liu, Zhi Du, Lu Zhang, Jinsong Ren and Xiaogang Qu*
Abstract: As a typical bioorthogonal reaction, copper-catalyzed
azide-alkyne cycloaddition (CuAAC) reaction has been used for drug
design and synthesis. However, for localized drug synthesis, it is still
an urgent conundrum for artificially determining the location where
CuAAC reaction occurred in living cells. Herein, we constructed a
heterogeneous copper catalyst on metal-organic frameworks, which
could preferentially accumulate in mitochondria of living cells with
high catalytic activity and have been successfully demonstrated by in
vivo tumor therapy. Our system could realize localized drug
synthesis via site-specific CuAAC reaction in mitochondria and had a
wide applicability for synthesizing multiple drugs with good
biocompatibility. Importantly, the subcellular catalytic process for
localized drug synthesis avoided the problems of delivery and
distribution of toxic molecules. In vivo tumor therapy experiments
indicated that the localized synthesized resveratrol derived drug
showed better antitumor efficacy, and could enhance the expected
functions and minimize the side effects of target drugs. This is
crucial for decreasing multiple side effects occurred in drug delivery
and distribution.
about toxicity, delivery and localization of the synthesized active
drug molecules are emergent and inevitable.[8] For living system,
not only the misplaced biomolecules would cause severe
diseases but also the misplaced drugs would cause serious side
effects.[9] Actually, the active drugs may have totally different
properties at different sites in living cells. For example,
mitochondria have been important targets of many drugs as their
critical roles in maintaining cellular survival and function.[10] So,
localized synthesis of drugs at corresponding drug target sites
has become a more attractive mode for drug intake, which can
maximize the expected functions and minimize the side effects
of the same drugs.[11] To solve the relative problems, the
concept of “click to release” for drug synthesis and delivery has
been put forward.[12] Although it is good at releasing active drugs
after click reactions occurring, the complex pre-modification of
each desire drug results in huge difficulties in application. In
contrast, through CuAAC reaction, the simplest terminal alkyne
and azide could achieve a desired compound or drug avoiding
complex pre-synthesis. This “Bottom-up” model for drug
synthesis is more suitable for a variety of desire drugs. However,
site-specific CuAAC reaction for localized drug synthesis in living
cells is still in infant stage.[13] Bradley et al. designed a
heterogeneous copper catalyst to synthesize an anticancer
agent. However, the size of their resin beads catalyst was
around 150 μm, which was much larger than cells. Thus, the
catalyst could not be endocytosed by living cells and the
reactions were carried out in extracellular matrix. They further
developed dual drug synthesis by using cancer-targeting
palladium catalysts.[13b]
As a typical catalyst for CuAAC reaction, CuI ion has
drawbacks in producing reactive oxygen species and causing
severe cytotoxicity in living cells.[14] Besides, homogeneous Cu-
organic ligands catalysts are still challenging in the issues of
water solubility, stability and biocompatibility.[15] Though copper-
free strain-promoted azide-alkyne cyclo-addition (SPAAC)
reaction could avoid toxic copper ion, the reaction substrates of
SPAAC reaction are limited to strained alkynes and the strained
alkynes may react with intracellular nucleophiles.[16] Recently,
non-toxic, heterogeneous metal catalysts are used successfully
in multiple bioorthogonal reactions.[17] Regretfully, so far, few
heterogeneous catalysts of CuAAC reaction could meet the
requirements of localized drug synthesis under subcellular
organelles.
Bioorthogonal chemistry has emerged as a powerful toolbox
for manipulating biological processes in the native
environment.[1]
A series of chemical reactions, which are
orthogonal to most functional groups in biological systems, have
shown great potential to selectively modulate specific events.[2]
Among them, owing to the high selectivity and efficiency, click
chemistry has demonstrated satisfactory adaptability in chemical
and biological fields.[3] Typically, the copper-catalyzed azide-
alkyne cycloaddition (CuAAC) reaction has become one of the
most powerful tools in chemical biology.[4] So far, the CuAAC
reactions and the derived reactions have been successfully
applied for labeling protein, glycans, lipids, and nucleic acids in
vitro.[5] Besides, another important contribution of click reaction
is present in pharmaceutical science. Click chemistry has an
advantage in drug synthesis, which can accelerate drug
discovery process.[6] However, most of the drug synthesis
through click chemistry by now are carried out under a “two-step”
model. In this strategy, the active drug is pre-synthesized in vitro
and then delivered to the organism.[7] Therefore, the problems
F. Wang, Y. Zhang, Z. Liu, Z. Du, L. Zhang, Prof. J. Ren, Prof. X. Qu
Laboratory of Chemical Biology and State Key Laboratory of Rare
Earth Resource Utilization,
Changchun Institute of Applied Chemistry,
Chinese Academy of Sciences,
Changchun, Jilin 130022, China
E-mail: xqu@ciac.ac.cn
F. Wang, Y. Zhang, Z. Liu, Z. Du, L. Zhang
University of Chinese Academy of Sciences,
Beijing 100039, China
Herein, a new strategy regarding site-specific CuAAC reaction
for localized drug synthesis in mitochondria has been presented.
We constructed a functionalized heterogeneous copper catalyst
on metal-organic frameworks (MOFs) with excellent catalytic
activity (Scheme 1). As porous inorganic-organic hybrid
materials, MOFs have attracted increasing attention in gas
separation, gas storage, drug delivery and heterogeneous
catalysis.[18] In this work, MOFs were used as scaffolds to
stabilize and protect ultra-small copper nanoparticles. Further,
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201901760
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by decorating a triphenylphosphonium (TPP) vector, the catalyst
could accumulate in the mitochondria of living cells. Importantly,
the localized drug synthesis could maximize the expected
functions of drugs, which had been proved in live cells and in
vivo tumor therapy. This new strategy provides
a more
biocompatible and effective way for localized drug synthesis
under subcellular organelles.
Figure 1. Catalytic reaction of MOF-Cu nanoparticles in vial. (a) The
schematic diagram of MOF-Cu catalyzed Huisen 1,3-dipolar cycloaddition
reaction between azides, 1, and terminal alkynes, 2, to produce the
fluorescent molecule, 3, in vial. (b) The fluorescent spectra of the click reaction
without (black line) and with (red line) MOF-Cu catalyst, corresponding
fluorescent photos of the experiment (insert photos). (c) The changes of
fluorescence spectra under different time of the reaction without catalyst (from
0 to 120 min). (d) The changes of fluorescence spectra under different time of
the reaction with MOF-Cu catalyst (from 0 to 120 min). The obvious increase
of the fluorescence intensity showed the good catalytic activity of MOF-Cu.
Data were presented as mean ± s.d. (n = 3).
As a prerequisite, we investigated whether the MOF-Cu
catalysts possessed catalytic activity for CuAAC reaction (Figure
1a). The formation of triazole, 3, between “pro-fluorophore” 1
and 2 would cause an obvious change of fluorescence intensity
(Figure 1b, Figure S12).[21] In order to study the role of Cu in the
catalytic process, we synthesized MOF-Cu with different Cu
doping levels as the controls, which were termed as MOF-Cua
(3.6 wt%), MOF-Cub (10.6 wt%) and MOF-Cuc (29.8 wt%),
respectively (Figure S9-S11). The content of Cu in MOF-Cu
complexes was determined by inductively coupled plasma mass
spectrometry (Table S1). MOF-Cua, MOF-Cub and MOF-Cuc
were incubated with precursor molecules in vial, respectively.
After 12 h, the tubes showed obvious cyan-blue fluorescence,
indicating the superior catalytic activity of the catalyst (Figure
S13-S14). Furthermore, the fluorescence spectra were also
monitored (Figure S15). All three MOF-Cu catalysts could
induce gradual increase in fluorescence intensity. As shown in
conversion curve, MOF-Cub and MOF-Cuc exhibited obviously
higher catalytic activity than MOF-Cua owing to more catalytic
centers. Though MOF-Cuc possessed slightly higher catalytic
efficiency than MOF-Cub, the excessive copper content induced
the presence of free Cu nanoparticles, which could destroy the
stability and uniformity of MOF-Cu (Figure S10). So, we chose
MOF-Cub as model catalyst in following experiments. To further
study the kinetic process and catalytic efficiency, we followed
fluorescence change from 0 to 120 min of MOF-Cub (Figure
1c,d). Remarkable increase of fluorescence intensity in 5 min
showed the excellent catalytic activity (Figure S16). The data of
high-performance liquid chromatography (HPLC) indicated that
the conversion of the catalytic process was above 80% at 8 h
(Figure S17). The related statistics of translation ratio and
Scheme 1. Illustration of constructing of mitochondria-targeted CuAAC
reaction catalysts and the in-situ drug synthesis under subcellular organelle.
(a) Zr metal-organic frameworks (MOF), Cu-combined MOF materials (MOF-
Cu) and TPP modified catalyst (MOF-Cu-TPP) used in the study. (b)
Intracellular bioorthogonal reaction for in-situ drug synthesis under
mitochondria catalyzed by MOF-Cu-TPP.
The heterogeneous MOF-Cu catalysts were synthesized in
three steps (Scheme 1a).[19] Construction of MOF scaffold, Cu
reduction and functionalization were carried out successively.[20]
The average diameter of MOF was 120 nm (Figure S1). Next,
ultrafine copper nanoparticles were synthesized and distributed
throughout MOF (MOF-Cu), which was clearly shown in the TEM
images (Figure S2) and distribution analysis (Figure S4). For the
ability of targeting mitochondria, MOF-Cu was further modified
by 3-Carboxypropyltriphenylphosphonium bromide (TPP) (MOF-
Cu-TPP). The powder X-ray diffraction (XRD) analysis indicated
that TPP modification did not destroy the structure of MOF
(Figure S5). The P elemental mapping (Figure S3), Fourier
transformation infrared spectroscopy (FT-IR) spectrum (Figure
S6) and X-ray photoelectron spectroscopy (XPS) analysis
(Figure S7) demonstrated the successful modification of TPP.
The quantity of TPP modified on MOF-Cu was estimated about
5% wt through the thermogravimetric analysis (TGA) curves
(Figure S8).
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concentration was consisted with the fluorescence results
(Figure S18). To evaluate the tolerance of different reaction
conditions, we carried out the reactions under H2O, phosphate
buffered saline (PBS) and cell culture medium with or without
serum, respectively (Figure S19-S20). Three groups all showed
the increase of fluorescence, indicating the applicability of the
designed catalyst. Furthermore, the reusability of MOF-Cu was
also studied. The catalysts were washed with water and
collected by centrifugation for next turn (Figure S21). The
relative activity and SEM of the cycled catalysts indicated that
our catalysts exhibited good reusability and stability under the
experimental conditions (Figure S22). In addition, the
supernatant of the catalysts after a 72 h treatment in H2O
showed no catalytic ability, further confirming the stability of
MOF-Cu.
To achieve our vision about localized drug synthesis in
subcellular organelles, we modified MOF-Cu with TPP moiety,
which is a well-established mitochondria-targeting group (MOF-
Cu-TPP). To monitor the ability of targeting mitochondria, we
incubated MOF-Cu-TPP with FITC as a fluorescence marker (f-
MOF-Cu-TPP). f-MOF-Cu-TPP showed an obvious fluorescence
emission at 512 nm (Figure S27). After incubating with f-MOF-
Cu-TPP, MCF-7 cells were labeled by
a
commercial
mitochondrial red dye (MitoTracker Red CMXRos) and nuclear
dye (Hoechest 33258). As shown in fluorescence images, f-
MOF-Cu-TPP gave remarkable fluorescence signal co-localized
with MitoTracker (Figure S28), confirming that MOF-Cu-TPP
could effectively target mitochondria. In addition, as indicated by
click reaction experiments, MOF-Cu-TPP still retained the
catalytic activity (Figure S29).
Next we explored their intracellular performance in human
breast adenocarcinoma cells (MCF-7 cells) (Figure 2a). Firstly,
the cellular uptake was quantified via analyzing [63.5Cu] by ICP-
MS. Both MOF-Cu and MOF-Cu-TPP could be endocytosed
effectively (Figure S23-S24). In addition, the cytotoxicity of the
catalysts was detailed studied by MTT method. From 0 to 100
μg mL-1, MOF-Cu (Figure S25) and MOF-Cu-TPP (Figure S26)
were observed negligible cytotoxicity. After that, click reaction
was carried out in situ in MCF-7 cells. Compared to the controls,
the cells treated with MOF-Cu showed significant increase of
fluorescence by flow cytometry analysis (Figure 2b). Meanwhile,
the live-cell fluorescence microscopy experiments also indicated
similar results (Figure 2c).
Figure 3. In-situ resveratrol analogue synthesis in mitochondria by the
designed mitochondria-targeted catalysts. (a) The schematic diagram of in-situ
resveratrol analogue synthesis in mitochondria. (b) The MTT of compound, 4,
and compound, 5, under low concentration on MCF-7 cells (from 0 to 10 μM).
(c) The MTT of compound, 6, in situ synthesized in mitochondria with MOF-
Cu-TPP catalyst (10 μM, 4; 10 μM, 5). (d) The flow cytometry analysis via
DCFH-DA probe about the accumulation of oxidative stress in cells when the
reaction occurred (10 μM, 4; 10 μM, 5). (e) The apoptosis experiment of MCF-
7 cells analyzed by double staining with Annexin V-FITC and propidium iodide
via flow cytometry analysis. Data were presented as mean ± s.d. (n = 3).
Figure 2. Click reaction in living cells catalyzed by the catalysts. (a) The
schematic diagram of MOF-Cu catalyzed click reaction between azides and
terminal alkynes in living cells. (b) The flow cytometry analysis of fluorescence
changes, control (cells alone), MOF-Cu alone, precursor 1 with 2 and MOF-Cu
with precursors, respectively. (c) Fluorescence images of MCF-7 cells treated
without (A-C) and with (D-F) MOF-Cu catalyst. (A) bright field image of cells,
(B) emission of the product 3 (blue channel), (C) merging with A and B, (D)
bright field image of cells, (E) emission of the product 3 (blue channel), (F)
merging with D and E. An obvious fluorescence was shown in the cells treated
with MOF-Cu catalyst (E) (Scale bar = 10 µm). Data were presented as mean
± s.d. (n = 3).
For finding suitable catalytic product, we put our sights in
resveratrol (Rsv). Previous research has indicated that Rsv and
its derivates may act as an anti-oxidant, reduce cardiovascular
disease, increase lifespan, and also be used as a cancer
chemopreventive agent.[22] However, the molecular mechanisms
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of Rsv and its derivates are complicated because they have
many biological targets and play different roles under different
conditions.[23] Previous studies indicate that Rsv and its
derivates can effectively induce cell apoptosis by causing
mitochondrial damage (Figure 3a).[24] Therefore, in situ synthesis
of Rsv analogues in mitochondria can improve its antitumor
efficacy and minimize the side effects. So, we synthesized
precursor molecule, 4 and 5. The cytotoxicity of precursors 4
and 5 was also evaluated. As shown in Figure 3b and Figure
S30, precursors 4 and 5 both have negligible cytotoxicity up to
25 μM in MCF-7 cells.
Besides, the therapy efficiency of in-suit drug synthesis by the
designed catalyst was evaluated by mice tumor model (Fig S41-
S44). Taking together, all the experimental results proved the
good tumor therapy efficiency of in-suit drug synthesis.
Then, in situ synthesis of 6 in mitochondria was studied.[25] As
shown in Figure 3c, an obvious decrease in cell viability was
observed. Meanwhile, induced the apoptosis of MCF-7 cells
owing to the synthesized active agent 6 was also proved by
double staining with Annexin V-FITC and propidium iodide
(Figure 3e). Furthermore, to verify the interaction between the
synthesized drug agent and mitochondria, the changes of
mitochondria at different time were monitored. Mitochondrial
damage would cause a decrease of membrane potential and fail
to sequester MitoTracker Red CMXRos dye, causing a much
less defined and decreased intensity of red staining. As shown
in Figure S31, after 6h, the contour and intensity of fluorescence
image became blurred and decreased gradually. There was an
obvious decrease in red fluorescence at 24 h, indicating the
mitochondrial damage. Interestingly, the accumulation of
oxidative stress and release of cytochrome c along with the
mitochondrial damage were also observed by flow cytometry
(Figure 3d) and western blot, respectively (Figure S32).
Furthermore, the LC-MS of the final product, 6, (269.10)
confirmed that the CuAAC reaction catalyzed by MOF-Cu-TPP
was carried out smoothly (Figure S33). As a control, we added
resveratrol and 6 in MCF-7 cells directly. The survival rate of
cells was above 80 % even at the high tested (50 µM)
concentration (Figure S34).[26] The accumulation of oxidative
stress experiment also indicated that the direct incubation of Rsv
Figure 4. Click reactions occurred in C. elegans model. (a) The schematic
diagram of click reactions catalyzed by designed catalyst in C. elegans. (b)
Kaplan-Meier survival curves of the N2 wild-type strain worm fed with or
without catalyst. (Scale bar = 10 µm). (c) The fluorescence images of C.
elegans in blue channel. The bright field images (A-C) and fluorescence
images (D-F). Control (A, D), catalyst alone (B, E), catalyst with fluorescent
precursor molecules (C, F). Plots are representative of three independent
experiments. Data were presented as mean ± s.d. (n = 3).
In summary, for the first time, we have successfully
constructed a mitochondria-targeted heterogeneous catalyst and
demonstrated their application in tumor therapy. The designed
catalyst possesses high catalytic activity and stability, which
could be reused conveniently. The catalyst can be used to
activate the profluorophore and to perform the localized drug
synthesis in mitochondria. The in-situ generation of an active
drug from inert prodrugs in subcellular organelles has
unparalleled advantages in minimizing the toxic side effects of
cytotoxic drugs and maximizing their efficacy. The C. elegans
experiments proved the biocompatibility of the designed catalyst
and in vivo tumor therapy indicated that the localized
synthesized resveratrol derived drug showed better antitumor
efficacy. Our work provides new insights into decreasing multiple
side effects occurred in drug delivery and distribution.
analogue
6 did not increase oxidative stress under our
experimental concentration (Figure S35). This could be due to
the drug agent with different distribution and multiple cellular
targets.[23a] The localized drug synthesis in targeted subcellular
organelles showed its unique advantage to improve efficacy and
avoid side effects.
Furthermore, we carried out this reaction in animal model
(Figure 4a). The C. elegans was chosen as a model first.[27] The
N2 wild-type strain worms were incubated with the designed
catalyst. Complete paralysis occurred around 15 days for both
control and experiment groups proving the biocompatibility of
catalyst (Figure 4b). Then, the click reaction in C. elegans was
studied through compounds 1 and 2. The group fed with catalyst
and precursors (C, F) showed an obvious fluorescence signal
proving the catalytic process (Figure 4c). In addition, no signs of
toxicity, and morphology alteration was emerged in C. elegans
(Figure S36). For observing the vitality of nematode directly, the
simple movie about movement of C. elegans indicated they
maintained energetic activity after reactions occurred (Movie S1).
Next, the biocompatibility of catalysts in mice model was tested
(Figure S37-S40).[28] All the results demonstrated the good
biocompatibility of the catalyst for possible in vivo therapeutic
applications and ineffectiveness of prodrugs without catalysts.
Acknowledgements
This work was supported by NSFC (21431007, 21533008,
21820102009, 21871249, 91856205) and CAS QYZDJ-SSW-
SLH052.
Keywords: Heterogeneous catalyst, bioorthogonal chemistry,
click reaction, drug synthesis, subcellular organelles
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10.1002/anie.201901760
Angewandte Chemie International Edition
COMMUNICATION
Table of Contents
COMMUNICATION
The complex MOF-Cu-TPP catalysts
realize localized drug synthesis via
site-specific CuAAC reaction in
mitochondria. This system has a wide
applicability for synthesizing multiple
drugs with good biocompatibility and
plays its unique advantage to improve
efficacy of active drugs avoid reduce
side effects.
Faming Wang, Yan Zhang, Zhengwei
Liu, Zhi Du, Lu Zhang, Jinsong Ren and
Xiaogang Qu*
Page No. – Page No.
Biocompatible heterogeneous MOF-
Cu catalyst used for in vivo drug
synthesis at targeted subcellular
organelles
This article is protected by copyright. All rights reserved.