Nanoscale Metal-Organic Layers Detect Mitochondrial Dysregulation and Chemoresistance via Ratiometric Sensing of Glutathione and pH

Article abstract of DOI:10.1021/jacs.0c11764

Mitochondrial dysregulation controls cell death and survival by changing endogenous molecule concentrations and ion flows across the membrane. Here, we report the design of a triply emissive nanoscale metal-organic layer (nMOL), NA@Zr-BTB/F/R, for sensing

Full text of DOI:10.1021/jacs.0c11764

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Communication
Nanoscale Metal−Organic Layers Detect Mitochondrial
Dysregulation and Chemoresistance via Ratiometric Sensing of
Glutathione and pH
Xiang Ling,# Deyan Gong,# Wenjie Shi, Ziwan Xu, Wenbo Han, Guangxu Lan, Youyou Li, Wenwu Qin,
and Wenbin Lin*
Cite This: J. Am. Chem. Soc. 2021, 143, 1284−1289
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ABSTRACT: Mitochondrial dysregulation controls cell death and survival by changing endogenous molecule concentrations and
ion flows across the membrane. Here, we report the design of a triply emissive nanoscale metal−organic layer (nMOL), NA@Zr-
BTB/F/R, for sensing mitochondrial dysregulation. Zr-BTB nMOL containing Zr6 secondary building units (SBUs) and 2,4,6-tris(4-
carboxyphenyl)aniline (BTB-NH2) ligands was postsynthetically functionalized to afford NA@Zr-BTB/F/R by exchanging formate
capping groups on the SBUs with glutathione(GSH)-selective (2E)-1-(2′-naphthyl)-3-(4-carboxyphenyl)-2-propen-1-one (NA) and
covalent conjugation of pH-sensitive fluorescein (F) and GSH/pH-independent rhodamine-B (R) to the BTB-NH2 ligands. Cell
imaging demonstrated NA@Zr-BTB/F/R as a ratiometric sensor for mitochondrial dysregulation and chemotherapy resistance via
GSH and pH sensing.
s the powerhouse of the cell, the mitochondrion exercises
Astrict homeostatic control of many potentially harmful
molecules.1 Dysregulation of mitochondrial homeostasis can
stop cell proliferation and elicit cell death.2 Understanding the
role of mitochondrial dysregulation in pathophysiological
processes is important for the development of therapeutic
strategies for many diseases, particularly chemoresistant
cancers.3,4 As an antioxidant for maintaining cellular redox
homeostasis, glutathione (GSH) is synthesized in the cytosol
and distributed into different subcellular compartments. The
mitochondrion has the same GSH concentration as the
cytosol.5 As many cell death-inducing stimuli interact with
mitochondria to cause oxidative stress,6 mitochondrial GSH
plays a critical role in maintaining a proper redox environment
for cell survival.7 While the pH value in normal mitochondria is
known to be alkaline,8 mitochondrial dysregulation impacts ion
influx and generates a proton gradient across the mitochondrial
membrane, lowering the pH in mitochondrial matrix.9 Thus,
the development of sensors for GSH and pH in mitochondria
can reveal important insights into mitochondrial dysregulation
and offer an opportunity to understand various pathophysio-
logical processes such as chemoresistant cancers.
Built from metal-oxo cluster secondary building units
(SBUs) and organic bridging ligands, nanoscale metal−organic
frameworks (nMOFs) have been exploited for chemical and
biological sensing applications.10−25 However, the strict
symmetry requirement of bridging ligands and small pores of
nMOFs have hindered their multifunctionalization and limited
their application in sensing large molecules. As a two-
dimensional version of nMOFs, nanoscale metal−organic
layers (nMOLs) not only retain the molecular tunability,
structure regularity, compositional diversity of nMOFs but also
possess high densities of open sites for multifunctionalization
and detection of large analytes,26 offering a versatile platform
to design ratiometric sensors for multiple analytes in biological
systems.
Herein, we report the design of an nMOL-based biosensor,
NA@Zr-BTB/F/R, for ratiometric GSH and pH sensing in
mitochondria (Figure 1). Zr-BTB nMOL comprising
[Zr6O4(OH)4(HCO2)6] SBUs and 2,4,6-tris(4-carboxy-
phenyl)aniline (BTB-NH2) ligands was postsynthetically
functionalized with GSH-selective (2E)-1-(2′-naphthyl)-3-(4-
carboxyphenyl)-2-propen-1-one (NA) via exchanging capping
groups on SBUs and conjugated with pH-sensitive fluorescein
isothiocyanate (FITC) and GSH/pH-independent rhodamine-
B isothiocyanate (RITC) to BTB-NH2 ligands to afford NA@
Zr-BTB/F/R. Fluorimetry and confocal laser scanning
microscopy (CLSM) studies demonstrated NA@Zr-BTB/F/
R as a reliable and accurate ratiometric sensor for GSH and pH
in mitochondria.
BTB-NH2 was synthesized by Suzuki coupling between p-
ethoxycarbonylphenyl boronic acid and 2,4,6-tribromoaniline
followed by base-catalyzed hydrolysis.27 NA was prepared by
aldol condensation between 2-acetonaphthone and 4-for-
mylbenzoic acid (Figures S1−4).28 NA itself exhibits weak
fluorescence at 440 nm, but selective recognition between NA
and GSH via the irreversible Michael addition reaction causes
a large fluorescence increase (Figures S5−7).29
Received: November 9, 2020
Published: January 15, 2021
https://dx.doi.org/10.1021/jacs.0c11764
J. Am. Chem. Soc. 2021, 143, 1284−1289
© 2021 American Chemical Society
1284

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Communication
Figure 1. (a) Schematic showing NA@Zr-BTB/F/R with NA capping
the Zr6 SBUs and FITC and RITC covalently linked to the BTB-NH2
ligands. (b) Excitation spectra (dotted lines) and emission spectra
(solid lines) of NA@Zr-BTB/F/R after incubation with 10 mM GSH
at 37 °C for 15 min at the NA (blue), FITC (green), and RITC (red)
channels. (c) Cationic NA@Zr-BTB/F/R ratiometrically senses
dysregulated mitochondria with GSH depletion and matrix acid-
ification.
Zr-BTB nMOL was solvothermally synthesized by heating a
DMF solution of ZrCl4 and BTB-NH2 at 80 °C for 24 h with
formic acid (FA) and H2O as modulators (Figure S8). The 6-
connected Zr6 SBUs are linked by 3-connected BTB-NH2
ligands to form an infinite 3,6-connected network of Zr6(μ3-
O)4(μ3-OH)4(HCO2)6(BTB-NH2)2 with Kagome topology.
The formulation of Zr-BTB nMOL was supported by
thermogravimetric analysis (Figure S10). The monolayer
morphology of Zr-BTB was demonstrated by transmission
electron microscopy (TEM, Figure 2a) showing a diameter of
∼180 nm and atomic force microscopy (AFM, Figure 2c,d)
Figure 2. (a) TEM image, (b) HRTEM image with the FFT pattern
in the inset, (c) AFM topography, and (d) height profile of Zr-BTB.
(e) PXRD patterns of Zr-BTB and NA@Zr-BTB/F/R, freshly
prepared or incubated with 40 mM GSH at 37 °C for 4 h, in
comparison to the simulated pattern for the Hf6−BTB MOL. (f)
Time-dependent fluorescence responses for NA@Zr-BTB/F/R
incubated with 40 mM GSH or HEPES (mean SD, n = 3).
giving a thickness of ∼1.5
0.1 nm. This thickness is
consistent with the modeled height of FA-terminated Zr6
clusters. The proposed structure was confirmed by its similar
powder X-ray diffraction (PXRD) pattern to that simulated for
Hf6-BTB MOL30 (Figure 2e) and high resolution TEM
(HRTEM) image along with its fast Fourier transform (FFT,
Figure 2b) showing lattice fringes and a distance of ∼2.0 nm
between adjacent spots expected for a 3,6-connected network.
NA@Zr-BTB was synthesized by treating Zr-BTB with an
74 mol % (relative to BTB-NH2), respectively, to achieve
comparable luminescence intensities for NA, FITC, and RITC
and mitochondrial targeting capability (Tables S1 and S2).
Dynamic light scattering (DLS) measurements showed Z-
averaged diameters of 165.3 3.8 and 162.2 2.0 nm for Zr-
BTB/R and NA@Zr-BTB/F/R, respectively (Figure S14).
DLS measurements supported the stability of NA@Zr-BTB/F/
R in HEPES and 0.1× PBS (Figure S15). Incubation of NA@
Zr-BTB/F/R in HEPES or 0.1× PBS for 4 h dissociated <2.4%
of dyes/Zr (Figure S16). The time-dependent fluorescence
response of NA@Zr-BTB/F/R after GSH addition displayed a
rapid enhancement which plateaued within 15 min (Figure 2f).
NA@Zr-BTB/F/R was highly selective toward GSH. Thirteen
different analytes including HEPES, GSH, cysteine, homo-
cysteine, Na2SO3, H2O2, isoleucine, alanine, histidine, glutamic
acid, tyrosine, lysine, and glycine were examined, but only
GHS caused a drastic increase in the NA/R fluorescence
intensity ratio (Figure S17).
NA@Zr-BTB/F/R was designed for ratiometric GSH
sensing based on the fluorescence ratio of GSH-selective NA
to GSH-independent RITC (rNA/R) and for pH sensing based
on the fluorescence ratio of pH-sensitive FITC to pH-
independent RITC (rF/R). Calibration curves and live cell
sensing were performed using excitation/emission wavelengths
of 352/443, 493/516, and 557/600 nm for NA, FITC, and
RITC, respectively (Figure S22). NA@Zr-BTB/F/R was
1
excess amount of NA in water at 25 °C for 12 h. H NMR
analysis of digested NA@Zr-BTB indicated replacement of up
to 84 mol % of FA by NA (Figures S9 and S11). FITC and
RITC were then covalently attached to NA@Zr-BTB via
forming BTB-F (BTB-NH2 and FITC) and BTB-R (BTB-NH2
and RITC) thiourea linkages to afford NA@Zr-BTB/F/R with
the formula of Zr6(μ3-O)4(μ3-OH)4(HCO2)6−m(NA)m(BTB-
NH2)2−x−y(BTB-F)x(BTB-R)y, where m, x, and y represent
NA, FITC, and RITC loadings, respectively. NA, BTB-R, and
BTB-F moieties in NA@Zr-BTB/F/R were confirmed by the
presence of characteristic UV−vis absorptions of free dyes
(Figure S18a) as well as the observation of [NA + H]+, [BTB-
F + H]+, and [BTB-R]+ peaks in the high-resolution mass
spectra (HRMS) of digested NA@Zr-BTB/F/R (Figure
S12a). TEM and PXRD showed that NA@Zr-BTB/F/R
retained the morphology and crystallinity of Zr-BTB (Figure
S13). NA, FITC, and RITC loadings were optimized to be 84
mol % (relative to FA), 21 mol % (relative to BTB-NH2), and
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rNA/R = 0.526 + 0.140(1 − e−c/0.788) + 0.792(1 − e−c/12.694
)
incubated in HEPES with GSH concentrations of 0, 1, 5, 10,
20, 30, and 40 mM and pH values of 5.04, 5.74, 6.06, 6.49,
6.97, 7.4, and 7.98. The fluorescence signals of NA, FITC, and
RITC in NA@Zr-BTB/F/R were collected by a fluorimeter
(Figure S23). NA responded only to GSH, FITC responded
only to pH, while RITC did not respond to either GSH or pH.
At pH 7.4 with different GSH concentrations, NA@Zr-BTB/
F/R showed significantly increased NA signals but constant
FITC and RITC signals (Figure 3a,b). On the other hand,
(1)
(2)
4.213 × 10−7 + 0.105e−2.303pH
rF/R
=
3.123 × 10−7 + e−2.303pH
The stability of NA@Zr-BTB/F/R under physiological
conditions was verified by the unchanged PXRD pattern
after incubation with 40 mM GSH at 37 °C for 4 h (Figure
2e). The highly positive ζ potentials of Zr-BTB/R (35.77
0.95 mV) and NA@Zr-BTB/F/R (31.90
2.95 mV)
facilitated their cellular uptake (Figure S26). NA@Zr-BTB/
F/R did not show any cytotoxicity at up to 300 μM Zr against
cisplatin-sensitive and cisplatin-resistant human ovarian
carcinoma cells A2780 and A2780cis using the MTS assay
(Figure S27). Time-dependent endo/lysosomal escape was
monitored by incubating A2780 cells with Zr-BTB/R for
preset time intervals (Figure S28). Within the first 2 h, the
enhanced red signals of Zr-BTB/R were mostly colocalized
with green signals representing endo/lysosomes with Pearson’s
coefficients higher than 0.478, suggesting rapid endocytosis.
However, the majority of Zr-BTB/R has escaped from endo/
lysosomes with a Pearson’s coefficient of <0.022 at 4 h. We
then studied nMOL subcellular localization in greater detail by
incubating A2780 cells with Zr-BTB/R for 4 h. Zr-BTB/R
primarily accumulated in mitochondria with no colocalization
with endoplasmic reticulum and endo/lysosomes (Figures 4a−
c and S29). As NA@Zr-BTB/F/R could not be studied by
CLSM colocalization analysis owing to its spectral overlap with
commercial MitoTracker, we extracted mitochondria31 and
Figure 3. (a) NA emission spectra of NA@Zr-BTB/F/R with
different GSH concentrations at pH 7.4. (b) NA, FITC, and RITC
fluorescence intensities of NA@Zr-BTB/F/R acquired by a
fluorimeter at different GSH concentrations (n = 3). (c) FITC
emission spectra of NA@Zr-BTB/F/R at different pH values with 0
mM GSH. (d) NA, FITC, and RITC fluorescence intensities of NA@
Zr-BTB/F/R acquired by a fluorimeter at different pH values (n = 3).
Ratios of NA fluorescence over RITC fluorescence (e) and FITC
fluorescence over RITC fluorescence (f) for NA@Zr-BTB/F/R.
These ratios serve as calibration curves for GSH and pH sensing,
respectively.
NA@Zr-BTB/F/R exhibited increased FITC signals but
constant NA and RITC signals at different pH values without
GSH (Figure 3c,d). GSH and pH calibration curves were then
established for NA@Zr-BTB/F/R using the fluorescence ratios
in Figure 3e,f. The ratiometric calibration curves for GSH and
pH were empirically constructed by fitting the dependence of
rNA/R on GSH concentration (C) according to eq 1 (R2 =
0.999, Figure S24a) and the dependence of rF/R on pH
according to eq 2 (R2 = 0.996, Figure S24b), respectively. The
fluorescence ratios determined by CLSM imaging also
quantitatively agreed with preset GSH concentrations and
pH values (Figure S25).
Figure 4. (a−c) Subcellular localization of Zr-BTB/R (red) in A2780
cells after incubation for 4 h. Nuclei were stained with DAPI (blue).
Endoplasmic reticulum (ER), endo/lysosomes, and mitochondria
were stained with ER-Tracker (green), LysoTracker (green), and
MitoTracker (green), respectively. (d) Time-dependent enrichment
of Zr-BTB/R and NA@Zr-BTB/F/R in mitochondria by Zr ICP-MS.
The equivalent Zr concentrations are 20 μM (n = 3); ns, not
significant.
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Figure 5. (a) Representative high-resolution ratiometric fluorescence imaging of cisplatin- or HEPES-treated A2780 and A2780cis cells with NA@
Zr-BTB/F/R. Left to right columns: Merged NA/F/R, NA, F, R, merged NA/R, and merged F/R signals, respectively. Scale bar = 5 μm. (b, c)
Scatter plots showing mitochondrial dysregulation with GSH depletion and matrix acidification as sensed by NA@Zr-BTB/F/R after incubation of
(b) A2780 and (c) A2780cis cells with or without cisplatin.
determined the percentages of intramitochondrial nMOLs by
ICP-MS (Figure 4d). Both Zr-BTB/R and NA@Zr-BTB/F/R
with a similar RITC loading were quickly enriched in
mitochondria after 4 h incubation and exhibited no difference
in mitochondrial uptake in 1, 2, and 4 h. This result indicates
that NA@Zr-BTB/F/R exhibits a similar mitochondrial
targeting as Zr-BTB/R.
Zr6 SBUs with NA groups and covalent conjugation of FITC
and RITC to the BTB-NH2 ligands afforded NA@Zr-BTB/F/
R as a mitochondria-targeted ratiometric nanosensor for
monitoring of GSH and pH independently in live cells.
Cellular imaging using CLSM revealed the quantitative
evidence of mitochondrial dysregulation with GSH depletion
and matrix acidification. This work should inspire the
development of nMOL-based ratiometric biosensors for
other biological analytes and for providing new insights into
pathophysiological conditions at the cellular level.
Many chemotherapeutics, including platinum drugs, induce
cell death by causing mitochondrial dysregulation.32,33 Recent
studies have also pinpointed the role of mitochondrial DNA
alterations on the onset of chemoresistance, which leads to
redox balance alterations and signal crosstalk with nuclei,
allowing a rewiring of cell metabolism.34,35 Cisplatin-sensitive
A2780 cells and cisplatin-resistant A2780cis cells were
pretreated with 1 μM cisplatin and then used to evaluate the
applicability of NA@Zr-BTB/F/R as a ratiometric nanosensor
by CLSM (Figures 5a and S30). A2780 cells with cisplatin
treatment showed dim blue and green signals of NA and FITC,
indicating low GSH concentrations and pH values. In contrast,
A2780 cells without cisplatin treatment presented high NA
signals and FITC signals, consistent with high GSH and pH
values. A2780cis cells with or without cisplatin treatment all
displayed high NA and FITC signals, suggesting high GSH and
neutral pH in mitochondria. NA@Zr-BTB/F/R accurately
detected chemoresistance of A2780cis cells. Regions of interest
(ROIs) were randomly picked from each CLSM image to
obtain intensity readouts by ImageJ (Figure S31). Repeated
studies showed the robustness and reproducibility of this
ratiometric sensing system (Figure S32). The suitability of
NA@Zr-BTB/F/R as GSH and pH sensors was confirmed in
4T1 and CT26 cells (Figure S33). Analysis of 100 ROIs for
each condition revealed that mitochondrial dysregulation with
GSH depletion and matrix acidification occurred only in cells
at late-apoptosis (Figure 5b, c).36−38
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11764.
■
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Synthesis and characterization of nMOLs, luminescence
analysis, and in vitro sensing of mitochondrial
dysregulation (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Wenbin Lin − Department of Chemistry and Department of
Radiation and Cellular Oncology and Ludwig Center for
Metastasis Research, The University of Chicago, Chicago,
Illinois 60637, United States; orcid.org/0000-0001-
7035-7759; Email: wenbinlin@uchicago.edu
Authors
Xiang Ling − Department of Chemistry, The University of
Chicago, Chicago, Illinois 60637, United States
Deyan Gong − Department of Chemistry, The University of
Chicago, Chicago, Illinois 60637, United States; Key
Laboratory of Nonferrous Metal Chemistry and Resources
Utilization of Gansu Province and State Key Laboratory of
Applied Organic Chemistry, College of Chemistry and
In summary, we constructed the first nMOL for simulta-
neous GSH and pH sensing. Replacement of FA groups on the
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Ziwan Xu − Department of Chemistry, The University of
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Wenbo Han − Department of Chemistry, The University of
Chicago, Chicago, Illinois 60637, United States
Guangxu Lan − Department of Chemistry, The University of
Chicago, Chicago, Illinois 60637, United States;
orcid.org/0000-0002-0415-5849
Youyou Li − Department of Chemistry, The University of
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Wenwu Qin − Key Laboratory of Nonferrous Metal Chemistry
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ACKNOWLEDGMENTS
■
We thank Xiaomin Jiang for experimental help. We acknowl-
edge the National Cancer Institute (U01-CA198989 and
1R01CA253655) and the University of Chicago Medicine
Comprehensive Cancer Center (NIHCCSG: P30 CA014599)
for funding support. D.G. and W.S. acknowledge financial
support from the China Scholarship Council.
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