Nanoscale Metal-Organic Frameworks for Ratiometric Oxygen Sensing in Live Cells

Article abstract of DOI:10.1021/jacs.5b13458

We report the design of a phosphorescence/fluorescence dual-emissive nanoscale metal-organic framework (NMOF), R-UiO, as an intracellular oxygen (O₂) sensor. R-UiO contains a Pt(II)-porphyrin ligand as an O₂-sensitive probe and a Rho

Full text of DOI:10.1021/jacs.5b13458

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Communication
Nanoscale Metal-Organic Frameworks for
Ratiometric Oxygen Sensing in Live Cells
Ruoyu Xu, Youfu Wang, Xiaopin Duan, Kuangda Lu, Daniel Micheroni, Aiguo Hu, and Wenbin Lin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b13458 • Publication Date (Web): 11 Feb 2016
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Nanoscale Metal-Organic Frameworks for Ratiometric Oxygen
Sensing in Live Cells
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Ruoyu Xu,†,1 Youfu Wang,†,1,2 Xiaopin Duan,1 Kuangda Lu,1 Daniel Micheroni,1 Aiguo Hu,2 and
Wenbin Lin,*,1
1Department of Chemistry, University of Chicago, 929 E 57th St, Chicago, Illinois 60637, United States
2Shanghai Key Laboratory of Advanced Polymeric Materials, School of Materials Science and Engineering, East Chi-
na University of Science and Technology, Shanghai 200237, China
Supporting Information Placeholder
Metal-organic frameworks (MOFs) are an emerging class
ABSTRACT: We report the design of
a phosphores-
of porous materials built from metal ions or clusters bridged
by organic linkers that have been explored as chemical sen-
sors.13 Nanoscale MOFs (NMOFs) have also been used for
small molecule sensing14 and biomedical imaging.15 NMOFs
exhibit several characteristics that make them ideal nano-
materials for biological and biomedical applications. First,
NMOFs have good crystallinity and structural tunability,
which allow synthetic elaborations for specific applications.
Second, NMOFs are highly porous, which allows them to
accommodate high loadings of imaging/therapeutic agents,
quickly diffuse small molecules (i.e., drugs, analysts), and
prevent dye self-quenching. Third, NMOFs do not suffer
from agent leaching due to covalent bonding. Fourth,
NMOFs are intrinsically biodegradable in the long term due
to their relatively labile metal–ligand bonds.16 For example,
we have recently used a fluorescent NMOF for real-time in-
tracellular pH sensing15a and a porphyrin-based NMOF in
photodynamic therapy.17 Herein, we report the first NMOF
probe for ratiometric O2 sensing in live cells.
cence/fluorescence dual-emissive nanoscale metal organic
framework (NMOF), R-UiO, as an intracellular oxygen (O2)
sensor. R-UiO contains a Pt(II)-porphyrin ligand as an O2-
sensitive probe and a Rhodamine-B isothiocyanate (RITC)
ligand as an O2-insensitive reference probe, and exhibits
good crystallinity, high stability, and excellent ratiometric
luminescence response to O2 partial pressure. In vitro exper-
iments confirmed the applicability of R-UiO as an intracellu-
lar O2 biosensor. This work is the first report of a NMOF-
based intracellular oxygen sensor and should inspire the de-
sign of ratiometric NMOF sensors for other important ana-
lytes in biological systems.
Oxygen (O2) is a vital component in aerobic respiration
that provides metabolic energy to cells. Hypoxia — a reduc-
tion in normal levels of O2— is related to various diseases,1
including vascular disease, pulmonary disease, and cancer.2
For instance, sustained hypoxia in a growing tumor can re-
sult in a more aggressive phenotype.3 Monitoring and quanti-
fying O2 levels in living cells are thus of great importance for
cancer diagnosis, tumor pathophysiology assessment, and
the evaluation of the therapeutic effects of anticancer treat-
ments. O2 tension can be detected and measured by several
methods, including polarographic O2 needle electrodes,4
immunohistochemical staining,5 positron emission tomogra-
phy imaging,6 magnetic resonance imaging7 and photolumi-
nescence imaging.8 Because of their high sensitivity and out-
standing spatial resolution, photoluminescence-based tech-
niques provide particularly powerful tools for sensing O2 in
living cells. Ratiometric sensing, which uses an O2-insensitive
reference and an O2-sensitive probe to measure emission
ratios at two different wavelengths, can compensate for sig-
nal changes caused by disturbance from external environ-
ment, such as light scattering and fluctuations in the excita-
tion source,9 allowing for accurate measurements of O2 con-
centrations. Since Kopelman and co-workers first developed
PEEBLEs (probes encapsulated by biologically localized em-
bedding) containing a cyanine-dye standard and a Pt-
porphyrin phosphor for ratiometric O2 sensing,10 a number of
polymeric nanoparticles,8c, 8e silica gels,11 and quantum dots12
have emerged as promising ratiometric O2 sensors.
Scheme 1. Synthesis of mixed-ligand M-UiO NMOF and its
postsynthesis modification to afford R-UiO NMOF.
We hypothesized that an NMOF with both O2-
independent and –sensitive ligands would serve as an excel-
lent ratiometric O2 sensor by taking advantage of the afore-
mentioned features of NMOFs. Pt-5, 15-di(p-benzoato)-
porphyrin (DBP-Pt) was chosen as an O2-sensitive bridging
ligand whereas Rhodamine-B isothiocyanate (RITC) conju-
gated quaterphenyldicarboxylate (QPDC) was used as an O2-
independent ligand to construct a ratiometric NMOF, R-UiO
(Scheme 1). Pt-porphyrin shows bright phosphorescence with
a long-lived triplet state at ambient temperature, and its
phosphorescence intensity is highly dependent on O2 con-
centration, making it an ideal choice as an O2-sensitive probe
in ratiometric O2 sensing.8c-e,10 We selected Rhodamine-B as
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a reference dye for the following reasons: (1) Absorption of
Fourier transform patterns of M-UiO. TEM images of R-UiO
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Rhodamine-B and H2DBP-Pt at 500-540 nm allows for the
simultaneous excitation of both dyes (Figure S5); (2) The
non-overlap of Rhodamine-B fluorescence (570 nm) and
H2DBP-Pt phosphorescence (630 nm) (Figure S5) facilitates
ratiometric luminescence quantifications; (3) The pH-
independent fluorescence of Rhodamine-B at pH > 6 pre-
vents disturbance due to cellular pH changes;18 (4) Emissions
of both dyes at relatively long wavelengths (> 570 nm) mini-
mize background autofluorescence from live cells.
(e) before and (f) after incubation in HBSS for 24 h.
H2QPDC-NH2 was obtained by Suzuki coupling between
4,4’-dibromo-2-amino-1,1’-biphenyl and 4-methoxycarbonyl-
phenylboronic acid, followed by hydrolysis. H2DBP-Pt was
synthesized
by
metalation
of
5,15-di(4-
methoxycarbonyl)porphyrin (Me2DBP) with K2PtCl4 in ben-
zonitrile under reflux, followed by hydrolysis in basic condi-
tions, and characterized by NMR spectroscopy and mass
spectrometry (Scheme S2). A solvothermal reaction between
9
We further hypothesized that a mixed ligand NMOF with
both DBP-Pt and amino-quaterphenyldicarboxylate (QPDC-
NH2) could be built due to the similar lengths of these lig-
ands. We observed that the unit cell parameter of Zn-
DPDBP-UiO17 (38.76 Å, DPDBP: 10, 20-diphenyl-5, 15-di(p-
benzoato)porphyrin), whose ligand is similar in structure to
DBP-Pt, is only 0.2% larger than that of TPHN-UiO19 (38.68
Å, TPHN: 4,4′-bis(carboxyphenyl)-2-nitro-1,1′-biphenyl). The
QPDC-NH2 ligands in the mixed ligand NMOF could be
readily conjugated with RITC to afford the dual-emissive R-
UiO NMOF. Furthermore, the relative intensities of RITC
fluorescence and DBP-Pt phosphorescence can be tuned by
adjusting the feed ratio of the two dyes during MOF synthe-
sis and post-synthesis modification, respectively.
H2DBP-Pt, H2QPDC-NH2
and HfCl4
in N, N-
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dimethylformamide (DMF) at 80 °C afforded the mixed-
ligand NMOF, M-UiO, as an orange powder (Scheme 1).
Transmission electron microscopy (TEM) revealed hexagonal
plate morphology with a diameter of ~200 nm and a thick-
ness of ~30 nm (Figure 1b). Powder X-ray diffraction (PXRD),
high-resolution TEM, and fast Fourier transform patterns
showed that M-UiO displayed good crystallinity (Figures 1).
The distance between adjacent secondary building units
(SBUs) was measured to be ~2.26 nm by TEM, consistent
with the distance of 2.18 nm calculated from the PXRD data.
UV-vis spectrum of M-UiO showed only two Q-band peaks,
suggesting no Pt leaching during NMOF synthesis (Figure
S4).19 Inductively coupled plasma−mass spectrometry (ICP-
MS) gave a DBP-Pt: QPDC-NH2 molar ratio of 6.2:93.8 in M-
UiO.
Rhodamine-B was covalently attached to M-UiO by form-
ing the thiourea linkage between QPDC-NH2 and RITC in R-
UiO, which was confirmed by mass spectrometry (Figure S6).
TEM images and PXRD patterns showed that R-UiO retained
the plate-like morphology and the crystallinity of M-UiO
(Figure 1a, 1f). Dynamic light scattering (DLS) measurements
gave an average diameter of 177.8 (PDI = 0.064) and 181.1
(PDI = 0.079) for M-UiO and R-UiO, respectively. The load-
ings of Rhodamine-B could be adjusted by controlling the
feed amount of RITC, leading to R-UiO-1 and R-UiO-2 that
contain 0.6 mol% and 1.6 mol% Rhodamine-B, respectively
(Figure S12 and S13).
R-UiO was incubated in Hank’s Balanced Salt Solution
(HBSS) buffer for 24 h to evaluate its stability in physiologi-
cal conditions. After incubation, the d111 peak in the PXRD
pattern was split into two peaks (Figure 1a), likely due to
minor lattice distortion in the buffer solution. Nevertheless,
TEM image clearly indicated the preservation of lattice fring-
es (Figure 2f, S9 and S10). Moreover, there is no Rhodamine-
B or DBP-Pt leaching after incubation (Figure S8), suggesting
adequate stability for oxygen sensing in the media.
To achieve ratiometric quantification using a single excita-
tion and simultaneous detection of RITC fluorescence and
DBP-Pt phosphorescence, there cannot be energy transfer
from DBP-Pt to Rhodamine-B. This lack of energy transfer
was confirmed by 1) a negligible overlap between H2DBP-Pt
emission and Rhodamine-B absorption (Figure S5), 2) the
presence of only characteristic DBP-Pt phosphorescence, but
not RITC fluorescence upon exciting R-UiO at 391 nm (corre-
sponding to H2DBP-Pt soret band, Figure S11) and 3) similar
phosphorescence lifetimes of R-UiO and H2DBP-Pt (Figure
S16). Ratiometric sensing was first carried out by fluorimetry
with a 514 nm excitation light source in order to match the
laser in confocal laser scanning microscopy (CLSM). Under
nitrogen-saturated atmosphere (pO2 = 0 mmHg), R-UiO-1
showed a strong emission at 630 nm from DBP-Pt and a weak
Figure 1. Structure and morphology of mixed ligand M-UiO
and R-UiO NMOF. (a) PXRD patterns of M-UiO, as-
synthesized R-UiO and R-UiO after incubation in HBSS for 12
h and 24 h. (b) TEM, (c) high-resolution TEM and (d) fast
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emission at 570 nm attributed to RITC (Figure 2a). As pO2
a 514 nm Argon laser, signals in the range of 620-660 nm and
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gradually increased to aerated atmosphere (pO2 = 160
mmHg), the RITC fluorescence remained unchanged, while
the DBP-Pt phosphorescence decreased significantly as ex-
pected. We quantitatively analyzed oxygen quenching by
fitting the data to the Stern-Volmer equation,20
540-580 nm were collected in two separate channels (Figure
S17) and analyzed by ImageJ to quantify the intensity ratios,
referred as IP/IF. Notably, the IP/IF - pO2 curve deviates from
that obtained by fluorimetry (Figure 2a), which is reasonable
given that the process of collecting photoluminescence on a
CLSM is much more complicated than using a fluorimeter.
Many factors besides pO2 such as laser power and dwell time
can influence the absolute and relative intensities of phos-
phorescence/fluorescence.23 We also noticed that the phos-
phorescence component was more prominent under CLSM
with our instrument settings, so we used R-UiO-2 with a
higher RITC loading for CLSM experiments. The IP/IF - pO2
curves obtained by CLSM are highly reproducible with the
IP/IF ratio gradually decreasing as pO2 increases, and are fit-
ted with a rational function (Formula S2, SI) which serves as
a standard curve for intracellular pO2 measurements.
ꢂ
ꢀꢁ
ꢃ 1 ꢄ ꢅꢆꢇꢈꢉ
(1)
ꢊ
ꢀꢁ
0
where KSV is the Stern-Volmer constant, and RI0 = IP0/IF and
RI = IP/IF are the ratio of phosphorescence intensity to fluo-
rescence intensity in the absence and presence of oxygen,
respectively. RI0/RI showed a good linear relationship with
respect to pO2 up to 80 mmHg (Figure 2b). Beyond this
point, the ratio deviated from the Stern-Volmer plot (Figure
S14). Such a deviation was also observed in previous reports7,
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and is probably related to the complicated dynamics in-
volved in the MOF structure. Fortunately, pO2 in biological
tissues is typically below 70 mmHg (except in arterial
blood).22 Within this range, the intensity ratio fitted well to
the Stern-Volmer equation with KSV = 0.015 mmHg-1. The O2
quenching experiment proved that R-UiO is a good O2 sen-
sor by providing pO2-specific IP/IF ratios.
Figure 3. (a) Calibration curve of the phosphores-
cence/fluorescence intensity of R-UiO-2 on CLSM under
different oxygen partial pressures. (b) Time-dependent cellu-
lar uptake of R-UiO-2 in CT26 cells determined by ICP-MS.
Ratiometric luminescence imaging (λex = 514 nm) of CT26
cells after incubation with R-UiO-2 under (c) hypoxia, (d)
normoxia, and (e) aerated conditions. Bar: 10 μm.
Figure 2. (a) Emission spectra (λex = 514 nm) and (c) phos-
phorescent decays (λex = 405 nm) of R-UiO-1 in HBSS buffer
under various oxygen partial pressures. Plots of RI0/RI (b) and
τ0/τ (d) as a function of oxygen pressure.
We chose mouse colon carcinoma CT26 cells with a low
background autofluorescence for in vitro imaging. The cellu-
lar uptake of R-UiO-2 in CT26 cells was first investigated by
incubating CT26 cells with 30 μg/mL R-UiO-2 for different
times. Cytotoxicity assay indicates that R-UiO is biocompati-
ble (Figure S18). Time-dependent endocytosis was quantified
by ICP-MS and shown in Figure 3b. Efficient cellular uptake
(~2.5 pg/cell) was observed after a 2 h incubation, which in-
dicates feasibility for intracellular pO2 measurements.
To further confirm the validity of ratiometric measure-
ments using R-UiO, the phosphorescence lifetime of R-UiO-1
in HBSS buffer was measured under different pO2 (Figure
2c). The data were fitted by bi-exponential decay. The ampli-
tude weighted lifetime τ (28.1 µs) in a deoxygenated (0
mmHg) atmosphere steadily decreased as pO2 increased and
reached 7.54 µs in an aerated atmosphere (160 mmHg). The
lifetime was fitted according to equation (2) (Figure 2d):
Finally we used R-UiO-2 to examine cellular O2 levels.
CT26 cells were incubated with R-UiO-2 for 2 h. The cultur-
ing media were then exchanged to HBSS buffer with different
pO2 in a sealed chamber, and cells were incubated for anoth-
er 15 min to ensure efficient oxygen exchange across cell
plasma membranes. CLSM settings were identical to those
used for the calibration curve. We tested three different pO2
conditions: 4 mmHg, 32 mmHg, and 160 mmHg, which rep-
resent hypoxia, normoxia and aerated conditions, respective-
ly. Different channels of cellular uptake of R-UiO-2 captured
by CLSM are shown in Figure S19. The IP/IF ratios of R-UiO-2
were shown by pseudocolor images in Figure 3c. The IP/IF
ꢋ0
ꢃ 1 ꢄ ꢅꢌꢍ
ꢈ
(2)
ꢎ2
ꢋ
where τ0 and τ are weighted lifetimes in the absence and
presence of oxygen, respectively. The obtained KSV = 0.017
mmHg-1 is similar to the ratiometric measurement result,
which indicates negligible static quenching of R-UiO-1.
Next we tested the validity of the ratiometric sensors by
CLSM. R-UiO-2 was dispersed in HBSS buffer and subjected
to CLSM imaging under different pO2. Upon excitation with
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Roussakis, E.; Klein, A.; Wu, J.; Runnels, J. M.; Zaher, W.;
values of internalized R-UiO-2 analyzed by ImageJ were 5.29
± 0.12, 4.45 ± 0.09, and 2.80 ± 0.06, corresponding to 5.1 ± 2.5
mmHg, 27.3 ± 3.1 mmHg, and 158 ± 11 mmHg (see SI for error
analysis) respectively according to the calibration curve in
Figure 3a. The results matched well with the preset pO2 in
each chamber. These data suggest the broad range and good
accuracy of R-UiO as intracellular oxygen sensors.
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3
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7
8
Mortensen, L. J.; Alt, C.; Turcotte, R. Nature. 2014, 508, 269ꢀ
273. (c) Wu, C.; Bull, B.; Christensen, K.; McNeill, J. Angew.
Chem. Int. Ed. 2009, 48, 2741ꢀ2745. (d) Wang, X.ꢀd.; Stolwijk, J.
A.; Lang, T.; Sperber, M.; Meier, R. J.; Wegener, J.; Wolfbeis, O.
S. J. Am. Chem. Soc. 2012, 134, 17011ꢀ17014. (e) Zhao, Q.;
Zhou, X.; Cao, T.; Zhang, K. Y.; Yang, L.; Liu, S.; Liang, H.;
Yang, H.; Li, F.; Huang, W. Chem. Sci. 2015, 6, 1825ꢀ1831. (f)
Yoshihara, T.; Yamaguchi, Y.; Hosaka, M.; Takeuchi, T.; Tobita,
S. Angew. Chem. Int. Ed. 2012, 51, 4148ꢀ4151.
9. Feng, Y.; Cheng, J.; Zhou, L.; Zhou, X.; Xiang, H. Analyst
2012, 137, 4885ꢀ4901.
10. Koo, Y.ꢀE. L.; Cao, Y.; Kopelman, R.; Koo, S. M.; Brasuel,
M.; Philbert, M. A. Anal. Chem. 2004, 76, 2498ꢀ2505.
11. Chojnacki, P.; Mistlberger, G.; Klimant, I. Angew. Chem. Int.
Ed. 2007, 46, 8850ꢀ8853.
In conclusion, we have for the first time reported the ra-
tional design and synthesis of stable, crystalline, porous, and
dual-emissive R-UiO NMOFs for ratiometric sensing of in-
tracellular oxygen in live cells. This study should inspire the
design of NMOF sensors for other biologically important
analytes by taking advantage of the synthetic tunability,
structural versatility, and other unique attributes of NMOFs.
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34
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36
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
12. Amelia, M.; LavieꢀCambot, A.; McClenaghan, N. D.; Credi,
A. Chem. Commun. 2011, 47, 325ꢀ327.
ASSOCIATED CONTENT
Supporting Information
13. (a) Kreno, L. E.; Leong, K.; Farha, O. K.; Allendorf, M.; Van
Duyne, R. P.; Hupp, J. T. Chem. Rev. 2011, 112, 1105ꢀ1125. (b)
Liu, D.; Lu, K.; Poon, C.; Lin, W. Inorg. Chem. 2013, 53, 1916ꢀ
1924. (c) Hu, Z.; Deibert, B. J.; Li, J. Chem. Soc. Rev. 2014, 43,
5815ꢀ5840. (d) Guo, Z.; Song, X.; Lei, H.; Wang, H.; Su, S.; Xu,
H.; Qian, G.; Zhang, H.; Chen, B. Chem. Commun. 2015, 51, 376ꢀ
379.
14. (a) Yang, W.; Feng, J.; Song, S.; Zhang, H. ChemPhysChem.
2012, 13, 2734ꢀ2738. (b) Suresh, V. M.; Chatterjee, S.; Modak,
R.; Tiwari, V.; Patel, A. B.; Kundu, T. K.; Maji, T. K. J. Phys.
Chem. C 2014, 118, 12241ꢀ12249. (c) Wu, P.; Wang, J.; He, C.;
Zhang, X.; Wang, Y.; Liu, T.; Duan, C. Adv. Funct. Mater. 2012,
22, 1698ꢀ1703.
15. (a) He, C.; Lu, K.; Lin, W. J. Am. Chem. Soc. 2014, 136,
12253ꢀ12256. (b) Taylor, K. M.; Rieter, W. J.; Lin, W. J. Am.
Chem. Soc. 2008, 130, 14358ꢀ14359. (c) deKrafft, K. E.; Xie, Z.;
Cao, G.; Tran, S.; Ma, L.; Zhou, O. Z.; Lin, W. Angew. Chem. Int.
Ed. 2009, 48, 9901ꢀ9904. (d) Hatakeyama, W.; Sanchez, T. J.;
Rowe, M. D.; Serkova, N. J.; Liberatore, M. W.; Boyes, S. G.
ACS Appl. Mater. Interfaces 2011, 3, 1502ꢀ1510. (e) Foucaultꢀ
Collet, A.; Gogick, K. A.; White, K. A.; Villette, S.; Pallier, A.;
Collet, G.; Kieda, C.; Li, T.; Geib, S. J.; Rosi, N. L. Proc. Natl.
Acad. Sci. U. S. A. 2013, 110, 17199ꢀ17204.
16. McKinlay, A. C.; Morris, R. E.; Horcajada, P.; Férey, G.;
Gref, R.; Couvreur, P.; Serre, C. Angew. Chem. Int. Ed. 2010, 49,
6260ꢀ6266.
17. Lu, K.; He, C.; Lin, W. J. Am. Chem. Soc. 2014, 136, 16712ꢀ
16715.
18. Coppeta, J.; Rogers, C. Exp. Fluids 1998, 25, 1ꢀ15.
19. Manna, K.; Zhang, T.; Greene, F. X.; Lin, W. J. Am. Chem.
Soc. 2015, 137, 2665ꢀ2673.
20. (a) Valeur, B.; BerberanꢀSantos, M. N. Molecular
fluorescence: principles and applications. John Wiley & Sons:
2012. (b) Turro, N. J.; Ramamurthy, V.; Scaiano, J. C. Modern
molecular photochemistry of organic molecules. Wiley Online
Library: 2012.
Experimental details for the synthesis and characterization of
M-UiO and R-UiO NMOFs, oxygen calibration and fitting,
cellular uptake and live cell imaging. This material is availa-
ble free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
wenbinlin@uchicago.edu
Author Contributions
†R.X. and Y.W. contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the NIH (UO1-CA198989 and P30 CA014599) for
funding support and Dr. Vytas Bindokas for help with confo-
cal microscopy imaging.
REFERENCES
1. Ikeda, E. Pathol. Int. 2005, 55 , 603ꢀ610.
2. Harris, A. L. Nat. Rev. Cancer 2002, 2, 38ꢀ47.
3. Höckel, M.; Schlenger, K.; Aral, B.; Mitze, M.; Schäffer, U.;
Vaupel, P. Cancer Res. 1996, 56, 4509ꢀ4515.
4. Gatenby, R. A.; Kessler, H. B.; Rosenblum, J. S.; Coia, L. R.;
Moldofsky, P. J.; Hartz, W. H.; Broder, G. J. Int. J. Radiat. Oncol.
Biol. Phys. 1988, 14, 831ꢀ838.
5. Hoogsteen, I. J.; Lok, J.; Marres, H. A.; Takes, R. P.; Rijken, P.
F.; van der Kogel, A. J.; Kaanders, J. H. Eur. J. Cancer 2009, 45,
2906ꢀ2914.
6. Mees, G.; Dierckx, R.; Vangestel, C.; Van de Wiele, C. Eur. J.
Nucl. Med. Mol. Imaging 2009, 36, 1674ꢀ1686.
7. (a) Cooper, R. A.; Carrington, B. M.; Loncaster, J. A.; Todd, S.
M.; Davidson, S. E.; Logue, J. P.; Luthra, A. D.; Jones, A. P.;
Stratford, I.; Hunter, R. D. Radiother. Oncol. 2000, 57, 53ꢀ59. (b)
Padhani, A. R.; Krohn, K. A.; Lewis, J. S.; Alber, M. Eur. Radiol.
2007, 17, 861ꢀ872.
21. Zhang, G.; Chen, J.; Payne, S. J.; Kooi, S. E.; Demas, J.;
Fraser, C. L. J. Am. Chem. Soc. 2007, 129, 8942ꢀ8943.
22. Carreau, A.; Hafny‐Rahbi, B. E.; Matejuk, A.; Grillon, C.;
Kieda, C. J. Cell. Mol. Med. 2011, 15, 1239ꢀ1253.
23. Finikova, O. S.; Lebedev, A. Y.; Aprelev, A.; Troxler, T.;
Gao, F.; Garnacho, C.; Muro, S.; Hochstrasser, R. M.;
Vinogradov, S. A. ChemPhysChem. 2008, 9, 1673ꢀ1679.
8. (a) Zhang, G.; Palmer, G. M.; Dewhirst, M. W.; Fraser, C. L.
Nat. Mater. 2009, 8, 747ꢀ751. (b) Spencer, J. A.; Ferraro, F.;
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