close

Вход

Забыли?

вход по аккаунту

?

acs.analchem.7b03597

код для вставкиСкачать
Subscriber access provided by the Henry Madden Library | California State University, Fresno
Article
A Bioluminescent Probe for Tumor Hypoxia
Detection via CYP450 Reductase in Living Animals
Yuqi Gao, Yuxing Lin, Tingting Liu, Hui Chen, Xiaofeng Yang, Chengsen Tian, Lupei Du, and Minyong Li
Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.7b03597 • Publication Date (Web): 27 Oct 2017
Downloaded from http://pubs.acs.org on October 27, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Analytical Chemistry is published by the American Chemical Society. 1155 Sixteenth
Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.
Page 1 of 7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Analytical Chemistry
A Bioluminescent Probe for Tumor Hypoxia Detection via CYP450
Reductase in Living Animals
Yuqi Gao,† Yuxing Lin,† Tingting Liu,† Hui Chen,† Xiaofeng Yang,§ Chengsen Tian,¶ Lupei Du,†
and Minyong Li†,‡,*
†
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong
University, Jinan, Shandong 250012, China. Tel./fax: +86-531-8838-2076; E-mail: mli@sdu.edu.cn
§
School of Chemistry and Chemical Engineering, University of Jinan, Jinan, Shandong 250022, China
¶
School of Chemistry and Chemical Engineering, Qilu Normal University, Jinan, Shandong 250200, China
‡
State Key Laboratory of Microbial Technology, Shandong University, Jinan, Shandong 250100, China
ABSTRACT: Hypoxia is a pathogenic characteristic of solid tumors owing to absent or abnormal vasculature in the tumor
microenvironment and essential in tumor progression, angiogenesis, metastasis, invasion and resistance to immune system and therapy. In hypoxic environments, CYP450 enzymes are more efficient than in normoxia. Herein, based on the
reductive capacity of CYP450 enzymes/NADPH system, we managed to cage aminoluciferin developing a reaction-based
bioluminescent probe as well as an imaging method for the hypoxia detection. Exhibiting enhanced about 3-fold total flux
in big (1.2 cm-diameter) tumors, Hypoxia BioLuminescent probe (HBL) can afford potential utility for in cellulo and in
vivo hypoxia imaging in tumor model mice.
Introduction
It is well known that the tumor microenvironment
(TME) is not the same with normal tissues, including a
highly reducing status, a low pH, and hypoxia. Hypoxia,
which is defined as lower-than-normal oxygen conditions,
is a pathogenic characteristic of solid tumors owing to
absent or abnormal vasculature in the tumor microenvironment.1,2 Compared to the physiologic oxygenation level (5%–10% O2), the oxygen level is recognized to be less
than 1.3% O2 in most solid tumor tissues. Developing hostile microenvironments such as hypoxia, solid tumors
typically exhibit unregulated growth.3-5 In order to adapt
to hypoxia, cancer cells promote survival pathways mediated through protein stabilization of hypoxia inducible
factor (HIF) subunits (HIF1α, HIF2α and HIF3α) which are
regulated by prolyl hydroxylase domain (PHD) and factor
inhibiting HIF1 (FIH-1) enzymes. Hydroxylated by PHD
and FIH-1, polyubiquitinated and degraded by the proteasome, HIFα subunits stay inactive in oxygenated cells.
While in hypoxia, HIFα dimerized with HIFβ subunit
which is constitutively expressed, after translocated into
the nucleus. As a result, the dimer binds to DNA to initiate gene transcription, supporting cancer cells survival.
Recently, cytochrome P450 enzymes were discovered to
perform a more powerful reductive capacity in cells under
hypoxia conditions through investigation on the reduction of azide-containing compounds under different oxygen levels.6 Consequently, hypoxia, as an important tumor microenvironmental factor, has a pivotal role in tu-
mor progression,3 angiogenesis,1 metastasis,6,7 invasion,5,8
and resistance to immune system2 and therapy.8-10
Awareness of resistant to chemotherapy and radiotherapy caused by overexpressed HIF1 promote explorations,
improvements and innovation in cancer diagnosis and
therapies.11-14 Considering that hypoxia emerges when the
diameter of solid tumor increases to approximate 350 μm
in the body, hypoxia imaging is essential in diagnosis of
cancer in early stage.15,16 Different kinds of imaging system
have been explored and developed for hypoxia detection,
including positron emission tomography (PET) and/or
magnetic resonance imaging (MRI) probes,17,18 phosphorescent probes,19,20 fluorescent probes,21-26 bioluminescent
probes27 and chemiluminescent probes,28 many of which
could be employed for hypoxia imaging in living cells and
animals.
In recent decade, bioluminescent imaging (BLI), a reliable, sensitive, convenient, and noninvasive imaging
method, has been extensively applied in pathogen detection, tumor imaging, therapeutic drug screening, and
many other aspects in life science. Usually, firefly luciferin
or aminoluciferin associated with firefly luciferase is employed in BLI system, transmitting light in the presence of
adenosine triphosphate (ATP), O2, and Mg2+. When 6’hydroxy (or 6’-amino) group of D-luciferin (or aminoluciferin) converted into an inactive “caged” form chemically, it cannot be recognized by luciferase, forbidding light
emission ultimately. However, the capability could recover once luciferin (or aminoluciferin) released from its
ACS Paragon Plus Environment
Analytical Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
caged form after reaction with specific reagents or in specific environment.29,30
Both the Nagano and Qian groups reported that probes
bearing azo group are sensitive to hypoxia.21-23 The results
manifested that the N=N bond performs as a novel and
effective moiety in designing a probe for hypoxia detection. In order to construct a promising approach for hypoxia imaging in living animals, we decided to take advantage of firefly bioluminescence imaging (BLI) as a noninvasive alternative on account of its ability to afford
high-sensitivity in vivo imaging. In the current exploration, we managed to introduce an azo group into firefly
luciferin to develop a hypoxia bioluminescent probe HBL
(Figure 1) with a high sensitivity and fine resolution in
living cells and animals using the “caging” strategy30, referencing the previous works in our group27,31-34.
Page 2 of 7
generated HBL at ambient temperature. The details for
the preparation of the compounds and their NMR and
HR-MS spectra can be found in the Supplementary Materials.
Bioluminescence measurements in vitro
Measurements for sensitive assays were performed in
Tris-HCl buffer (10 mM, pH 7.44). Hypoxia bioluminescence probe was incubated with various concentrations of
cytochrome P450 reductase at various concentrations (0
to 10 μg/mL) and NADPH tetrasoldium at 37 °C for 60
min. After that, 50 μL of Tris buffer containing firefly luciferase (20 μg/mL), ATP (2 mM) and Mg2+ (10 mM) was
added, and bioluminescence intensity was measured immediately with an acquisition time of 0.5 s by IVIS Kinetic
imaging system equipped with a cooled CCD camera.
Measurements for selectivity assays were also performed in Tris-HCl buffer (10 mM, pH 7.44). Hypoxia bioluminescence probe was incubated with various concentrations of reductive species at 37 °C for 60 min. After that,
50 μL of firefly luciferase (20 μg/mL) in Tris buffer containing ATP (2 mM) and Mg2+ (10 mM) was added, and
bioluminescence intensity was measured immediately
with an acquisition time of 0.5 s by IVIS Kinetic imaging
system equipped with a cooled CCD camera.
Biolu-
Bioluminescence measurements in cellulo
Figure 1. Proposed mechanism of bioluminescent probe
HBL for the detection of hypoxia.
Experiments
All reagents and solvents available from commercial
sources were used without further purified unless otherwise noted. The reactions were visually monitored with
TLC analysis performed on glass-backed silica plates associated with UV light (or I2). Water used for the bioluminescence studies was doubly distilled and further purified
with a Milli-Q filtration system. HPLC analysis was undertaken with a 1260 Infinity HPLC (Agilent Technologies,
Santa Clara, CA). For bioactivity evaluation of HBL, bioluminescence intensity was measured by IVIS Kinetic imaging system (Caliper Life Sciences, Hopkinton, Massachusetts, USA) instrument equipped with a cooled
charge-coupled device (CCD) camera. Using Living Image
software, the data were quantified and reported as total
photon flux within a circular region of interest (ROI) in
photons per second.
Sythesis
Our hypoxia probe can be prepared with an efficient
and easy-operated approach as depicted in Scheme S1. In
breif, 6-aminobenzo[d]thiazole-2-carbonitrile (1) reacted
with sodium nitrite in diluted hydrochloric acid (6 M) in
ice-salt bath forming the diazonium salt which further
reacted with N, N-diethylaniline then to obtain pure azo
intermediate 2 after neutralization and column chromatography separation. A subsequent cross-coupling reaction of the intermediates 2 with D-cysteine hydrochloride
To qualify HBL for hypoxia assay in living cells, luciferase-transfected human ovarian cancer cell lines ES-2 (ES2-luc) were used. ES-2-luc cells were passed and plated
(4×104 cells per well) in 96-well plates (Corning, 3603).
After incubated overnight, the medium was replaced with
of cobalt chloride solution of various concentrations (0 to
2000 μM) dissolved in FBS free medium. After 4 hourincubation at 37 °C, the medium containing CoCl2 was
discarded and FBS free medium was added. Incubated for
30 min, the medium was removed and HBL in saline solution was added. The bioluminescence intensity was
measured immediately with an acquisition time of 60 s by
IVIS Kinetic imaging system equipped with a cooled CCD
camera.
ES-2-luc cells were passed and plated (4×104 cells per
well) in two 96-well plates (Corning, 3603). After incubated overnight, one of them was transferred into a tri-gas
incubator with 1% pO2 while the other remained in
normoxic condition (20% pO2). After 6 hour-incubation
at 37 °C, the medium was removed and HBL in saline solution of various concentrations (0 to 100 μM) was added.
The bioluminescence intensity was measured with an
acquisition time of 60 s by an IVIS Kinetic imaging system
equipped with a cooled CCD camera.
Bioluminescence imaging in vivo
All animal studies were approved by the Ethics Committee and IACUC of Cheeloo College of Medicine, Shandong University, and were conducted in compliance with
European guidelines for the care and use of laboratory
animals. BALB/c nude mice were purchased from the Animal Center of the China Academy of Medical Sciences
ACS Paragon Plus Environment
Page 3 of 7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Analytical Chemistry
(Beijing, China). To investigate hypoxia imaging of HBL
in vivo, ES-2-luc cells (approximate 1.5×106) were grafted
subcutaneously under the right forelimb armpit of
BALB/c nude mice, aged 6 weeks. After about 3 weeks,
tumors were harvested and cut into pieces, and then 10mg or 5-mg tumor pieces were implanted subcutaneously
into the right armpit region of another group of nude
mice. Tumor xenografts with diameters of around 10 and
13 mm were formed respectively after two weeks. The
mice were anesthetized by single intraperitoneal injected
chloral hydrate (8%) before imaging. Then, 50 μL of HBL
(1 mM) in saline. Photon emission was collected using a
cooled CCD camera with an acquisition time of 20 s.
combined with beneficial characteristics of the bioluminescence technique, can afford potential utility for in cellulo and in vivo hypoxia imaging.
RESULTS AND DISCUSSION
Initial experiments focused on the confirmation of our
bioluminescent probe’s mechanism. As azo compounds is
liable to reductants, HBL can be reduced to aminoluciferin as the reduced product. To test the liability of HBL to
chemical reductant, the probe in aqueous solution was
reacted with stannous chloride in strong acidic condition
at room temperature. The color of the solution changed
from orange to yellow distinctly, after reaction for about
30 min at room temperature. Moreover, cytochrome P450
reductase (CYP450 reductase), a common reductase in
endoplasmic reticulum and mitochondria of animals’ cells,
was selected to examine the reducible ability of HBL to
bio-reductant. A similar phenomenon was observed when
HBL was reacted with cytochrome P450 reductase and
nicotinamide adenine dinucleotide phosphate (NADPH)
in Tris-HCl (10 mM) buffered to pH 7.44 at 37 ºC for 5 h.
The previously conjected mechanism of the probe was
confirmed with HPLC by comparing the reduction sample
of HBL by stannous chloride or cytochrome P450 reductase with amino-luciferin. When reacted with reductants,
absorbance at 20.6 min (the retention time of HBL) declined, while new peaks appeared at 3.6 min, as the retention time of aminoluciferin (Figure S1).
Luciferin/luciferase system is highly efficient and sensitive to
afford a significant enhancement of bioluminescent signal
for cell and animal imaging, despite only a trace amount
of aminoluciferin generated though the reduction procedure. 27,32,33,35 Therefore, further investigations involving
performance of HBL towards hypoxia were carried out.
Selectivity of HBL (50 µM) for cytochrome P450 reductase (5 µg/mL) against a range of reductive species existing in tumor cells, including nitroreductase (NTR) (5
µg/mL), NADPH (100 µM), Vitamin C (1000 µM), reduced
glutathione (GSH) (1000 µM) and HS- (1000 µM), was assessed consequently in aqueous system. As illustrated in
Figure 2, when cytochrome P450 reductase and NADPH
was added simultaneously, an evident enhancement in
bioluminescence intensity displayed, compared with NTR
and other reductants. That means our bioluminescent
probe is more liable to CYP450 reductase/NADPH system,
which is a primary and oxygen-dependent reductive system in metabolism.6 These response and selectivity data
suggested that HBL with fine sensitivity and selectivity,
Figure 2. Response and selectivity assay of HBL in vitro.
(A) Bioluminescence imaging of selectivity of HBL towards various relevant reductants which may exist in cells
(cytochrome P450 reductase, NADPH, NTR, Vitamin C,
GSH, HS-) with luciferase, ATP and Mg2+ added in a 96well plate. (B) Quantification of bioluminescence intensity of HBL for each condition.
Afterwards, the ability of HBL to image hypoxia in living in cellulo was investigated. To qualify HBL for hypoxia
assay in living cells, cobalt chloride was utilized to induce
hypoxia in luciferase-transfected human ovarian cancer
cell lines ES-2 (ES-2-luc).27,36,37 As illustrated in Figure 3,
bioluminescence intensity increased continually with the
gradually increasing concentrations (0−800 µM) of cobalt
chloride with the peak value (293% relative increase) at
800 µM CoCl2. The results expose that Co2+ ion with different concentrations can induce living cells’ hypoxia in
different degrees effectively and suggest that intracellular
level of reducing substances and reductase (such as cytochrome P450 reductase and NTR27,28), may elevate under
hypoxia stimulation from a side. Furthermore, HBL was
confirmed to be capable for monitoring hypoxia at cellular level with a series of dynamic changes. According to
the results of cytotoxicity test accomplished by SRB cytotoxicity assay, the hypoxia bioluminescent probe HBL is
low-toxic and fine-biocompatible (Figure S5). Meanwhile,
the cytotoxicity of cobalt chloride was also tested (Figure
S5). Exhibiting low cytotoxicity at high concentrations, a
large excess amount of cobalt ion may decrease the activi-
ACS Paragon Plus Environment
Analytical Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ty of enzymes in cells, bringing down the bioluminescence intensity in turn.
Page 4 of 7
manner along with the increasing concentration of probe.
In brief, these results further confirmed that HBL is capable of hypoxia detection at the cellular level. To some
extent, the results also coincided with and experimentally
proved the oxygen-dependent manner of CYP450 enzymes6.
Figure 4. Bioluminescence measurement in ES-2-luc cells
under hypoxic condition (1% pO2). (A) Bioluminescence
imaging in hypoxic living cells with diverse concentrations (0, 5, 10, 20, 40, 60, 70, 80, 90, 100 µM) of HBL; (B)
quantification of bioluminescence intensity of HBL for
each condition.
Figure 3. Hypoxia assay in ES-2-luc cells using HBL. (A)
Bioluminescence imaging in hypoxic living cells induced
by diverse concentrations (0, 25, 50, 100, 200, 400, 600,
800, 1000, 2000 µM) of cobalt chloride; (B) quantification
of bioluminescence intensity of HBL for each condition;
(C) variation of relative bioluminescence intensity in 45
min.
In order to validate the capability of HBL for hypoxic
microenvironment detection, ES-2-luc cells were incubated under hypoxic condition (1% pO2) for 6 h. Compared
with the control group (cells incubated in normoxic conditions), an increasing bioluminescence intensity was
observed in hypoxic cells (Figure 4). Meanwhile, the total
photon emission exhibited a concentration-dependent
Finally, having confirmed that HBL can provide a
method for monitoring oscillations of hypoxia with significant selectivity and sensitivity in living cells, we interrogated the capability of HBL for hypoxia visualization in
human tumor xenograft models. ES-2-luc cells were subcutaneously grown on the axilla of BALB/c nude mice. We
attempted to inject the bioluminescent probe in tumors
with different diameters (less than 1.0 cm and more than
1.2 cm) on the nude mice, respectively. Thereafter, the
subsequent bioluminescence intensity was kinetically
recorded with living imaging system. As shown in Figure
5, after intratumoral injection of HBL, distinctly enhancing emission signal from tumor regions in nude mice were
observed, reaching peak values immediately. The enhanced bioluminescence intensity from the whole tumors
lasted for about 5 min. Within 1 min after HBL injected,
the average flux value of the “big” group (over 1.2 cmdiameter tumors) was 3-fold higher than that of the
“small” group (less-than 1.0 cm-diameter tumors). The
bioluminescence intensity of the “big” group declined
significantly over time, while the “small” group decreased
slightly. The emission signals of the two groups trended
ACS Paragon Plus Environment
Page 5 of 7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Analytical Chemistry
to be uniform about 30 min after HBL injection.
Conclusion
In summary, by introducing an azo group, which can be
reduced by CYP450 reductase, into amino luciferin, we
designed and prepared a Hypoxia BioLuminescent probe
(HBL). The investigation results obviously demonstrated
that the bioluminescent probe is able to monitor hypoxia
visually both in cellulo and in vivo. Moreover, not only did
the experimental data establish a clear correlation between dynamic hypoxia degrees and tumors with different size, but also implied that it is capable of HBL offer-
ing a valuable approach for dynamic hypoxia monitoring
in tumor development in living animals. Therefore, exhibiting fine selectivity and sensitivity as well as other beneficial characteristics, HBL presents a powerful tool in hypoxia bioimaging and provides a feasible approach for
visualizing hypoxia via CYP450 enzymes in the development of tumors. As a result, by using such a promising
toolkit, a valuable opportunity was supplied to understand hypoxia and its role in tumor processes. It is believable that the novel hypoxia bioluminescent probe will
expand the hypoxia imaging toolkit as well as applications
of bioluminescence technology.
Figure 5. Bioluminescence imaging of living ES-2-fluc-GFP ovarian tumor xenografts on BALB/c nude mice. (A) Timedependent bioluminescence imaging of tumors with different diameters (“big”: more than 1.2 cm, “small”: less than 1.0
cm) (B) Fluctuation of total flux from the tumoral areas of the nude mice of triplicates (n=3 mice) at 0−30 min. (C) Quantification of bioluminescence intensity from the tumoral areas of the nude mice of triplicates (n=3).
Corresponding Author
ASSOCIATED CONTENT
*Tel. /Fax: +86-531-8838-2076. E-mail: mli@sdu.edu.cn
Supporting Information
Full experimental procedure, NMR, MS, fluorescence, and
cell imaging data. The Supporting Information is available
free of charge on the ACS Publications website at DOI:
10.1021/.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of the manuscript.
ACKNOWLEDGMENTS
AUTHOR INFORMATION
ACS Paragon Plus Environment
Analytical Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The present work was supported by grants from the
National Program on Key Basic Research Project of China
(No. 2013CB734000), the National Natural Science
Foundation of China (No. 81673393), the Taishan Scholar
Program at Shandong Province, the Qilu Scholar Program
at Shandong University and the Major Project of Science
and
Technology
of
Shandong
Province
(No.
2015ZDJS04001).
Notes
The authors declare no competing financial interest.
REFERENCES
(1) Carmeliet, P.; Dor, Y.; Herbert, J.-M.; Fukumura, D.;
Brusselmans, K.; Dewerchin, M.; Neeman, M.; Bono, F.;
Abramovitch, R.; Maxwell, P.; Koch, C. J.; Ratcliffe, P.;
Moons, L.; Jain, R. K.; Collen, D.; Keshet, E. Nature 1998, 394,
485-490.
(2) Shehade, H.; Oldenhove, G.; Moser, M. BioMed Res. Int.
2014, 44, 2550-2557.
(3) Ackerman, D.; Simon, M. C. Trends Cell Biol. 2014, 24,
472-478.
(4) Shay, J. E.; Celeste Simon, M. Semin. Cell Dev. Biol. 2012,
23, 389-394.
(5) Taddei, M. L.; Giannoni, E.; Comito, G.; Chiarugi, P.
Cancer Lett. 2013, 341, 80-96.
(6) O’Connor, L. J.; Mistry, I. N.; Collins, S. L.; Folkes, L. K.;
Brown, G.; Conway, S. J.; Hammond, E. M. ACS Cent.
Sci. 2017, 3, 20-30.
(7) Abaza, M.; Luqmani, Y. A. Expert Rev. Anticancer Ther.
2013, 13, 1229-1242.
(8) Yuen, A.; Diaz, B. Hypoxia (Auckland, N.Z.) 2014, 2, 91106.
(9) Muz, B.; de la Puente, P.; Azab, F.; Azab, A. K. Hypoxia
(Auckland, N.Z.) 2015, 3, 83-92.
(10) Barker, H. E.; Paget, J. T.; Khan, A. A.; Harrington, K. J.
Nat. Rev. Cancer 2015, 15, 409-425.
(11) Semenza, G. L. Nat. Rev. Cancer 2003, 3, 721-732.
(12) Policastro, L. L.; Ibanez, I. L.; Notcovich, C.; Duran, H.
A.; Podhajcer, O. L. Antioxid. Redox Signaling 2013, 19, 854895.
(13) Phillips, R. M. Cancer Chemother. Pharmacol. 2016, 77,
441-457.
(14) Manoochehri Khoshinani, H.; Afshar, S.; Najafi, R.
Cancer Invest. 2016, 34, 536-545.
(15) Vaupel, P.; Kallinowski, F.; Okunieff, P. Cancer Res.
1989, 49, 6449-6465.
(16) Yoshihara, T.; Hirakawa, Y.; Hosaka, M.; Nangaku, M.;
Tobita, S. J. Photochem. Photobiol., C 2017, 30, 71-95.
(17) Wolf, G.; Abolmaali, N. Recent Results Cancer Res. 2013,
187, 257-310.
(18) Jung, K. o.; Youn, H.; Kim, S. H.; Kim, Y.-H.; Kang, K. W.;
Chung, J.-K. Biochem. Biophys. Res. Commun. 2016, 477, 483489.
(19) Dmitriev, R. I.; Zhdanov, A. V.; Nolan, Y. M.; Papkovsky,
D. B. Biomaterials 2013, 34, 9307-9317.
(20) Sun, L.; Chen, Y.; Kuang, S.; Li, G.; Guan, R.; Liu, J.; Ji, L.;
Chao, H. Chem. - Eur. J. 2016, 22, 8955-8965.
(21) Kiyose, K.; Hanaoka, K.; Oushiki, D.; Nakamura, T.;
Kajimura, M.; Suematsu, M.; Nishimatsu, H.; Yamane, T.;
Terai, T.; Hirata, Y.; Nagano, T. J. Am. Chem. Soc. 2010, 132,
15846-15848.
Page 6 of 7
(22) Piao, W.; Tsuda, S.; Tanaka, Y.; Maeda, S.; Liu, F.;
Takahashi, S.; Kushida, Y.; Komatsu, T.; Ueno, T.; Terai, T.;
Nakazawa, T.; Uchiyama, M.; Morokuma, K.; Nagano, T.;
Hanaoka, K. Angew. Chem., Int. Ed. Engl. 2013, 52, 1302813032.
(23) Cai, Q.; Yu, T.; Zhu, W.; Xu, Y.; Qian, X. Chem. Commun.
2015, 51, 14739-14741.
(24) Hou, T.-C.; Wu, Y.-Y.; Chiang, P.-Y.; Tan, K.-T. Chem.
Sci. 2015, 6, 4643-4649.
(25) Zhang, J.; Liu, H.-W.; Hu, X.-X.; Li, J.; Liang, L.-H.;
Zhang, X.-B.; Tan, W. Anal. Chem. 2015, 87, 11832-11839.
(26) Xiao, H.; Li, P.; Zhang, W.; Tang, B. Chem. Sci. 2016, 7,
1588-1593.
(27) Feng, P.; Zhang, H.; Deng, Q.; Liu, W.; Yang, L.; Li, G.;
Chen, G.; Du, L.; Ke, B.; Li, M. Anal. Chem. 2016, 88, 56105614.
(28) Cao, J.; Campbell, J.; Liu, L.; Mason, R. P.; Lippert, A. R.
Anal. Chem. 2016, 88, 4995-5002.
(29) Nakatsu, T.; Ichiyama, S.; Hiratake, J.; Saldanha, A.;
Kobashi, N.; Sakata, K.; Kato, H. Nature 2006, 440, 372-376.
(30) Li, J.; Chen, L.; Du, L.; Li, M. Chem. Soc. Rev. 2013, 42,
662-676.
(31) Li, J.; Chen, L.; Wu, W.; Zhang, W.; Ma, Z.; Cheng, Y.;
Du, L.; Li, M. Anal. Chem. 2014, 86, 2747-2751.
(32) Wu, W.; Li, J.; Chen, L.; Ma, Z.; Zhang, W.; Liu, Z.;
Cheng, Y.; Du, L.; Li, M. Anal. Chem. 2014, 86, 9800-9806.
(33) Ke, B.; Wu, W.; Liu, W.; Liang, H.; Gong, D.; Hu, X.; Li,
M. Anal. Chem. 2016, 88, 592-595.
(34) Wu, W.; Su, J.; Tang, C.; Bai, H.; Ma, Z.; Zhang, T.; Yuan,
Z.; Li, Z.; Zhou, W.; Zhang, H.; Liu, Z.; Wang, Y.; Zhou, Y.;
Du, L.; Gu, L.; Li, M. Anal. Chem. 2017, 89, 4808-4816.
(35) Cohen, A. S.; Dubikovskaya, E. A.; Rush, J. S.; Bertozzi,
C. R. J. Am. Chem. Soc. 2010, 132, 8563-8565.
(36) Van Liew, H. D.; Chen, P. Y. J. Appl. Physiol. 1972, 32, 315319.
(37) Wang, G.; Hazra, T. K.; Mitra, S.; Lee, H. M.; Englander,
E. W. Nucleic Acids Res. 2000, 28, 2135-2140.
ACS Paragon Plus Environment
6
Page 7 of 7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Analytical Chemistry
For TOC only
ACS Paragon Plus Environment
7
Документ
Категория
Без категории
Просмотров
0
Размер файла
917 Кб
Теги
analchem, acs, 7b03597
1/--страниц
Пожаловаться на содержимое документа