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A water soluble fluorescent probe with dual mitochondria/ lysosome targetability for selective superoxide detection in live cells and in zebrafish embryos Xiuhong Lu, Zhongjian Chen, Xiaochun Dong, and Weili Zhao ACS Sens., Just Accepted Manuscript • DOI: 10.1021/acssensors.7b00831 • Publication Date (Web): 16 Jan 2018 Downloaded from http://pubs.acs.org on January 17, 2018
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A water soluble fluorescent probe with dual mitochondria/lysosome targetability for selective superoxide detection in live cells and in zebrafish embryos Xiuhong Lu, †,§Zhongjian Chen,*,‖Xiaochun Dong,*,† and Weili Zhao*,†,‡ [†] School of Pharmacy Fudan University, 826 Zhangheng Road, Shanghai, 201203, P. R. China [‡] Key Laboratory for Special Functional Material of the Ministry of Education, Henan University, Kaifeng, 475004, P. R. China [§] PET Center,Huashan Hospital, Fudan University, 518 East Wuzhong Road, Shanghai 200235, P. R. China [‖] Shanghai Dermatology Hospital, Shanghai, 200443, P. R. China
Supporting Information Placeholder ABSTRACT:
A novel water soluble fluorescein-based fluorescent probe for superoxide detection was developed. The probe is fairly stable under neutral and acidic conditions. It can be used to detect superoxide both in solution with the detection limit of 2.2 µM and in living cells. Cell imaging experiments indicated that such a probe displayed good cell penetration and O2•− could be detected with PMA-stimulated HepG2 cells in both mitochondria and lysosome. Such a probe is the first dual mitochondriaand lysosometargetable fluorescent chemodosimeter. Additionally, O2•− in intact live zebrafish embryos was successfully visualized under PMA-stimulated conditions and the possible detection mechanism was studied as well.
rescent probes have obvious advantages over redox-based ones because of much less interfering analytes, and some good examples are listed in Scheme 1. A major challenge in achieving reliable O2•− detection is to differentiate O2•−-induced deprotection from other deprotection reactions induced by good nucleophiles other than O2•− such as H2O2-induced perhydrolysis, as well as thiol-induced SNAr substitution.
F HO
O
perhydrolysis
O O
F O
O O as H2O2 probe
O F S
F
F
HO
Me O O S O
O
as Thiol or Selenol probe O2N
F
NO2
F O
O
Key Words: Fluorescent probe; Fluorescein; KO2; Superoxide; Mitochondria-targeting; Lysosome-targeting; Dual targetable
The study of reactive oxygen species (ROS) which include hydrogen peroxide (H2O2), hypochlorous acid (HOCl) and hypochlorite (ClO−), singlet oxygen (1O2), superoxide (O2•−), hydroxyl radicals (•OH), and ozone (O3) is an area which attracts tremendous research interest due to their essential roles in cell signaling and homeostasis,[1] such as aging,[2] pathogen response,[3] and anti-inflammation regulation.[4] As the product of the one-electron reduction of dioxygen O2, O2•− is known to be involved in the onset of various diseases such as cancer, cardiovascular diseases, immune system decline and diabetes.[5] O2•− is a fascinating analyte in that it is both a radical and anion. It acts as an oxidant, a reductant, as well as a supernucleophile due to α-effect.[6] As a major ROS and parent species of other ROS, O2•− is particularly important as a marker for early ROS generation.[7] Thus the selective and sensitive detection of superoxide is very crucial and an ongoing challenge due to the multi-function of O2•−. Recently, the detection of O2•− was implemented by fluorescent probes through redox[8,9] or protection-deprotection[10] process. Among available tools for O2•− detection, the protection-deprotection-based O2•− fluo-
SNAr substitution
O
Me
S O2N
O
F O
O
O
F O
O
O
O
O
NO2
F
O
O
O PPh2
O Ph2P
as O2- probe S N
O O2N
O O
-
O
as biothiol and O2 probe NO2
F3 C
O O O
O
O -
as O2 probe D. Yang (2015)
NO2
D. G. Churchill (2013)
O O
NO2
O -
O
S
O PPh2
O O O P
as O2 probe NO2 D. G. Churchill (2013) D. G. Churchill (2013)
O
O
as O2- probe B. Tang (2007) O
O
as O2 probe
OMe
O O
B. Tang (2007) S N
-
OMe
O2N
O
O
O
O S
O
H. Maeda (2007) as O2- probe O
O
O Ph2P
F O
O F
F F O N H. Maeda (2005) 2 as O2- probe
NO2
O
F
O
O S
O
O
O
O S
S
CF3 NI
O
O O -
O
as O2 probe Probe 1 (This work)
O S I N
Scheme 1. Protection-deprotection-based fluorescent probes developed for superoxide, as well as the possible interfering reactions. The pioneer work by Maeda et al. provided a breakthrough for selective O2•− fluorescent sensing using tetrafluoro fluorescein as fluorophore and 2,4-dinitrobenzenesulfonyl as masking moiety to
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differentiate from H2O2, however with undesirable reactivity toward thiols e.g. reduced glutathione (GSH) (Scheme 1).[10a,11] The selectivity toward O2•− over GSH and ROS was subsequently improved with 4,5-dimethoxy-2-nitro-phenylsulfonly tetrafluoro fluorescein derivative.[10b] On the basis of the O2•−-induced deprotection of the diphenylphosphinyl unit, two phosphinated fluorescein analogues were reported by Tang et al. with high selectivity for O2•−.[10c,10d] Churchill’s group communicated ESIPT (excited state intramolecular proton transfer) probes for O2•− based on deprotection of phosphinate or 4-nitrophenyl ether of 2(benzothiazol-2-yl)-phenol (HBT) compound, however, the selectivity against GSH was unknown.[10e] A fluorescein bis(2,4dinitrobenzoate) reported from the same group acted as dual thioland O2•−-responsive probe.[10f] Lately a fluorescein bistriflate was reported by D. Yang’s group to be sensitive O2•− probe to allowed detection of O2•− in zebrafish.[10g] Moreover, a mitochondriatargetable version was also developed.[10g] It is known that a major endogenous source of superoxide is the mitochondrial electrontransport chain (mETC).[12,13] Superoxide is the major reactive oxygen species regulating autophagy (a lysosome-mediated degradation process).[12] Therefore, to visualized O2•− in subcellular level as organelle-targetable imaging of ROS is tremendously meaningful, especially with the aid of fluorescent imaging techniques since their high sensitivity and the satisfying spatial and temporal resolution.
Previous probes for O2•− were generally poorly water-soluble and only a few probes were used to detect O2•− at subcellular levels on mitochondria. Despite significant progresses have been achieved for organelle-targetable ROS detection in mitochondria (by taking advantage of positive lipophilic cation moieties binding to the negative membrane potential mitochrondria) and lysosome (frequently using alkaline moieties as targeting group due to the acidic nature of lysosome),[14] none of the fluorescent probe with dual mitochondria and lysosome targeting ability was ever reported. For O2•− detection, a water soluble and organelle-targetable probe is highly desirable.[15] In this communication, we report a water soluble fluorescent probe for selective detection of O2•− in both mitochondria and lysosome.
Figure 1. Time-course fluorescence response of probe 1 (10 µM) upon addition of KO2 (0 µM, 10 µM, 50 µM, 100 µM, 1 mM) in deionized water at room temperature monitored at 513 nm (λex = 492 nm, slit: 2.5 nm/2.5 nm). Recently we found that pyridinium modified fluoresceinbisacrylate behaved as a water soluble multi-functional fluorescent probe for basic amino acids and biothiols.[16] Encouraged by recent study that bistriphenylphosphonium modified BODIPY (boron dipyrromethene) dye showed unusual lysosome-targeting capability, which deviates from the common knowledge that the
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positively charged triphenylphosphonium always leads to the accumulation in mitochondria of negative potential and targeting acidic lysosome requires basic moieties.[14] We speculated that bispyridinium may possibly result in lysosome-targeting ability since pyridinium is mitochondria-targetable.[14] Using simple fluorescein as fluorophore and selection of pyridinium-containing group as O2•− responsive moiety led to the discovery of fluorescein-bis-[(N-methylpyridinium-3-yl)sulfonate iodide] (probe 1, Scheme 1) as the first example of dual mitochondria/lysosome targetable water soluble fluorescent probe for O2•−. The response of fluorescent probe to O2•− can be conveniently measured using KO2 as a surrogate of O2•−.[8d,10] To our delight, probe 1 is easily soluble in water and weak fluorescence was observed. When probe 1 (10 µM) in PBS buffer was subjected to KO2 (100 µM) at room temperature for 10 minutes, increase in fluorescence with the characteristics of fluorescein (absorption maximum at 494 nm; emission maximum of 514 nm) was noticed. These observations promoted us to investigate the response of probe 1 to KO2 in detail. Probe 1 showed dose-dependent response to KO2 in a wide range from micromolar to millimolar with dramatically increased responding rate when concentrated KO2 was applied (Figure 1). From the concentration-dependent time response profile (Figures S1 and S2 in the Supporting Information), linearly proportional to analyte concentration was observed to be in the range of 1−50 µM and the detection limit of probe 1 for KO2 was found to be 2.2 µM.
To evaluate the selectivity of probe 1, H2O2 and GSH as the suspected major interfering analytes were investigated both in PBS buffer (Figure 2) and in deionized water (Figure S3 in the supporting information). In addition, various reductant (hydroquinone), oxidants (NaClO, t-BuOOH, m-CPBA), nucleophiles (H2S, PhSH), and other common amino acids e.g. glutamic acid (Glu), proline (Pro), serine (Ser), phenylalanine (Phe), lysine (Lys), tyrosine (Tyr), alanine (Ala), leucine (Leu), glycine (Gly), arginine (Arg), threonine (Thr), tryptophan (Trp), glutamine (Gln), methionine (Met), aspartic acid (Asp), homocystein (Hcy), cystein (Cys) were evaluated as well (Figure 2). To our delight, neither H2O2 nor GSH interrupts the response of probe 1 to KO2. Only histidine and mCPBA were found to cause a little fluorescence enhancement among the tested potential interferents. Thus probe 1 is able to detect KO2 with high selectivity.
Figure 2. Fluorescence responses of probe 1 (10 µM) to KO2, H2O2, NaClO, t-BuOOH, m-CPBA, hydroquinone, H2S, PhSH, GSH and amino acids (100 µM each) at room temperature in PBS buffer. Data were recorded at 10 minutes after addition of various analytes (λex = 492 nm, λem = 513 nm, slit: 2.5 nm/2.5 nm). The concern of potential hydrolysis of probe 1 which contains pyridiniumsulfonate moiety under the experimental conditions
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was addressed through pH-effect studies (Figures S3 and S4 in the Supporting Information). Probe 1 is sufficiently stable with superior stability below pH of 9, which enables probe 1 to be effective in the range of pH 6−9 (Figure S4).
The unique structure of probe 1 and selective response to KO2 attracted our interest for the mechanistic studies. HPLC-MS and HPLC-HRMS techniques were used to monitor the sensing reaction and fluorescein was found to be the expected product. Meanwhile, a component with MS value in consistence with the structure of N-methylpyridniumsulfonic acid (MS: 174, HRMS: 174.0219, see Figure S5 in the Supporting Information) was identified. Such evidence suggests that the response pathway follows a SN2 nucleophilic attack to the sulfonyl moiety as expected in accordance to the design concept. In addition, a species assigned to Nmethylpyridiniumhydroperoxide was also identified (MS: 126, HRMS: 126.0500, see Figure S5 in the Supporting Information). Such species was found to have limited lifetime. It could be detected in 5 min however could not be traced at 20 min under the experimental conditions. Such finding suggested that a second reaction pathway through SNAr reaction mechanism may also play in part a role in the sensing process. The two discussed possible sensing pathways were illustrated in Scheme S1 in the Supporting Information.
Figure 3. Confocal fluorescence images of HepG2 cells with multiple labels. HepG2 cells were stimulated for 1 h with PMA (100 ng/mL) and incubated for 20 min with probe 1 (20 µM), organelle-tracker (5 µM) simultaneously. Images shown above are signals from (A) and (D) Probe 1, green channel; (B) Mito-SOX Red, red channel; (C) merged image of A and B. (E) Lyso-Tracker Red DND-99, red channel; (F) merged image of D and E. Scale bar = 10 µm. Confocal cell imaging experiments were successfully carried out using phorbolmyristate acetate (PMA, a stimulator of cell respiratory burst to produce ROS) to stimulate generation of O2•− on HepG2 cells which are more tolerated by the stimulation.[18] When HepG2 cells were stimulated with PMA for 1 h and then incubated with probe 1 (20 µM), the bright fluorescence images in green channel were distinctly observed in response to the stimulation (Figures 3A and 3D). It is notable that when Tiron (1,2dihydroxy-3,5-benzenedisulfonic acid disodium salt, a cellpermeable O2•− scavenger,[19] 100 µM) was used after PMA stimulation, the HepG2 cells displayed significantly diminished fluorescence after incubation with probe 1 (see Figure S6 in the Supporting Information). In order to confirm the presumed organelle targeting ability of probe 1, colocalization experiments involving probe 1 were performed using a known mitochondrion-specific fluorescent probe Mito-SOX Red, and lysosome-specific probe
Lyso-Tracker Red DND-99 as targetable dyes respectively (Figure 3). The fluorescence image of Figure 3A produced using probe 1 overlaps only partially with the region stained with MitoSOX Red (Figure 3B) from the merged image (Figure 3C). Those non-overlapped parts viewed as spherical-shaped like were expected to be lysosome-targeted area. This expectation was supported by co-stained images from Lyso-Tracker Red DND-99 (Figure 3E) with the image of probe 1 (Figure 3D) and merged images (Figure 3F) wherein the Lyso-Tracker stained spherical lysosome overlapped well with the spherical green part of image of probe 1, however with partial green residues un-overlapped. Thus, immobilization of probe 1 in subcellular level was demonstrated to be within the mitochondria and the lysosome, reflecting the unique dual targeting property of probe 1.
To explore the potential usage of probe 1 as an in vivo imaging tool, we applied it to O2•− detection in living zebrafish embryos (Figure 4). Compared to the untreated control, significantly increased O2•− levels were observed in PMA treated zebrafish, with distinct fluorescence distribution (Figure 4c). Treatment with Tiron (100 µM) for 20 minutes after PMA stimulation resulted in significantly diminished fluorescence (Figure 4e).
Figure 4. Confocal imaging of endogenous O2•− in 72 h postfertilization zebrafish embryos. a, b) Zebrafish embryos preloaded with probe 1 (10 µM) for 20 min; c, d) Zebrafish embryos briefly challenged with PMA (200 ng/mL) for 20 min after preloaded with probe 1 (10 µM) for 20 min; e, f) Zebrafish initially stimulated with PMA (100 ng/mL) for 20 min and treated with Tiron (100 µM) for 20 min was loaded with probe 1 (10 µM) for 20 min. a, c, e: green channel, b, d, f: bright channel. Scale bar = 1 mm. In conclusion, a novel water soluble fluorescent probe for superoxide detection was developed. Such a fluorescein-based probe contains (N-methylpyridinium-3-yl) sulfonate moiety as novel superoxide trapper and responds selectively to superoxide with the detection limit of 2.2 µM. The probe developed is fairly stable under neutral and acidic conditions. The mechanism studies suggested that both SN2 nucleophilic attack and SNAr reaction may be involved. Cell imaging experiments indicated that probe 1 displayed good cell penetration. It was demonstrated that O2•− may be detected in both mitochondria and lysosome of PMA-stimulated HepG2 cells. Moreover, strong turn-on response toward O2•− was demonstrated with probe 1 in zebrafish embryos. Thus, our studies disclosed the first dual mitochondria and lysosome targetable fluorescent probe. We anticipate that these results would inspire and encourage lots of researchers to focus on the regulation effects of ROS on mitochondria and lysosomes in the biology and pharmacology.
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ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. General information, synthetic details of probe 1, additional spectroscopic investigations, LC-MS studies and 1H-NMR spectra.
AUTHOR INFORMATION Corresponding Author *
[email protected];
[email protected] [email protected];
zhao-
NOTES The authors declare no competing financial interest.
ACKNOWLEDGMENT This research was supported by NSFC (21372063, 81601173). Shanghai Municipal Science & Technology Program (16411968700). We thank Prof. Dr. Jianming Chen, Dr, Mingliang Chen at Key Lab of Marine Biogenetic Resources, Third Institute of Oceanography, for confocal imaing of zebrafish embryos.
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