CN105884734B - A kind of two-photon fluorescence probe of quick detection nitroreductase - Google Patents
A kind of two-photon fluorescence probe of quick detection nitroreductase Download PDFInfo
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Abstract
The invention discloses a kind of two-photon fluorescence probes that can detecte nitroreductase, the fluorescence probe is named as 3- nitro -7- diethylaminocoumarin, two-photon fluorescence probe disclosed by the invention has response to the nitroreductase in cell, and with the increase of intracellular nitroreductase concentration, fluorescence intensity accordingly enhances, and probe provided by the invention can be detected by nitroreductase of the fluorescence imaging to oxygen weary in tumour region.
Description
Technical field
The present invention relates to the fluorescence probes that a kind of quick response nitroreductase (NTR) has two-photon effect, belong to
Small organic molecule fluorescence probe field.
Background technique
Weary oxygen refers to a kind of physiological status of tissue hypoxia, is usually observed in entity tumor, is tumour micro-loop
The performance of border medium vessels missing or exception.Clinic study discovery, the observation to the weary oxygen region of entity tumor, with tumour
It shifts potential quality and has close ties to the pernicious characterization of treatment-resistant.Therefore, development of clinical studies carries out the novelty side of weary oxygen detection
Method is of great significance.The degree of oxygen deficiency of anoxic zones rises in the effect and correlative study of prediction treatment of cancer in assessment tumour
To key player.
It is well known that weary oxygen can induce the expression for accelerating bioreduction and leading to intracellular reductase, also such as quinone
Protoenzyme, azo reductase and nitroreductase (NTR).Wherein, nitroreductase is most representative.In the state of anoxic
In the presence of electron donor niacinamide, intracellular nitroaromatic is obvious as the substrate feature of nitroreductase.
This enzymatic one-electron reduction reaction is proved to be the design of a kind of effective positioning and the imaging area Fa Yang.
Recently, there has been many according to the also intrinsic nitroreductase probe of nitroaromatic enzyme, some are
It is employed for the imaging of the area Fa Yang tumour cell.But these common fluorescence probes have powerful connections more, interference, scattering interference etc. are lacked
It falls into, sensitivity is not high, and the response time is longer, detects limit for height, is possible to influence in this way to restore nitro in complex physiologic environment
The application of enzyme detection.Two-photon fluorescence probe has that near-infrared excitation, background interference is small, scattering interference is small, sensitivity and selection
Property it is higher, avoid photobleaching and photic malicious phenomenon from generating, and it is small to organism injury the advantages that, in biological living analysis detection
In show very big superiority.
Summary of the invention
For the deficiency of existing detection technique, the present invention proposes a kind of two-photon probe of quickly detection nitroreductase
(CNO2- HY), and bio-imaging is carried out to the probe.Using the nitroreductase of present invention detection anoxic zone, to tumor area
Weary oxygen level is assessed.
The two-photon fluorescence probe of quick detection nitroreductase of the present invention is named are as follows: 3- nitro -7- diethylamine
Butylcoumariii.
Chemical structural formula are as follows:
。
(I)
The synthetic method of above-mentioned two-photon fluorescence probe is as follows: in 100 milliliters of round-bottomed flasks, 10 mMs of 4- bis- are added
Ethylamino- salicylide and 30 milliliters of n-butanols are stirred at room temperature and lower 11 mMs of ethyl nitroacetates are added, and 0.15 milli is then added dropwise
Rise piperidines and 0.3 milliliter of glacial acetic acid.Reaction system is cooled to room temperature after being heated to reflux 12 hours, is filtered under diminished pressure, filter cake ethyl alcohol
Recrystallization, obtains product, yield 77%.
Above-mentioned probe to prepare reaction equation as follows:
Mechanism:
It is demonstrated experimentally that the two-photon fluorescence probe solution of detection nitroreductase of the present invention, in nitroreductase
In the presence of issue intense fluorescence, which illustrates that probe has response to nitroreductase, and for the application of bio-imaging, established can
The theoretical basis leaned on.Expect that the present invention can play a significant role in the detection of nitroreductase level in tumor hypoxia area.
Detailed description of the invention
Fig. 1: the nuclear-magnetism characterization of probe:1H H NMR spectroscopy and13C H NMR spectroscopy；
Fig. 2: abosrption spectrogram of the probe in phosphate buffer.Concentration and probe concentration: 5 μM；
Fig. 3: the dynamic experiment of probe in detecting nitroreductase: wherein excitation wavelength is 385 nm；The concentration of probe: 5
µM；Nitroreductase concentration is respectively 0,0.1,0.25,0.5,0.75,1.5 μ g/mL, the testing time: 45 min, between test
Every: 5 min；
Fig. 4: the titration experiments of the detected nitroreductase concentration of probe；Wherein excitation wavelength is 385 nm；Probe it is dense
Degree: 5 μM；
Fig. 5: selectivity of the probe in phosphate buffer.Wherein excitation wavelength is 385 nm；The concentration of probe: 5 μM,
The concentration of selective ion is 2.5 mM；
Fig. 6: the single photon cell imaging application of probe.Excitation wavelength: 405 nm and 488 nm, emission band: 425-
475 nm and 500-550 nm；
Fig. 7: the two-photon cell imaging application of probe.Excitation wavelength: 760 nm, emission band: 425-475 nm and
500 - 550 nm。
Fig. 8: the two-photon imaging of tissue application of probe.Excitation wavelength: 760 nm, emission band: 500-550 nm.
Specific embodiment
Below by embodiment and attached drawing, the present invention will be described.
Embodiment 1
Compound CNO2The synthesis of-HY
In 100 mL round-bottomed flasks, 10 mmol 4- diethylin salicylides and 30 mL n-butanols are added, are stirred at room temperature
11 mmol ethyl nitroacetates of lower addition, are then added dropwise 0.15 mL piperidines and 0.3 mL glacial acetic acid.Reaction system is heated to reflux
It is cooled to room temperature after 12 hours, is filtered under diminished pressure, filtrate ethyl alcohol recrystallization obtains product, name are as follows: 3- nitro -7- diethyl
Amido cumarin, abbreviation CNO2- HY, yield 77%.1H H NMR spectroscopy and13C NMR spectra such as Fig. 1.
1H NMR (400 MHz, DMSO-d 6 ): 9.02 (s, 1H), 7.72 (d, J = 9.2 Hz, 1H),
6.91 (dd, J 1 = 9.2 Hz, J 2 = 2.4 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 3.53 (q, J
= 7.2 Hz, 4H), 1.15 (t, J= 7.2 Hz, 6H)； 13C NMR (400 MHz, DMSO-d 6 ): 158.86,
154.97,153.39,144.52,133.83,126.31,111.85,106.62,96.51,45.24,12.82.
Embodiment 2
Compound CNO2The absorption spectrum of the weary oxygen fluorescence probe of-HY two-photon is tested
Prepare the two-photon fluorescence probe CNO of the 1 mM detection nitroreductase of the present invention of 1 part of 5 mL2The two of-HY
Methyl sulfoxide (DMSO) solution.It takes 25 μ L probe mother liquors to be added in 2 identical 5 mL volumetric flasks respectively, it is molten that DMSO is added
225 μ L of liquid, all 500 μM of addition nicotinamide adenine dinucleotide (NADH).One of phosphorus that nitroreductase is added
Acid buffering solution (10 μ g/mL, 500 μ L), another is not added.Two volumetric flasks all use phosphate buffer (PBS, pH=
7.4) then constant volume carries out absorption spectrum test to 5 mL, 37 DEG C of 45 min of effect.As a result see Fig. 2 probe CNO2- HY exists
Absorption curve in phosphate buffer solution (PBS).Concentration and probe concentration is 5 μM.(a): the absorption curve of probe itself；(b):
Probe and 0.75 μ g/mL nitroreductase act on the absorption curve of 45 min.
Embodiment 3
Compound CNO2The kinetic test of the weary oxygen fluorescence probe of-HY two-photon and nitroreductase effect
Prepare the aqueous solution that 5 mL concentration are 10 μ g/mL nitroreductases and the detection of the present invention that concentration is 1 mM
The two-photon fluorescence probe mother liquor of anoxic zones nitroreductase is as spare.Solution with manufacturing probe and nitroreductase,
Concentration is respectively as follows: 5 μM of probe；Nitroreductase: 0,0.1,0.25,0.5,0.75,1.5 μ g/mL.Carry out fluorescence detection (λex=
450 nm, λem=511 nm), it is primary every 5 min test, 45 min are tested, the fluorescence changed over time in each system is recorded
Intensity establishes the standard curve that fluorescence intensity changes over time.As shown in figure 3,20 min of reaction, reaction system fluorescence intensity reach
To saturation state.So 20 min can be taken as the reaction time.In Fig. 3, concentration and probe concentration is 5 μM, and nitroreductase is dense
Degree are as follows: 0-1.5 μ g/mL, excitation wavelength be 385 nm, launch wavelength be 511 nm, the testing time: 45 min, between test
Every: 5 min.
Embodiment 4
The nitroreductase of various concentration is to compound CNO2The titration of the weary oxygen fluorescence probe of-HY two-photon detects
Prepare the aqueous solution that 5 mL concentration are 10 μ g/mL nitroreductases and the detection of the present invention that concentration is 1 mM
The two-photon fluorescence probe mother liquor of anoxic zones nitroreductase is as spare.
Final concentration of 5 μM with manufacturing probe, the PBS solution containing 5 % DMSO solutions is restored with the nitro of various concentration respectively
Enzyme (0-1.5 μ g/mL) sufficiently effect at moderate temperatures, carries out fluorescence detection (λex= 385 nm, λem=511 nm),
Reaction time is 20 min.Fluorescence intensity in each system is obtained, fluorescence intensity and nitroreductase concentration standard curve are established.Such as figure
Shown in 4, with the increase of nitroreductase concentration, reaction system fluorescence intensity is gradually increased, when nitroreductase concentration reaches
When 0.75 μ g/mL, reaction system fluorescence intensity reaches saturation state.In Fig. 4, concentration and probe concentration is 5 μM, nitroreductase concentration
For 0-1.5 μ g/mL, excitation wavelength is 385 nm, and launch wavelength is 511 nm.Testing time is 20 min.
Embodiment 5
Compound CNO2Selectivity of the weary oxygen fluorescence probe of-HY two-photon to different ions and active small molecular, amino acid
Prepare the two-photon fluorescence probe CNO of the 1 mM detection nitroreductase of the present invention of 1 part of 5 mL2The two of-HY
Methyl sulfoxide (DMSO) solution.Dose volume is 5 mL, and concentration is the various different ions of 40 mM, amino acid and active oxygen,
Active nitrogen solution is as spare.
Be added in the volumetric flask of 5 mL 25 μ L probe mother liquors, 225 μ L DMSO and 500 equivalents each solion or
Each amino acid solution of 1000 equivalents carries out fluorescence detection (λ with phosphate buffer constant volume after shaking upex= 385 nm, λem=
511 nm), the histogram (result is shown in Fig. 5) of fluorescence intensity Yu each ion is established, the concentration of test ion is 2.5 mM, amino
The concentration of acid is 5 mM, and activity of reactive oxygen species nitrogen concentration is 100 μM.The fluorescence emission spectrum variation that solution is detected after 20 min, by
Fig. 5 it can be found that other ions (or amino acid) to compound CNO2The fluorescence of-HY has little effect.In Fig. 5, excitation
Wavelength is 385nm；Probe CNO2The concentration of-HY: 5 μM, the concentration of test ion is 2.5 mM, and the concentration of amino acid is 5 mM,
Activity of reactive oxygen species nitrogen concentration is 100 μM.The ion of 1-No. 26 addition is respectively: probe CNO2- HY, NADH, NaClO, H2O2,
Tert-butyl peroxide, tert-butyl peroxide alcohol, NO (sodium nitroprusside), CaCl2, MgCl2, Na2SO3, NaNO2, NaHSO3, NaHS,
GSH, Cys, Hcy, NaNO3, KBr, ZnCl2, LiCl, KI, citric acid, sodium acetate, tert-butyl oxygroup, OH(hydroxyl radical free radical),
NTR (contains NADH).
Embodiment 6
Compound CNO2The single photon cell imaging of the weary oxygen fluorescence probe of-HY two-photon is tested
It is 3 × 10 by density5 The HeLa cell inoculation of a/mL is covered with coverslip (22 mm × 22 to sterilizing
Mm in 35 mm culture dishes), in CO2(temperature is 37 DEG C to incubator, 5 % CO2) in be divided into two groups of cultures, it is adherent to cell
Afterwards, one group normoxic condition (temperature be 37 DEG C, 5 % CO2) in culture；One group in hypoxic condition, (temperature is 37 DEG C, 5 %
CO2, 1 % O2) in culture, cultivate 12 h.Detection anoxic zones nitro reduction of the present invention is added into two groups of culture dishes
The two-photon fluorescence probe of enzyme, making its final concentration is 5 μM.Continue to cultivate 0.5 h under two conditions respectively, it then will be thin
Born of the same parents' culture solution siphons away, and is rinsed cell 3 times with PBS buffer solution, two groups of cells are shot fluorescent image under the conditions of single photon respectively,
It was found that the fluorescence that the cancer cell grown under hypoxic condition issues is significantly stronger.(result is shown in Fig. 6).
In Fig. 6, excitation wavelength: 405 nm and 488 nm, emission band: 425-475 nm and 500-550 nm；
(a) the often light field imaging of the Hela cell of oxygen condition culture;(b) the Hela cell of normal oxygen condition culture is 425-475
The fluorescence imaging in the channel nm;(c) fluorescence imaging of the Hela cell of normal oxygen condition culture in the channel 500-550 nm; (d)
Anoxia state (1 % O2) culture Hela cell light field imaging;(e) anoxia state (1 % O2) culture Hela it is thin
Fluorescence imaging of the born of the same parents in the channel 425-475 nm;(f) anoxia state (1 % O2) culture Hela cell in 500-550
The fluorescence imaging in the channel nm;(g) light field that often probe (5 μM) are added in the Hela cell of oxygen condition culture is imaged;(h) often
Probe (5 μM) are added in the fluorescence imaging in 425-475 channels nm in the Hela cell of oxygen condition culture;(i) normal oxygen condition
Probe (5 μM) are added in the fluorescence imaging in 500-550 channels nm in the Hela cell of culture;(j) anoxia state (1 %
O2) culture Hela cell be added probe (5 μM) light field imaging;(k) anoxia state (1 % O2) culture Hela
Probe (5 μM) are added in the fluorescence imaging in 425-475 channels nm in cell;(l) anoxia state (1 % O2) culture
Probe (5 μM) are added in the fluorescence imaging in 500-550 channels nm in Hela cell.
Embodiment 7
Compound CNO2The two-photon cell imaging of the weary oxygen fluorescence probe of-HY two-photon is tested
The cell that example 6 is cultivated is shot to the fluorescence photo of two groups of cells respectively under the conditions of two-photon, is found weary
(result is shown in Fig. 7) is remarkably reinforced in the fluorescence that the cancer cell grown under the conditions of oxygen issues.
In Fig. 7, excitation wavelength: 760nm, emission band: 425-475 nm and 500-550 nm;(a) normal oxygen shape
The light field of the Hela cell of state culture is imaged;(b) the Hela cell of normal oxygen condition culture is in the glimmering of 425-475 channels nm
Light imaging;(c) fluorescence imaging of the Hela cell of normal oxygen condition culture in 500-550 channels nm;(d) anoxia state
(1 % O2) culture Hela cell light field imaging;(e) anoxia state (1 % O2) culture Hela cell 425-
The fluorescence imaging in 475 channels nm;(f) anoxia state (1 % O2) culture Hela cell in 500-550 channels nm
Fluorescence imaging;(g) light field that often probe (5 μM) are added in the Hela cell of oxygen condition culture is imaged;(h) often oxygen condition training
Probe (5 μM) are added in the fluorescence imaging in 425-475 channels nm in feeding Hela cell;(i) normal oxygen condition culture
Probe (5 μM) are added in the fluorescence imaging in 500-550 channels nm in Hela cell;(j) anoxia state (1 % O2) culture
Hela cell be added probe (5 μM) light field imaging;(k) anoxia state (1 % O2) culture Hela cell be added
Fluorescence imaging of the probe (5 μM) in 425-475 channels nm;(l) anoxia state (1 % O2) culture Hela cell add
Enter probe (5 μM) in the fluorescence imaging in 500-550 channels nm.
Embodiment 8
Compound CNO2The two-photon imaging of tissue of the weary oxygen fluorescence probe of-HY two-photon is tested
Prepare two mouse injections tumour cell (source of mouse breast cancer cell 4T-1), cultivate mouse breast cancer tumour model,
Solution takes tumour, and tumor biopsy is made.A part of tumor biopsy is immersed in tissue culture medium, CO2(temperature is incubator
37 DEG C, 5 % CO2) cultivate；Another part tumor biopsy is immersed in the tissue culture medium containing concentration for 5 μM of probe solutions
In, CO2(temperature is 37 DEG C to incubator, 5 % CO2) cultivate.After half an hour, tissue culture medium is siphoned away, is rushed with PBS buffer solution
It washes 3 times, two groups of tumor tissues is shot into fluorescent image respectively under the conditions of two-photon, find to soak in the culture solution that probe is added
The fluorescence that the tissue of bubble issues is significantly stronger (result is shown in Fig. 8).In Fig. 8, A) it is the double light for being immersed in the tumour of tissue culture medium
Sub- fluorescence imaging；B) the tumour two-photon fluorescence imaging to be immersed in the tissue culture medium containing 5 μM of probe solutions.
Claims (1)
1. application of following compounds in terms of as the two-photon fluorescence probe of detection nitroreductase, which is characterized in that institute
State the chemical structural formula of compound are as follows:
；
Name are as follows: 3- nitro -7- diethylaminocoumarin；
The cell imaging of probe is tested: being 3 × 10 by density5 The HeLa cell inoculation of a/mL is covered with coverslip to sterilizing
35 mm culture dishes in, in CO2It is divided into two groups of cultures in incubator, after cell is adherent, one group is cultivated in normoxic condition；
One group is cultivated in hypoxic condition, cultivates 12 h；3- nitro -7- diethylaminocoumarin is added into two groups of culture dishes, makes
Its final concentration is 5 μM；Continue to cultivate 0.5 h under two conditions respectively, then cell culture fluid is siphoned away, is buffered with PBS
Liquid rinses cell 3 times, two groups of cells is shot fluorescent image respectively under the conditions of single photon or will be by two groups of cells in two-photon
Under the conditions of shoot fluorescent image respectively；
The coverslip is the mm of 22 mm × 22；
The CO2Incubator is that temperature is 37 DEG C, 5 % CO2；
The normoxic condition temperature is 37 DEG C, 5 % CO2；
The hypoxic condition is that temperature is 37 DEG C, 5 % CO2, 1 % O2。
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| CN108727223B (en) * | 2018-07-24 | 2020-07-31 | 南京工业大学 | Nitroreductase NTR probe capable of being detected by two-photon fluorescence and preparation method thereof |
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