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Synthesis and application of fluorescent probe capable of reversibly detecting hypoxic environment

A fluorescent probe and fluorescent group technology, which is used in the synthesis of reversible hypoxia fluorescent probes and in the application field

Inactive Publication Date: 2013-12-04
UNIV OF SHANGHAI FOR SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the reported fluorescent probes can only show the existence of hypoxia, but cannot avoid the misjudgment caused by the diffusion of fluorescence caused by molecular diffusion and the transfer of hypoxic regions.

Method used

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  • Synthesis and application of fluorescent probe capable of reversibly detecting hypoxic environment
  • Synthesis and application of fluorescent probe capable of reversibly detecting hypoxic environment
  • Synthesis and application of fluorescent probe capable of reversibly detecting hypoxic environment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] In this example, a cyanine dye is preferably used as the fluorescent group, and the connecting arm is C 2 alkane, a fluorescent probe synthesized by benzoquinone redox acceptor group, the fluorescent group can also be rhodamine derivatives, fluorescein and its derivatives, fluoroboryrrole derivatives and acenaphthylenine derivatives any kind.

[0029] The synthetic formula of the compound cyanine dye-benzoquinone (Cy7-BQ):

[0030]

[0031] 1) Synthesis of 2,5-dimethoxy-3,4,6,-trimethylphenylacrylic acid using Wittig reagent:

[0032] Add ethyl bromoacetate (1mmol), tributylphosphine (1mmol) and dichloromethane (30mL) sequentially into a 50mL single-necked flask and stir at room temperature to react. After about 4h, a white solid was filtered by suction. Put the obtained solid compound into another 50mL single-necked flask, add anhydrous THF (20mL), potassium tert-butoxide (1.1mmol), react at room temperature for about 3h, and then add 3,4,6-trimethyl- 2,5-Dimethoxy...

Embodiment 2

[0054] In this example, cyanine dyes are preferably used as fluorescent probes synthesized by fluorescent groups and benzoquinone redox acceptors.

[0055] The synthetic formula of the compound cyanine dye-(3,4,6-trimethyl-2,4-benzoquinoyl)-3-methyl-1-butane (Cy7-TBQ):

[0056]

[0057] 1) Synthesis of 6-hydroxy-4,4,7,8-tetramethylchromen-2-one:

[0058] 2,3,5-trimethyl-1,4-diphenol as raw material and 3-methyl-butenoic acid methyl ester are reacted at a molar ratio of 1:1 to obtain 6-hydroxy-4,4,7,8 -Tetramethylchromen-2-one.

[0059] 2) Synthesis of intermediate (3,4,6-trimethyl-2,4-benzoquinone)-3-methyl-butyric acid:

[0060] The intermediate (3,4,6-trimethyl -2,4-benzoquinoyl)-3-methyl-butanoic acid.

[0061] 3) Synthesis of (3,4,6-trimethyl-2,4-benzoquinoyl)-3-methyl-1-butanoic acid:

[0062] Reduction of (3,4,6-trimethyl-2,4-benzoquinone)-3-methyl-butanoic acid compound using lithium aluminum hydride as a reducing agent afforded (3,4,6-trimethyl- 2,4-Benzoquino...

Embodiment 3

[0066] Probe pair redox system determination:

[0067] Hydroquinone reductase (lyophilized powder) was purchased from Sigma-Aldrich. All tests were done with 40 µL microfluometry cuvettes.

[0068] figure 1 It is a schematic diagram of the fluorescence spectrum of the probe catalyzed by hydroquinone reductase in Tris-HCl (containing 1% DMSO) buffer at pH=7.4.

[0069] Such as figure 1 As shown, the DMSO master solution of the prepared compound Cy7-TBQ / Cy7-BQ fluorescent probe was added to the test buffer (0.01M NADH, PBS buffer, pH7.0), and the final DMSO concentration was determined to be 1%. Firstly, the hydroquinone reductase was diluted to a certain concentration, so that the final concentration in the test system was maintained at 10 μg / mL. The temperature during the test was kept at 37°C, the excitation wavelength of the fluorescence was 790nm, the fluorescence response curve was collected every 30s, and the spectral signal near 790nm was collected.

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Abstract

The invention relates to a fluorescent probe capable of reversibly detecting a hypoxic environment and used in a living body environment. The fluorescent probe adopts a quinone functional group capable of performing reversible oxidation-reduction reaction in the vivo biological environment as a receptor, and uses a fluorophore of which the wave length is in a near infrared band as a signal source, and the receptor and the signal source are connected through an applicable connecting arm. In-vitro and in-vivo tests show that the probe can realize free conversion under aerobic and hypoxic conditions, and can be used in tracking of a hypoxic zone in vivo; under the hypoxic condition, fluorescent emitted by the fluorescent probe excited by laser with the wave length of 680 nm can be obviously found at a point of which the wave length is 790 nm; while under the aerobic microenvironment, the fluorescent completely disappears, so that transfer of the hypoxic zone in a body of a tumor patient can be tracked, thereby providing a judgment basis for clinical individualized administration.

Description

technical field [0001] The invention relates to a design scheme of a reversible hypoxic fluorescent probe and its application in the tracking of the hypoxic area in the body of tumor patients, that is, in the aspect of personalized drug delivery. Background technique [0002] Experimental observation and measurement show that hypoxic cells exist in almost all solid tumors. The formation of hypoxic cells in solid tumors is caused by barriers or insufficient oxygen diffusion in the tumor, that is, tumor cells far away from blood vessels are in a hypoxic state because they exceed the effective diffusion distance of oxygen (100-150 μm). According to WHO statistics, as of 2010, the 5-year cure rate of malignant tumors was 56%, of which radiotherapy contributed 39%. Statistics show that more than 70% of malignant tumor patients have received radiation therapy during treatment. With the popularization and application of radiotherapy in clinical practice, oncologists gradually rea...

Claims

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Application Information

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IPC IPC(8): C09K11/06C07D209/12G01N33/574
Inventor 崔雷田振然
Owner UNIV OF SHANGHAI FOR SCI & TECH
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