Tumor microenvironment H2O2 response cross-linked near infrared molecular probe and application thereof

A tumor microenvironment, H2O2 technology, applied in the field of near-infrared dye functional modification, can solve the problems of tumor imaging effect, short residence time, rapid excretion of biological tissues, etc., and achieve good fluorescence imaging performance and prolong the effect of residence time.

Active Publication Date: 2019-11-05
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A large number of literature reports have designed many near-infrared fluorescent probes for tumor imaging based on this dye, but due to their own reasons, they are easily excreted by biological tissues, resulting in a short residence time in the body, which seriously affects the imaging effect of tumors.

Method used

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  • Tumor microenvironment H2O2 response cross-linked near infrared molecular probe and application thereof
  • Tumor microenvironment H2O2 response cross-linked near infrared molecular probe and application thereof
  • Tumor microenvironment H2O2 response cross-linked near infrared molecular probe and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1: H 2 o 2 Synthesis and characterization of responsive near-infrared molecular probe DATC and control probe TC

[0066] (1) Add N-tert-butoxycarbonyl-N'-fluorenylmethoxycarbonyl-D-lysine (2.34g, 5mmol), N,N-dimethylformamide (30mL), Benzotriazole-1-tetramethylhexafluorophosphate (2.28g, 6mmol), 1-hydroxybenzotriazole (0.81g, 6mmol) and diisopropylethylamine (1.02mL, 6mmol) were stirred in an ice-water bath 15min. Subsequently, propargylamine (330 μL, 6 mmol) was added into the reaction flask, and the reaction was continued at room temperature for 15 hours under stirring. After the reaction was completed, the solvent was removed by rotary evaporation, and 150 mL of ethyl acetate was added to redissolve the intermediate product. Subsequently, the organic phase was washed once with 30mL deionized water, saturated sodium bicarbonate and sodium chloride aqueous solution, dried with anhydrous sodium chloride, and spin-dried to obtain white powdery intermediate A0...

Embodiment 2

[0076] Example 2: H 2 o 2 Cross-linking of Responsive Near Infrared Molecular Probe DATC under the Action of Hydrogen Peroxide

[0077] 4T1 cells were first treated with 100 μM hydrogen peroxide for 15 min, and then the H 2 o 2 The responsive near-infrared molecular probe DATC was diluted into the cell culture medium, and then added to the 4T1 cell culture dish for incubation (the probe concentration was 5 μM). The sulfhydryl group on the 4T1 intracellular protein treated with hydrogen oxide will be oxidized to sulfenic acid, and when the probe enters the tumor cell, the group 3,5-dioxocyclohexanecarboxylic acid will combine with Acid cross-linking forms a C-S covalent bond, which firmly connects the probe molecule with the macromolecular protein in the tumor cell, thereby prolonging the residence time of the molecular probe in the tumor cell and improving the imaging effect of the probe molecule. For technical effects, see Figure 8 .

Embodiment 3

[0078] Example 3: H 2 o 2 Purity Characterization and Mass Spectrometry Characterization of Responsive Near Infrared Molecular Probe DATC in High Performance Liquid Chromatography

[0079] The H prepared in Example 1 2 o 2 The responsive near-infrared molecular probe was diluted with solvent methanol to a concentration of 5 μM, its molecular weight was determined by mass spectrometry, and its purity was analyzed by high performance liquid chromatography.

[0080] Such as Figure 4 As shown in a, the sample was analyzed by Agilent 1260 high performance liquid chromatography, the retention time of the probe DATC was 5.260 minutes, and the sub-area was further integrated to calculate the concentration of the probe in the sample as high as 98%. Figure 4 b shows the theoretical m / z of the probe DATC: 1378.64, and the m / z ([M+ TFA+2Cl]-) in the mass spectrum actually obtained: 1562.0, the two are consistent, which is the desired compound.

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Abstract

The invention discloses a tumor microenvironment H2O2 response cross-linked near infrared molecular probe and application thereof. The preparation method comprises the following steps: propargyl amineand N-tert-butoxycarbonyl-N'-fluorenylmethoxycarbonyl-D-lysine undergo amide condensation reaction to obtain a compound A01-01; a protecting group of the compound A01-01 is removed to obtain a compound C1-2; the compound C1-2 is reacted with (3-carboxypropyl) triphenylphosphine bromide activated by NHS to obtain a compound C1-3; a protecting group is removed from the compound C1-3 to obtain a compound C1-4; the compound C1-4 is reacted with NHS activated 3,5-dioxane carboxylic acid to obtain a compound C1-5; and the compound C1-5 reacts with a near infrared dye to obtain the tumor microenvironment H2O2 response cross-linked near infrared molecular probe. The probe itself uses H2O2 in tumor microenvironment to be cross-linked at a tumor site to achieve the purpose of long-term retention, thereby improving the tumor imaging effect and providing a new strategy and means for improving the long-term retention of near infrared molecular probes at the tumor site.

Description

technical field [0001] The invention belongs to the technical field of functional modification of near-infrared dyes, and relates to tumor microenvironment H 2 o 2 The preparation method of the traditional near-infrared dye Cy5 modified by the cross-linking 1,3-cyclohexanedione group, the molecular probe prepared by this method, and the application of the probe in near-infrared fluorescence imaging of tumors. Background technique [0002] In the diagnosis of cancer, near-infrared fluorescent dye detection technology can realize in situ, targeted and non-invasive dynamic monitoring of cancer. Indocyanine Green (ICG), a near-infrared fluorescent dye approved by the U.S. Food and Drug Administration (FDA), can be used for clinical diagnosis. A large number of literature reports have designed many near-infrared fluorescent probes for tumor imaging based on this dye, but due to its own reasons, it is easily excreted by biological tissues quickly, resulting in a short residence ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/54C09K11/06A61K49/00
CPCC07F9/5442C09K11/06A61K49/0021C09K2211/1007C09K2211/1029C09K2211/1014C09K2211/1059Y02P20/55A61P35/00A61K49/0032A61K49/0052C09B23/083
Inventor 史海斌高银佳
Owner SUZHOU UNIV
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