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Matrix metalloproteinase-2 specific multi-modality molecular image probe and preparation method and application in preparation of tumor imaging agent thereof

A matrix metal and molecular imaging technology, applied in the directions of in vivo radioactive preparations, echo/ultrasonic imaging agents, general/multifunctional contrast agents, etc. performance, improve sensitivity and accuracy, and achieve the effect of precise positioning

Active Publication Date: 2018-09-11
苏州智影特生物医药技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Using the specificity and responsiveness of the probe to MMP-2 protease, the probe can be selectively enriched at the tumor site to improve the targeting of the probe to the tumor; through the use of advanced molecular imaging such as optics, photoacoustics and SPECT The technology can carry out multi-modal imaging of tumors in vivo, improve the sensitivity and accuracy of tumor imaging, and finally realize the precise positioning of tumors. scientific research significance and application value, and effectively solve the problem that existing technologies focus on tumor cell imaging and cannot effectively perform tumor tissue imaging

Method used

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  • Matrix metalloproteinase-2 specific multi-modality molecular image probe and preparation method and application in preparation of tumor imaging agent thereof
  • Matrix metalloproteinase-2 specific multi-modality molecular image probe and preparation method and application in preparation of tumor imaging agent thereof
  • Matrix metalloproteinase-2 specific multi-modality molecular image probe and preparation method and application in preparation of tumor imaging agent thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1: Synthesis and characterization of matrix metalloproteinase-2 specific recognition multimodal molecular imaging probe

[0044] (1) Alkyne-terminated amino acid compound (GPL-Pra or KCP-Pra) (0.0055 mmol) and Cy5.5-N 3 or Cy5-N 3 (0.0050 mmol) was dissolved in 1 mL DMSO and stirred at room temperature to obtain a clear solution; sodium ascorbate (0.0060 mmol) and CuSO 4 (0.003 mmol) dissolved in 1 mL H 2 O, mixed evenly, added dropwise to the above DMSO solution, and stirred at room temperature in the dark for 3 h, and the reaction was monitored by HPLC. The solution after the reaction was separated and purified with a preparative chromatographic column to obtain the target product GPL-Cy5.5, HR-MS: C 85 h 115 N 19 o 23 S 4 , ([M+2H] 2+ ): 949.8726, found: ESI-MS: m / z 949.8612; KCP-Cy5, HR-MS: C 87 h 127 N 21 o 19 S 3 , ([M+H] + ): 1866.8857, found: ESI-MS: m / z 1866.7682.

[0045] (2) Dissolve GPL-Cy5.5 or KCP-Cy5 (0.005 mmol) and QSY21 NHS (0.00...

Embodiment 2

[0047] Example 2: Probe QC 5.5 Study on the hydrated particle size, TEM image and stability of

[0048] Prepare the purified probe QSY21-GPL-Cy5.5 into 40 μM PBS solution (pH = 7.4), and measure the hydrated particle size (see figure 2 a) and TEM (see figure 2 b). The solution is placed in a refrigerator at 4°C for 30 days, and the hydrated particle size is measured every 5 days. The data is as follows: figure 2 As shown in c, it shows that the probe has good stability in PBS; probe QC 5.5 (40μM) hydrated particle size in PBS (pH=7.4) (a); transmission electron microscopy and particle size statistics (b); stability at different times (c) see figure 2 .

Embodiment 3

[0049] Example 3: Probe QC 5.5 Reaction studies with in vitro enzymes

[0050] Mix the probe (4 μM) with 0, 5, 10, 20, 40, 80, 160, 320 ng mL -1 Different concentrations of MMP-2 were added to the HEPES buffer solution (pH = 7.4), and after reacting at 37°C for 2 h, the fluorescence intensity of the solution after the reaction was detected by a FLS980 steady-state transient fluorescence spectrometer. image 3 Shown in a.

[0051] Mix the probe (4 μM) with MMP-2 (320 ng mL -1 ) into the HEPES buffer solution (pH = 7.4), reacted at 37°C for 2 h, and compared the changes before and after shearing with the probe that had not reacted with the enzyme by HPLC, as shown in image 3 Shown in b.

[0052] Mix MMP-2 inhibitor (GM6001, 100 μM) with MMP-2 (320 ng mL -1 ) at 37°C for 0.5 h, the probe (4 μM) was added, and the reaction was continued for 2 h. Probe (4 μM), probe (4 μM) and MMP-2 (320 ng mL -1 ) while reacting at 37°C for 2 h. The fluorescence intensity of the solution ...

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Abstract

The invention discloses a matrix metalloproteinase-2 specific multi-modality molecular image probe preparation method and application thereof. The preparation method comprises the following steps: 1)preparing peptide substrates for matrix metalloproteinase-2(MMP-2) specific identification; 2) modifying near infrared fluorescent dye on peptide substrate; 3) modifying fluorescent quenching group onpeptide substrate; 4) connecting different molecular weight PEG or tumor targeting group RGD on peptide substrate modified with near infrared fluorescent dye and fluorescent quenching group; 5) labeling the nuclide on the above modified peptide substrate side chain tyrosine. Compared with the prior art, the matrix metalloproteinase-2 specific multi-modality molecular image probe preparation method has the advantages that: 1) by utilizing the specificity and responsiveness of the MMP-2 protease by the probe, so that the probe is selectively enriched at the tumor site so as to improve the targeting property of the probe to the tumor; 2) performing multi-modality imaging in a living body tumor by using advanced molecular imaging technology such as optical, opto-acoustic, SPECT and the like,improving the sensitivity and accuracy of tumor imaging, and finally achieving accurate positioning of the tumor; 3) providing a new train of thought and method for early diagnosis, process research and prognosis evaluation of tumor.

Description

technical field [0001] The invention belongs to the technical field of small-molecule fluorescent probes, and in particular relates to a method for preparing a matrix metalloproteinase-2-specific multimodal molecular imaging probe, a small-molecule probe prepared by the method, and such a small-molecule probe Application in imaging agents for early diagnosis of tumors. Background technique [0002] Matrix metalloproteinase-2 (MMP-2) is a class of proteolytic enzymes that can degrade extracellular matrix, and plays a very important role in the growth, invasion, metastasis and angiogenesis of malignant tumors. Clinically, MMP-2 has become a reliable and valuable tumor biomarker, widely used in the early diagnosis and identification of tumors. The construction of MMP-2 protease-responsive molecular probes can not only improve the accuracy and sensitivity of tumor detection, but also use the properties of materials to treat tumors, which provides new ideas and methods for early...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K51/08A61K49/22A61K49/04A61K49/00A61K101/02
CPCA61K49/0002A61K49/0021A61K49/0056A61K49/04A61K49/22A61K51/082
Inventor 史海斌尹玲
Owner 苏州智影特生物医药技术有限公司
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