Tumor-targeted GRP analogue and application thereof

A technology of tumor targeting and analogues, applied in the field of medical bioengineering, can solve different problems

Active Publication Date: 2020-02-28
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, its transformation mainly focuses on metal chelating agents and linking groups, and the sequence of the GRP receptor targeting peptide is also different from that of the present invention

Method used

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  • Tumor-targeted GRP analogue and application thereof
  • Tumor-targeted GRP analogue and application thereof
  • Tumor-targeted GRP analogue and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] The synthesis of embodiment 1 near-infrared fluorescent dye MPA

[0072] For the synthesis steps, refer to an invention patent previously applied by our research group, authorized patent number: CN101440282, the main synthesis steps are as follows:

[0073] 1. Add 30mL of glacial acetic acid to a mixture of p-hydrazinobenzenesulfonic acid (6g), methyl isopropyl ketone (7mL) and sodium acetate (2g). The obtained brown suspension was heated to boiling and refluxed for 16 hours. Then filter while hot with a sintered glass filter to remove unreacted suspended matter. After the filtrate was cooled to room temperature, the product was precipitated with dichloromethane, and the product was brown (2,2,3-trimethyl[3H]-indole-5-sulfonic acid).

[0074] 2. Take 50 mL o-dichlorobenzene and add to 2,2,3-trimethyl[3H]-indole-5-sulfonic acid (15 g) and 1,3-propane sultone (4 mL). The mixture was heated to 130°C and held for 15 hours. The resulting solid was triturated with dichlor...

Embodiment 2Y

[0077] The synthesis of embodiment 2YQG-1

[0078] 1) Resin swelling

[0079] Weigh the Rink Amide MBHA resin, put it into the reaction column, add an appropriate amount of dichloromethane (DCM), blow nitrogen slightly for 10-30 minutes, and fully expand the resin. Remove the DCM solution, wash 3 times with DMF, and drain.

[0080] 2) Remove Fmoc

[0081] Add 20% hexahydropyridine DMF solution to the reaction column, and deprotect once every 5 minutes, once every 8 minutes. After the reaction was finished, it was washed 6 times with DMF.

[0082] 3) Coupling

[0083] Accurately weigh Fmoc-His(trt)-OH and O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) which is 3 times the mole number of the feed resin, Completely dissolve in DMF, add N,N-diisopropylethylamine (DIPEA) to activate the carboxyl group, then add the solution to the reaction column for reaction, detect after 1h, and the detection structure is positive. The Fmoc was decoupled sequentially ...

Embodiment 3

[0089] Example 3 Preparation of fluorescent targeting compound MPA-Aca-YQG-1

[0090] Weigh 10 mg of the Aca-YQG-1 compound synthesized by solid phase, and add 12.38 mg of the pure dye MPA to 200 μL of dimethyl sulfoxide (DMSO), and then add 2.3 mg of 1-(3-dimethylaminopropyl) -3-Ethylcarbodiimide hydrochloride (EDCI) coupling agent and 3.82mg N-hydroxysuccinimide (NHS), after mixing, add 4.1mg N,N-diisopropylethylamine (DIPEA), react overnight at room temperature, after the reaction is completed, use the preparative liquid phase to separate and purify, and the preparative liquid phase conditions are as follows: Agilent ZORBAX SB-C18 semi-preparative column (9.4 × 250mm, 5um ), gradient elution for 60 minutes, flow rate 2mL / min, wherein mobile phase A is ultrapure water (0.01% TFA), and B is acetonitrile (0.01% TFA). The elution gradient was set as: 95% A and 5% B at 0-5 minutes, 80% A and 20% B at 15 minutes, 50% A and 50% B at 45 minutes, 5% A and 95 at 60 minutes %B. The...

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Abstract

The invention discloses a tumor-targeting GRP analogue and application thereof. The GRP analogue is selected from any of linear polypeptide Gln-5-Htp-beta-Ala-Nva-Gly-His-NH2, annular polypeptide Lys-Cys-Gln-5-Htp-beta-Ala-Nva-Gly-His-CysHis-Gly-Nva-beta-Ala-5-Htp-Gln-NH2 and the like. High-affinity polypeptides can be specifically combined with various tumor cells, and this high-affinity characteristic can be used for optical imaging and nuclear medicine imaging of malignant tumor. The high-affinity polypeptides when being coupled with fluorescent dye can serve as a tumor specific-targeting molecular probe, the tumor-targeting GRP analogue is expected to realize effect of accurately positioning tumor boundary, can bring about instantaneity for preoperative and intraoperative image navigation and has the advantage of improving operative accuracy.

Description

technical field [0001] The invention belongs to the field of medical bioengineering, and relates to tumor-targeted GRP analogs and applications thereof. Background technique [0002] Tumor has become the chief culprit threatening human health and life. Therefore, the early diagnosis of tumor and the effective treatment of tumor are particularly important and urgent. For tumors, conventional imaging diagnostic techniques are mainly B-ultrasound, CT and MRI. These imaging diagnostic techniques achieve diagnostic results by displaying tissue function changes and have good application value. There are still some deficiencies in the evaluation. It is undeniable that screening and optimizing tumor-targeting peptides is a new way to develop new molecular imaging drugs for tumor diagnosis, staging, and surgical guidance, and to find smaller lesions and achieve early diagnosis. [0003] Cyanine dyes have the advantages of small molecular weight, low toxicity, wide adjustable wavele...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/02A61K49/00A61K51/08
CPCC07K7/02A61K49/0056A61K51/08
Inventor 顾月清涂远彪陶吉王芳
Owner CHINA PHARM UNIV
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