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Conjugates and their preparation and use

A conjugate and application technology, applied in the fields of life science and chemical biology, can solve the problems of difficult to predict the quantitative relationship of antibody/drug coupling, poor tissue penetration ability, product heterogeneity, etc., so that it is not easy to cause immune response , Strong tissue penetration ability, small molecular weight effect

Active Publication Date: 2019-08-16
INST OF CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] However, with the in-depth study of tumors, researchers have found that antibodies, as biomacromolecule targeting probes, have some obvious limitations. For example, most antibodies come from animals and are immunogenic after entering the human body; antibodies are large in size. , poor tissue penetration; antibody-drug conjugation can only be carried out in aqueous phase; it is difficult to predict the quantitative relationship of antibody / drug conjugation, and there is heterogeneity in the product, etc.
[0006] Therefore, the current research on ligand-drug conjugates still needs to be strengthened.

Method used

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  • Conjugates and their preparation and use
  • Conjugates and their preparation and use
  • Conjugates and their preparation and use

Examples

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preparation example Construction

[0087] Preparation method of the conjugate

[0088] According to another aspect of the present invention, the present invention also provides a method for preparing the aforementioned conjugate. According to an embodiment of the invention, the method includes:

[0089] (1) Synthesize the targeting peptide by solid-phase peptide synthesis, so as to obtain the resin bonded with the targeting peptide, wherein the targeting peptide has the amino acid sequence IHGHHIISVG, and use Fmoc in the solid-phase peptide synthesis - Glycine-Wang resin, the glycine bonding amount of the Fmoc-glycine-Wang resin is 0.4mmol / g as a starting material, and N,N-dimethylformamide containing 20 volume% hexahydropyridine is used for deprotection ( DMF) solution, deprotection 2 times, each 5min, the coupling step uses 3 times the molar amount of Fmoc-amino acid and 3 times the molar amount of O-benzotriazole-tetramethyluronium hexafluorophosphate (HBTU), N-methylmorpholine (NMM) as a basic catalyst; ...

Embodiment 1

[0100] Example 1 Synthesis and Performance Investigation of Amide Bond-Coupled Polypeptide Drug Conjugate-1 (AP2H-DOX)

[0101] (1) Design and synthesis of AP2H-DOX

[0102] Amino acids form polypeptides through the condensation of amino groups and carboxyl groups. Based on this, the inventors first simulated the chemical bond-amide bond that forms the polypeptide, and condensed the carboxyl group at the C-terminal of the AP2H polypeptide with the amino group of the anticancer drug doxorubicin to form an amide bond to form a polypeptide drug. Conjugate-1 (AP2H-DOX), the synthesis process is as follows figure 1 . Dissolve AP2H polypeptide (1eq) in DMF, add DOX·HCl (2eq) to it, then add DIPEA (10eq), EDC·HCl (3eq), HOBt·H 2 O(3eq), react at room temperature for 6h. The reaction solution was purified by a semi-preparative liquid chromatography column to obtain the final product AP2H-DOX. After purification by liquid chromatography, the product was identified using ESI mass sp...

Embodiment 2

[0107] Example 2 Synthesis and Performance Investigation of Redox Responsive Polypeptide Drug Conjugate-2 (AP2H-s-s-DOX)

[0108] (1) Design and synthesis of AP2H-s-s-DOX

[0109] Using the commercial reagent 3,3-dithiodipropionate (N-succinimide) ester (DSP) to couple AP2H to DOX, the peptide drug conjugate-2 (AP2H-s-s-DOX) The synthesis process and the principle of GSH-responsive drug release such as Figure 5 shown. Specifically, AP2H polypeptide (1eq) was dissolved in DMSO, DOX·HCl (1eq) was added, after mixing evenly, DSP (1eq) was added, and then Et 3 N (6eq), react at room temperature for 12h. The reaction solution was purified by a semi-preparative liquid chromatography column to obtain the final product AP2H-s-s-DOX. After purification of the reaction target by liquid chromatography, the product was identified by ESI mass spectrometry, it can be seen that [M+H] + :1787.01,[M+2H] 2+ :894.05,[M+3H] 3+ :596.24 and other mass spectrum signals, indicating that the t...

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Abstract

The invention discloses a conjugate, and a preparation method and application thereof. The conjugate has a structure of TP-L-D, wherein TP represents targeting peptide which is applicable to targeting the conjugate to tumor cells, and the surfaces of the tumor cells carrying lysosome tetraspanin LAPTM4B are used as a specific target of the targeting peptide; D represents a treatment activator; and L represents a linking arm which is used for connecting the treatment activator to the targeting peptide and connected with the treatment activator through a hydrazone bond. The conjugate provided by the invention can realize targeted killing of tumor cells carrying LAPTM4B protein on its surfaces, has strong targeting and destruction performance, is hard to incur immunoreactions, and can be used for treating or preventing tumors or preparing pharmaceutical compositions for treating or preventing tumors.

Description

technical field [0001] The present invention relates to the fields of life science and chemical biology, in particular, to the conjugate and its preparation method and use. Background technique [0002] Almost all life processes in nature are regulated by molecular recognition and molecular interaction, and the specific interaction between peptides and proteins is a key step in molecular recognition in organisms. The basic unit that constitutes a polypeptide includes 20 kinds of amino acids with different properties. The polypeptide library formed from this has a wide variety and different properties. In addition, the good biocompatibility, cell / tissue penetration and chemical stability of the polypeptide endow the polypeptide with huge It is widely used in research fields such as life sciences, chemical biology, and medicine. [0003] Malignant tumors are a serious threat to human life and health, and researchers have developed many diagnostic methods and therapeutic metho...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/64A61K45/00A61K31/704A61P35/00C07K7/06
CPCY02P20/55
Inventor 赵睿金钰龙黄嫣嫣
Owner INST OF CHEM CHINESE ACAD OF SCI
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