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Linker, drug-loaded linker, cell-penetrating peptide-coupled drug, antibody-coupled drug and preparation method thereof

A linker and drug-loading technology, applied to the linker, can solve the problems of toxic and side effects, and achieve the effect of controllable delivery

Active Publication Date: 2021-02-19
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, during the cleavage process of these two types of linkers, products with toxic side effects, such as quinone methides, may be produced, resulting in additional side effects

Method used

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  • Linker, drug-loaded linker, cell-penetrating peptide-coupled drug, antibody-coupled drug and preparation method thereof
  • Linker, drug-loaded linker, cell-penetrating peptide-coupled drug, antibody-coupled drug and preparation method thereof
  • Linker, drug-loaded linker, cell-penetrating peptide-coupled drug, antibody-coupled drug and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] Take by weighing the compound shown in the formula (a1) of 1.0eq (wherein, in formula (a1), " R 3 ” is benzoyl), dissolved with 60mL of anhydrous dimethylformamide under the protection of argon; then added 3.0eq imidazole and 1.5eq tert-butyldiphenylchlorosilane to the reaction system. Diluted with ethyl ester, washed with water, dried the separated organic phase with anhydrous magnesium sulfate, filtered, concentrated, and sucked dry to obtain the compound represented by the crude product formula (a2).

[0126] Get last step product (wherein, in formula (a2), " R 2 "is tert-butyldiphenylsilyl) dissolved in 60mL of dichloromethane, added 7.0mL of 25% by mass sodium methoxide methanol solution, stirred at room temperature for 1h. Concentrated under reduced pressure, separated by column chromatography to obtain two isomers , 85% yield in two steps.

[0127] Isomer a: 1 H NMR (400MHz, CDCl 3 )δ7.65-7.62(m,4H),7.44-7.38(m,6H),5.12(dd,J=5.6,2.0Hz,1H),4.51-4.47(m,1H),4.10...

Embodiment 2

[0148] This example is to illustrate the process of preparing a cell-penetrating peptide-conjugated drug by coupling the drug-loaded linker prepared in Example 1 with a cell-penetrating peptide.

[0149] Include the following steps:

[0150] 1) The drug-loaded linker Mal-PC4AP-DOX prepared in Example 1 was dissolved in dimethylformamide to obtain a stock solution of the drug-loaded linker with a concentration of 1.5 mM. The H3-V45C protein was dissolved in sterile water to obtain a stock solution with a concentration of 300 μM.

[0151] 2) Mix 33.5 microliters of drug-loaded linker stock solution with 160 microliters of H3-V35C protein in HEPES buffer at pH 7.5 (20 mM), and incubate at 37° C. for 1 hour.

[0152] 3) After the reaction, the obtained cell-penetrating peptide-conjugated drug (H3-PC4AP-DOX, whose structure is shown in Formula 5) needs to be further purified and desalted using PD MiniTrap G-25 desalting column. Specific desalting method: load 200 microliters of s...

Embodiment 3

[0154] This example is to illustrate that the cell-penetrating peptide-conjugated drug H3-PC4AP-DOX prepared in Example 2 can be used for light-controlled release of doxorubicin DOX in HeLa cells.

[0155] 3.1 Confocal microscopy to detect the cellular localization of DOX and H3-PC4AP-DOX

[0156] HeLa cells in logarithmic growth phase were digested with trypsin, washed and centrifuged to prepare single cell suspension. The counted cells were seeded in a 24-well plate (density 1.0×10 5 per well) at 37°C containing 5% CO 2 overnight in a constant temperature incubator. After overnight culture, the cells were washed twice with PBS, and the complete medium containing 10 μM doxorubicin and H3-PC4AP-DOX were added respectively. After continuing to culture for different periods of time, the original culture solution was sucked off, the cells were soaked twice in PBS, and fixed with 300 μL of 4% paraformaldehyde at room temperature for 20 minutes. After soaking in PBS for 2 times...

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Abstract

The invention relates to the field of drug delivery, and discloses a linker, a drug-loaded linker, a cell-penetrating peptide-coupled drug, an antibody-coupled drug and a preparation method thereof. The linker has a structure shown in formula (I), and the invention provides The light-responsive self-catalytic cleavage linker and the drug-loaded linker can couple the drug to the polypeptide or protein delivery carrier, and can realize the controllable delivery of the drug into the cell.

Description

technical field [0001] The invention relates to the field of drug delivery, in particular to a light-responsive self-catalytic cleavage linker, a photo-responsive self-catalytic cleavage drug-loaded linker and a preparation method thereof, and a method for preparing cell-penetrating peptide-coupled drugs The method and the cell-penetrating peptide-coupled drug prepared by the method, a method for preparing the antibody-coupled drug and the antibody-coupled drug prepared by the method. Background technique [0002] Prodrug strategies are widely used in the design and development of drugs, the purpose of which is to improve the pharmacokinetic properties of the parent drug, especially the ability to target delivery (Nat.Rev.Drug Discov.2108,17,559-587; Chem.Soc . Rev. 2019, 48, 1077-1094). [0003] In general, prodrugs are constructed by coupling drug molecules to carriers via linkers containing “trigger switches”. After the prodrug is delivered to the target cells or tissue...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/26C07H1/00A61K47/54A61K47/60A61K47/64A61K47/68
CPCA61K47/545A61K47/60A61K47/64A61K47/6801C07H1/00C07H15/26Y02P20/55
Inventor 周传政臧传龙
Owner NANKAI UNIV
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