A kind of crgd sequence peptide modified chitosan-loaded pad4 inhibitor and its preparation method and application

A chitosan and inhibitor technology, applied in the field of PAD4 inhibitor and its preparation, can solve the problem of low active targeting, and achieve the effects of reducing adverse drug reactions, enhancing selectivity and good anti-tumor effect

Active Publication Date: 2022-07-15
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

So far, there have been a variety of relatively mature drug carriers, including water-soluble high molecular weight polymer carriers, polymer nanoparticles, polymer micelles, dendrimers, liposomes, virus particles, carbon nanotubes and Graphene oxide, etc., however, the active targeting of these supports is often not high

Method used

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  • A kind of crgd sequence peptide modified chitosan-loaded pad4 inhibitor and its preparation method and application
  • A kind of crgd sequence peptide modified chitosan-loaded pad4 inhibitor and its preparation method and application
  • A kind of crgd sequence peptide modified chitosan-loaded pad4 inhibitor and its preparation method and application

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preparation example Construction

[0065] The present invention provides a preparation method of the above-mentioned CRGD sequence peptide-modified chitosan-loaded PAD4 inhibitor, comprising the following steps:

[0066] (1) mixing chitosan, acryloyl chloride, the first acid binding agent with the first organic solvent, and carrying out a nucleophilic substitution reaction to obtain chitosan modified with acryloyl chloride;

[0067] (2) mixing the acryloyl chloride modified chitosan, the CRGD sequence peptide, the second acid binding agent and the second organic solvent, and performing a Michael addition reaction to obtain a CRGD sequence peptide modified chitosan carrier;

[0068] (3) stirring and mixing the CRGD sequence peptide-modified chitosan carrier, the PAD4 inhibitor and the third organic solvent to obtain the CRGD sequence peptide-modified chitosan-loaded PAD4 inhibitor.

[0069] In the present invention, chitosan, acryloyl chloride, a first acid binding agent and a first organic solvent are mixed to ...

Embodiment 1

[0107] (1) Synthesis of CRGD sequence peptide

[0108] (1) Solid-phase synthesis of CRGDV

[0109] 1) Swelling: In a solid-phase synthesis tube, soak 300 mg of Fmoc-Val-Wang resin with 10 mL of anhydrous DMF for 3 h to swell it.

[0110] 2) Deprotection: the anhydrous DMF was removed by suction filtration under reduced pressure, and 8-10 mL of a deprotecting agent (anhydrous DMF:hexahydropyridine=4:1) was added, and after the shaking reaction for 3 min, the deprotecting agent was removed by suction filtration under reduced pressure, Then 8-10 mL of deprotecting agent was added, and the reaction was shaken for 8 min.

[0111] 3) Washing: the deprotecting agent was removed by suction filtration under reduced pressure, followed by anhydrous DMF, CH 2 Cl 2 , washed with anhydrous DMF, and each solution was washed twice.

[0112] 4) Color development: Ninhydrin method detects resin (detection-NH 2 ), showing a deep purple color.

[0113] 5) Coupling: Weigh Fmoc-Asp (OtBu) and...

Embodiment 2

[0150] Example 2 Synthesis of CRGDV-chitosan-4B

[0151] (1) Synthesis of Chitosan-Acryloyl Chloride

[0152] First, chitosan (0.6 g, 0.20 mmol) and triethylamine (Et3N, 50 µL, 0.36 mmol) were dissolved in 20 mL of N,N-dimethylformamide (DMF). After cooling at 0°C, acryloyl chloride (8 μL, 0.10 mmol) in 8 mL of dichloromethane solution was added dropwise to the stirred solution. The reaction was carried out at room temperature for 24 hours and then dialyzed against distilled water (molecular weight cut-off 700-1000 Da) for 48 hours. A pale yellow solid was obtained after lyophilization.

[0153] (2) Synthesis of Chitosan-CRGDV

[0154] Chitosan-acryloyl chloride (0.3 g, 0.10 mmol) and CRGDV (98 mg, 0.18 mmol) were dissolved in 5 mL of dimethyl sulfoxide and Et3N (10 μL, 0.07 mmol) was added at room temperature. The reaction was stirred at room temperature for 12-24 hours and dialyzed against distilled water (MWCO: 700-1000 Da) for 48 hours. After lyophilization, a pale ye...

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Abstract

The invention provides a PAD4 inhibitor loaded with CRGD sequence peptide modified chitosan and a preparation method and application thereof, belonging to the technical field of antitumor drugs. The present invention uses CRGD sequence peptide modified chitosan as a drug carrier, wherein chitosan has good biocompatibility and biodegradability, and the RGD sequence peptide in the CRGD sequence peptide can be specifically combined in target cells for overexpression On the corresponding receptors of the tumor cells, the targeting effect achieved by the specific binding of the receptors on the tumor cell surface and the ligands of the targeting preparations to deliver the drugs to the target area can be achieved. The invention uses the CRGD sequence peptide to modify the chitosan to load the PAD4 inhibitor, which can enhance the selectivity of the PAD4 inhibitor to the target tumor cells, reduce the adverse drug reactions, and make it have good anti-tumor activity.

Description

technical field [0001] The invention relates to the technical field of anti-tumor drugs, in particular to a PAD4 inhibitor loaded with CRGD sequence peptide modified chitosan and a preparation method and application thereof. Background technique [0002] According to statistics, cancer is already the main disease causing death in most countries. The growth of cancer cells is uncontrolled, and they can grow and multiply indefinitely by drawing nutrients from the host body. There are many types of cancer cells, so the treatment of cancer is very important. challenging. [0003] Peptidylarginine deiminase 4 (PAD4) has become one of the important targets of cancer. As a co-inhibitor of p53, PAD4 can co-repress the expression of tumor suppressor genes (such as p21 / CDKN1A and GADD45) together with the histone deacetylase HDAC2. But PAD4 has lower bioavailability. [0004] In order to improve the bioavailability of drugs, it is a common method to use drug carriers to deliver dru...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/16A61K47/36A61K31/69A61K47/64A61P35/00C08B37/08
CPCA61K9/1652A61K31/69A61K47/64A61P35/00C08B37/003
Inventor 王玉记王彦明贾翌江阿依江朱迪卢玉冯琦琦
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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