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CRGD sequence peptide modified chitosan loaded PAD4 inhibitor and preparation method and application thereof

A chitosan and inhibitor technology, applied in the field of PAD4 inhibitor and its preparation, can solve the problem of low active targeting and so on

Active Publication Date: 2021-09-07
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • 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

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  • CRGD sequence peptide modified chitosan loaded PAD4 inhibitor and preparation method and application thereof
  • CRGD sequence peptide modified chitosan loaded PAD4 inhibitor and preparation method and application thereof
  • CRGD sequence peptide modified chitosan loaded PAD4 inhibitor and preparation method and application thereof

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preparation example Construction

[0065] The present invention provides the preparation method of the PAD4 inhibitor of above-mentioned CRGD sequence peptide modification chitosan load, comprises the following steps:

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

[0067] (2) Mix the chitosan modified by the acryloyl chloride, the CRGD sequence peptide, the second acid-binding agent with the second organic solvent, and carry out Michael addition reaction to obtain the CRGD sequence peptide modified chitosan carrier;

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

[0069] The invention mixes chitosan, acryloyl chloride, a first acid-binding agent and a first organic solvent to carry...

Embodiment 1

[0107] (1) Synthesis of CRGD sequence peptide

[0108] (1) Solid phase synthesis of CRGDV

[0109] 1) Swelling: Soak 300 mg of Fmoc-Val-Wang resin with 10 mL of anhydrous DMF in a solid-phase synthesis tube for 3 hours to make it swell.

[0110] 2) Deprotection: remove anhydrous DMF by suction filtration under reduced pressure, and add 8-10 mL of deprotection agent (anhydrous DMF:hexahydropyridine=4:1), shake the reaction for 3 minutes, remove the deprotection agent by suction filtration under reduced pressure, Then add 8-10mL of deprotection agent, shake and react for 8min.

[0111] 3) Washing: remove the deprotection agent by suction filtration under reduced pressure, and wash with anhydrous DMF, CH 2 Cl 2 1. Washing with anhydrous DMF, each solution was washed twice.

[0112] 4) Color development: ninhydrin method for detection of resin (detection-NH 2 ), showing dark purple.

[0113] 5) Coupling: Weigh Fmoc-Asp (OtBu) and condensing agent HBTU, dissolve with coupling...

Embodiment 2

[0150] The synthesis of embodiment 2 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 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 700-1000Da) for 48 hours. A light 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 CRGD sequence peptide modified chitosan loaded PAD4 inhibitor and a preparation method and application thereof, and belongs to the technical field of antitumor drugs. According to the CRGD sequence peptide modified chitosan loaded PAD4 inhibitor and the preparation method and application thereof, CRGD sequence peptide modified chitosan is used as a drug carrier, wherein the chitosan has good biocompatibility and biodegradability, RGD sequence peptide in CRGD sequence peptide can be specifically combined on a corresponding receptor overexpressed by target cells, and the targeting effect achieved by targeting delivery of drugs to a target area can be achieved by using specific combination of the receptor on the surface of tumor cells and a ligand of a targeting preparation. According to the CRGD sequence peptide modified chitosan loaded PAD4 inhibitor and the preparation method and application thereof, the CRGD sequence peptide modified chitosan is used for loading the PAD4 inhibitor, the selectivity of the PAD4 inhibitor to the target tumor cells can be enhanced, adverse drug reactions are reduced, and the PAD4 inhibitor has good antitumor activity.

Description

technical field [0001] The invention relates to the technical field of antitumor drugs, in particular to a CRGD sequence peptide modified chitosan-loaded PAD4 inhibitor and a preparation method and application thereof. Background technique [0002] According to statistics, cancer is already the main disease that causes death in most countries. Cancer cells grow uncontrollably. They can grow and reproduce indefinitely by absorbing 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. PAD4, as an auxiliary inhibitor of p53, can jointly inhibit the expression of tumor suppressor genes (such as p21 / CDKN1A and GADD45) with histone deacetylase HDAC2. But PAD4 has low bioavailability. [0004] In order to improve the bioavailability of drugs, it is a common method to use drug carriers to deliver drugs. So far, t...

Claims

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Application Information

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Patent Type & Authority Applications(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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