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Reduced response-type amphiphilic polymer prodrug and preparation method and application thereof

A technology of amphiphilic polymers and polymers, applied in drug combinations, pharmaceutical formulations, anti-tumor drugs, etc., can solve the problems of slow hydrolysis, affecting the anti-tumor effect of drugs, incompleteness, etc., and achieve high yield and product purity , Facilitate mass production, mild reaction conditions

Inactive Publication Date: 2019-07-19
烟台药物研究所
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the most commonly used disulfide linking arms are mainly 2,2'-dithiodiacetic acid, 3,3'-dithiodipropionic acid, etc., but these disulfide linking arms are used to link hydrophilic polymers After interacting with hydrophobic drugs, under reducing conditions such as GSH and DTT, the disulfide bond will be broken rapidly, but the drug released after the break is still connected with a "tail" such as a sulfhydryl group and an ester bond, rather than the raw material molecular form, China The polymer prodrug disclosed in the patent CN102775596 belongs to the above-mentioned situation when the disulfide bond is broken to release the drug. To obtain the drug in the molecular form of the raw material, it needs to go through the step of ester bond hydrolysis, and the weak alkaline in human cells Under certain conditions, the hydrolysis of the ester bond is slow and incomplete, which directly affects the antitumor effect of the drug

Method used

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  • Reduced response-type amphiphilic polymer prodrug and preparation method and application thereof
  • Reduced response-type amphiphilic polymer prodrug and preparation method and application thereof
  • Reduced response-type amphiphilic polymer prodrug and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] A reduction-responsive amphiphilic polymer prodrug has the following structural formula:

[0044]

[0045]where 5

[0046] The preparation method of above-mentioned amphiphilic polymer prodrug is as follows:

[0047] 1) Preparation of 2-(2-pyridyldithio)ethanol:

[0048] 2-Mercaptoethanol (0.87g, 11.1mmol) and 2,2'-dithiobipyridine (Py-SS-Py, 2.44g, 11.1mmol) were added into 100mL of methanol, and stirred at room temperature for 12 hours. Methanol was distilled off under reduced pressure, purified by silica gel column, concentrated, and dried in vacuo to obtain 1.6 g of light yellow oily product with a yield of 77.1%. products tested 1 H NMR showed that 2-(2-pyridyldithio)ethanol represented by formula a was obtained.

[0049] 2) Preparation of 4-nitrophenyl-2-(2-pyridyldithio)ethyl carbonate:

[0050] 2-(2-Pyridyldithio)ethanol (1.6g, 8.56mmol) and triethylamine (1.73g, 17.1mmol) were dissolved in 100mL of dichloromethane, and phenyl p-nitrochloroformate...

Embodiment 2

[0059] A nanomicelle containing the amphiphilic polymer prodrug obtained in Example 1 is prepared by the following method: 20 mg of the polymer prodrug and 10 μL of medium-chain fatty acid triglyceride are placed in water, then ultrasonicated for 1 min, and filtered Add mannitol to the membrane and freeze-dry it to obtain the reduction-responsive polymer nanomicelle freeze-dried powder. Use dynamic light scattering (DynamicLight Scattering, DLS) to measure the particle size and distribution of nanomicelle, such as image 3 shown.

Embodiment 3

[0061] A reduction-responsive amphiphilic polymer prodrug has the following structural formula:

[0062]

[0063] where 100

[0064] The preparation method of above-mentioned amphiphilic polymer prodrug is as follows:

[0065] 1) Preparation of 3-(2-pyridyldithio)propanol:

[0066] Add 3-mercaptopropanol (0.5 g, 5.43 mmol) and 2,2′-dithiobipyridine (Py-SS-Py, 2.4 g, 10.9 mmol) into 60 mL of methanol, and stir at room temperature for 24 hours. The methanol was distilled off under reduced pressure, purified by silica gel column, concentrated, and dried in vacuo to obtain 0.87 g of a light yellow oily liquid product shown in formula e, with a yield of 79.7%.

[0067] 2) Preparation of 4-nitrophenyl-3-(2-pyridyldithio)propyl carbonate:

[0068] 3-(2-pyridyldithio)propanol (0.87g, 4.33mmol) and triethylamine (0.52g, 5.15mmol) were dissolved in 50mL of dichloromethane, and p-nitrochloroformic acid benzene was stirred under room temperature The ester (0.87 g, 4.33 mmol)...

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Abstract

The invention relates to a reduced response-type amphiphilic polymer prodrug and a preparation method and an application thereof. The prodrug has a molecular structure as a formula I, wherein X is O or NH, ROH is a hydrophobic antitumor drug, n is from 5 to 1,000, and m is 1 or 2. The prodrug provided by the invention can achieve targeted administration, which not only retains the advantages of anano drug-loading system, but also exhibits the characteristic of specific degradation of a disulfide bond at the tumor site. Compared with conventional 2,2'-disulfanediyldiacetic acid, 3,3'-dithiodipropionic acid and other connecting arms, the prodrug and the preparation method thereof have the advantage that an anticancer drug with an original drug molecular form can be obtained without furtherhydrolysis.

Description

technical field [0001] The invention relates to a polymer drug prodrug and its preparation method and application, in particular to a PEGylated amphiphilic polymer drug prodrug applicable to tumor treatment as well as its preparation method and application. Background technique [0002] Chemotherapy is a basic tumor treatment method, which mainly uses anticancer drugs to kill tumor cells to achieve the purpose of treating tumors. Clinically commonly used anticancer drugs mainly include camptothecins, taxanes, vinblastine, and anthraquinones, etc., but these anticancer drugs have poor physical and chemical properties (such as insoluble in water, poor selectivity, etc.), and are not effective for normal The cells and tissues have serious toxic and side effects, resulting in poor tumor chemotherapy effect, so the clinical application is limited. [0003] Hydrophilic groups are introduced into the molecular structure of drugs through chemical modification to prepare water-solub...

Claims

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Application Information

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IPC IPC(8): A61K9/107A61K47/14A61K47/26A61K31/4745A61P35/00
CPCA61K9/1075A61K31/4745A61K47/14A61K47/26
Inventor 任春光李亚平李泽民孔德旭栾委静李暖暖李艺张丽徐梅霞
Owner 烟台药物研究所
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