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
View PDF7 Cites 3 Cited by
  • 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 mate

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 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

Example Embodiment

[0042] Example 1:

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

[0044]

[0045] Of which 5

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

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

[0048] 2-Mercaptoethanol (0.87g, 11.1mmol) and 2,2'-disulfidepyridine (Py-SS-Py, 2.44g, 11.1mmol) were added to 100mL of methanol, and the reaction was stirred at room temperature for 12 hours. The methanol was evaporated under reduced pressure, purified by a silica gel column, concentrated, and dried in vacuo to obtain 1.6 g of a pale yellow oily product with a yield of 77.1%. Tested product 1 H NMR indicated that 2-(2-pyridyldithio)ethanol represented by formula a was obtained.

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

[0050] Dissolve 2-(2-pyridyldisulfide) ethanol (1.6g, 8.56mmol) and triethylamine (1.73g, 17.1 mmol) in 100mL of dichloromethane,...

Example Embodiment

[0058] Example 2:

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

Example Embodiment

[0060] Example 3:

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

[0062]

[0063] Of which 100

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

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

[0066] 3-Mercaptopropanol (0.5 g, 5.43 mmol) and 2,2'-dithiodipyridine (Py-SS-Py, 2.4 g, 10.9 mmol) were added to 60 mL of methanol, and the reaction was stirred at room temperature for 24 hours. The methanol was evaporated under reduced pressure, purified by a silica gel column, concentrated, and dried under vacuum to obtain 0.87 g of a pale yellow oily liquid product as shown in formula e, with a yield of 79.7%.

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

[0068] Dissolve 3-(2-pyridyldithio)propanol (0.87g, 4.33mmol) and triethylamine (0.52g, 5.15mmol) in 50mL of dichloromethane, and mix the p-nitrochloroformate with benzene under stirring at room tempe...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
Particle sizeaaaaaaaaaa
Drug loadingaaaaaaaaaa
Login to view more

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
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
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap