Polymer prodrug micelle with reduction responsiveness as well as preparation method and application thereof

A polymer and responsive technology, applied in the field of biomedicine, can solve the problems of different drug metabolism rates, cumbersome preparation methods, obvious toxic and side effects, etc., and achieve the effects of fast and simple preparation process, improved reaction efficiency, and improved inhibitory effect

Active Publication Date: 2020-11-17
NANKAI UNIV
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  • Abstract
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Problems solved by technology

However, although a batch of HDACi drugs have been marketed, there are still some problems in the clinical application of HDACi: 1) HDACi has a narrow therapeutic window, and it is difficult to maintain the effective blood drug concentration; 2) The toxic and side effects are obvious, and serious adverse reactions are prone to occur; 3 ) when used in combination, due to the difference in the physical and chemical properties of the drug, the distribution and metabolic rate of the drug in the body are different, which makes it difficult for the concentration of the drug molecule to reach the lesion to reach the effective therapeutic concentration; 4) It is difficult to achieve generalization of the treatment plan
Nevertheless, polymer prodrugs still have problems such as cumbersome preparation methods that cannot ensure the homogeneity of polymer prodrugs, and chemical bonds that cannot be broken rapidly in tumor environments, which limit the application of this method. Therefore, new polymer prodrug systems still need Continue to study

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  • Polymer prodrug micelle with reduction responsiveness as well as preparation method and application thereof
  • Polymer prodrug micelle with reduction responsiveness as well as preparation method and application thereof
  • Polymer prodrug micelle with reduction responsiveness as well as preparation method and application thereof

Examples

Experimental program
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Effect test

preparation example Construction

[0056] Following 7-7,-dithiodiheptanoic acid can be synthesized according to prior art, and its preparation method is provided below, comprising the following steps:

[0057] 1) Cycloheptanolactone is prepared from cycloheptanone;

[0058] Put the compound m-chloroperoxybenzoic acid (335mmol) into the reaction flask, add dichloromethane (500mL) and cycloheptanone (223mmol) successively at 0°C, and react for 7 days; (300mL×2) was washed twice, the organic layer was washed twice with saturated sodium bicarbonate solution (300mL×2); the organic layer was dried with anhydrous sodium sulfate, suction filtered and spin-dried to obtain a yellow oil;

[0059] 1 H NMR (400MHz, CDCl 3 )δ=4.32–4.24(t,2H),2.52–2.44(t,2H),1.83–1.70(m,4H),1.60–1.46(m,4H). 13 C NMR (101MHz, CDCl 3 )δ=176.69, 67.87, 31.25, 30.86, 28.33, 25.77, 23.89.

[0060] 2) Preparation of 7-hydroxyheptanoic acid methyl ester by ring-opening cycloheptanolide;

[0061] Take anhydrous methanol (55mL) and pour it into ...

Embodiment 1

[0082] A Reduction Responsive Polymer Prodrug mPEG 2000 -mMAP 12 -mPEG 2000 The preparation method of micelle, comprises the following steps:

[0083]

[0084] Preparation of S1, 1H-imidazole-1-carboxylic acid-N-tert-butoxycarbonyl-3-aminobenzyl ester;

[0085] Dissolve N-tert-butoxycarbonyl-3-aminobenzyl alcohol (1.5mmol) in tetrahydrofuran (1.5mL), add dropwise carbonyldiimidazole (5mmol) dissolved in tetrahydrofuran (4.5mL), react at 25°C for 12h; spin dry Add 10 mL of ethyl acetate to dissolve, wash with saturated brine (10 mL×2) twice; dry the organic phase over anhydrous sodium sulfate, filter with suction and spin dry to obtain a yellow oil; figure 1 gives the resulting product 1 H NMR spectrum.

[0086] S2, preparation of bis-N-tert-butoxy-3-aminobenzyl carbonate;

[0087] Add the compound N-tert-butoxycarbonyl-3-aminobenzyl alcohol (35mmol) into a three-necked flask, add tetrahydrofuran (70mL), add sodium hydride (35mmol) at 0°C and stir for 1h, then drop int...

Embodiment 2

[0097] A Reduction Responsive Polymer Prodrug mPEG 2000 -mMAP 26 -mPEG 2000 The preparation method of micelle, step is with embodiment 1, difference is:

[0098] S1, react at 20°C for 20 hours, the molar ratio of N-tert-butoxycarbonyl-3-aminobenzyl alcohol to carbonyldiimidazole is 1:2;

[0099] S2. Reaction at 20°C for 10 hours, 1H-imidazole-1-carboxylic acid-N-tert-butoxycarbonyl-3-aminobenzyl ester:N-tert-butoxycarbonyl-3-aminobenzyl alcohol:sodium hydride is 1:0.5:0.5;

[0100] S4, the reaction time is set to 10min;

[0101] S5, the HOOC-mMAP 12 -COOH is replaced by HOOC-mMAP 26 -COOH, reacted at 20℃ for 24h, HOOC-mMAP 26 -COOH:mPEG-NH 2 :HOAT:HATU is 1:2:3:3;

[0102] S6, the mPEG 2000 -mMAP 12 -mPEG 2000 Replace with mPEG 2000 -mMAP 26 -mPEG 2000 .

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Abstract

The invention provides a polymer prodrug micelle with reduction responsiveness as well as a preparation method and application thereof, belonging to the technical field of biological medicines. The polymer prodrug micelle is prepared from a prodrug polymer with a structure as shown in a formula (I) which is described in the specification. According to the method, 7-7'-dithiodiheptanoic acid and methyl di-3-aminophenylcarbonate are taken as raw materials, 1-hydroxy-7-azobenzotriazole and 2-(7-oxybenzotriazol)-N,N,N',N'-tetramethylurea hexafluorophosphate are taken as condensing agents, N,N-diisopropylethylamine is taken as a catalyst, a microwave technology is adopted for realizing condensation polymerization, and pegylation is conducted to obtain the polymer prodrug micelle. The preparation method is rapid, simple and convenient inprocess and friendlyto environment, and has the potential of realizing batch production; and the polymer prodrug micelle has a good treatment effect on humancolon cancer cells, and shows good application prospects.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a reduction-responsive polymer prodrug micelle and a preparation method and application thereof. Background technique [0002] Histone deacetylase (HDAC) plays an important role in the epigenetic regulation of genes. A large number of studies have shown that the occurrence and development of tumors are closely related to the overexpression or abnormal activity of HDAC. At present, HDAC has been used as the target of tumor therapy in many researches and clinical treatments. Histone deacetylase inhibitors (HDACi) can inhibit the deacetylation process of histones, and can also play a role in other biological processes such as cell cycle, angiogenesis, immune regulation and apoptosis. [0003] It is well known that the occurrence and development of tumors is regulated by multiple signaling pathways, each of which restricts and influences each other. Therefore, a sin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G65/334A61K31/704A61P35/00
CPCC08G65/3348A61K31/704A61P35/00
Inventor 王燕铭沈杰韩京华王达远王雅洁黄晴晴
Owner NANKAI UNIV
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