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PH responsive thrombolytic drug targeting nanogel, synthesis method and application thereof

A thrombolytic drug and nanogel technology, applied in the field of biomedicine, can solve the problems of reducing the biological activity of the drug, unstable immunogenicity, uneven drug-antibody coupling agent, etc., to prolong the time of hydrolysis and blood circulation. The effect of prolonging the half-life

Active Publication Date: 2015-07-08
NINGBO UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, these methods have certain limitations
First, covalently bonding antibodies or proteins will reduce the biological activity of drugs; second, the heterogeneity of drug-antibody conjugates, instability in long-term storage and immunogenicity are the main problems of chemically modified drugs; moreover, How to better control the low release / low activity of thrombolytic drugs in the circulatory system, and the rapid release / recovery of activity after they accurately reach the thrombus site, resulting in thrombolysis, thereby reducing the risk of bleeding in the body

Method used

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  • PH responsive thrombolytic drug targeting nanogel, synthesis method and application thereof
  • PH responsive thrombolytic drug targeting nanogel, synthesis method and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0027] (1) Synthesis of oxidized dextran

[0028] Dissolve 1g of dextran (Mn 40000) in 30mL of water, add 0.956g of sodium periodate (dissolved in 20mL of water), and react in the dark for 24 hours at room temperature, then add 0.411g of glycerol, continue to stir for 15min, and mix the reaction The solution was transferred to a dialysis bag and dialyzed in deionized water for 48 h, changing the water every four hours. The dialyzed sample was freeze-dried to obtain the product as a white powder. By changing the molar ratio of dextran and sodium periodate, oxidized dextran with different aldehyde content can be prepared.

[0029] (2) Synthesis of oxidized dextran-RGD

[0030] Add 0.0382g RGD, 0.5g oxidized dextran (oxidation degree 0.5) and 0.1227g 4-dimethylaminopyridine (DMAP) into a 100ml single-necked flask, add 30ml of dichloromethane to dissolve, put the single-necked flask into 37 °C in a water bath, stirring evenly. Weigh 0.1917g of 1-(3-dimethylaminopropyl)-3-ethyl...

Embodiment 2

[0034] (4) Synthesis of oxidized dextran

[0035] Dissolve 1g of dextran (Mn 40000) in 30mL of water, add 0.956g of sodium periodate (dissolved in 20mL of water), and react in the dark for 24 hours at room temperature, then add 0.411g of glycerol, continue to stir for 15min, and mix the reaction The solution was transferred to a dialysis bag and dialyzed in deionized water for 24 h, with the water changed every four hours. The dialyzed sample was freeze-dried to obtain the product as a white powder. By changing the molar ratio of dextran and sodium periodate, oxidized dextran with different aldehyde content can be prepared.

[0036] (5) Synthesis of oxidized dextran-RGD

[0037] Add 0.0382g RGD, 0.5g oxidized dextran (oxidation degree 0.5) and 0.1227g 4-dimethylaminopyridine (DMAP) into a 100ml single-necked flask, add 30ml of dichloromethane to dissolve, put the single-necked flask into 60 °C in a water bath, stirring evenly. Weigh 0.1917g of 1-(3-dimethylaminopropyl)-3-e...

Embodiment 3

[0041] (7) Synthesis of oxidized dextran

[0042] Dissolve 1g of dextran (Mn 40000) in 30mL of water, add 0.956g of sodium periodate (dissolved in 20mL of water), and react in the dark for 48 hours at room temperature, add 0.411g of glycerin, continue to stir for 15min, and mix the reaction The solution was transferred to a dialysis bag and dialyzed in deionized water for 48 h, changing the water every four hours. The dialyzed sample was freeze-dried to obtain the product as a white powder. By changing the molar ratio of dextran and sodium periodate, oxidized dextran with different aldehyde content can be prepared.

[0043] (8) Synthesis of oxidized dextran-RGD

[0044] Add 0.0382g RGD, 0.5g oxidized dextran (oxidation degree 0.5) and 0.1227g 4-dimethylaminopyridine (DMAP) into a 100ml single-necked flask, add 30ml of dichloromethane to dissolve, put the single-necked flask into 4 °C in a water bath, stirring evenly. Weigh 0.1917g of 1-(3-dimethylaminopropyl)-3-ethylcarbod...

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Abstract

The invention relates to a pH responsive thrombolytic drug targeting nanogel, a synthesis method and application thereof. The nanogel is formed by covalent linkage of a thrombolytic drug and oxidative dextran through a pH sensitive imine linkage and introduction of a thrombus-targeted ligand to an oxidative dextran molecular chain. The imine linkage is stable under normal physiological pH value, and can hydrolyze under a weak acid pH value. The thrombus-targeted ligand enables the nanogel with thrombus active targeting ability, is stable in a circulation system, and releases drug molecules after reaching an embolism part, thus reducing the risk of body bleeding caused by the thrombolytic drug. The nanogel has reversible biological properties. By regulating the molecular weight, reaction ratio and functional group of the polymer, the hydrolysis resistant degree and opportunity of thrombolytic drug protein molecules to hydrolase can be regulated, and also activity release to drug molecules can be controlled. The microsystem can be used as a thrombolytic drug carrier for transportation of protein or peptide drugs so as to realize synergistic treatment of drugs.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and specifically relates to a pH-responsive thrombolytic drug targeting nanogel based on imine bonds and a synthesis method thereof, as well as the application of the nanogel as a thrombolytic drug carrier. Background technique [0002] In recent years, thrombotic diseases (such as acute myocardial infarction, ischemic stroke) are the main cause of clinical death and disability. Among them, stroke has become one of the three major diseases of human death due to its high incidence, disability, mortality and recurrence [Lancet Neurology 2004, 3, 391-393; Lancet 2005, 365, 2160-2161.], It seriously endangers human health and brings a heavy economic burden to families and society. With the continuous development of my country's national economy, changes in people's lifestyles and dietary structures, and the acceleration of population aging, the incidence of cerebrovascular diseases is increasing...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K9/06A61P7/02
Inventor 俞洁赵玲玲张冬未郑静霞张雅娟王瑞梁洪泽
Owner NINGBO UNIV
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