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Cysteine-functionalized hyaluronic acid conjugates and their synthesis and application in injectable in situ formed hydrogels

A technology of hyaluronic acid and cysteine, which is applied in the field of biomedicine, can solve problems such as inability to achieve in situ injection and reduce cell repair damage, and achieve good application prospects, good bioadhesion, and the effect of expanding applications

Active Publication Date: 2016-04-06
HAINAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Reducing the negative charge of hyaluronic acid will affect the interaction between cell CD44 receptors and hyaluronic acid, thereby reducing the ability of cells to repair damage , Kidney Int. 2007, 72:430-441.]
However, the hyaluronic acid hydrogel obtained through the reaction of its hydroxyl group often requires a pre-formed hydrogel by light reaction or other methods, so that in situ injection cannot be achieved.

Method used

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  • Cysteine-functionalized hyaluronic acid conjugates and their synthesis and application in injectable in situ formed hydrogels
  • Cysteine-functionalized hyaluronic acid conjugates and their synthesis and application in injectable in situ formed hydrogels
  • Cysteine-functionalized hyaluronic acid conjugates and their synthesis and application in injectable in situ formed hydrogels

Examples

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preparation example Construction

[0067] ① Preparation of compound 2: take compound 1 cysteine ​​hydrochloride, add at least 20 times the volume (volume / mass) of compound 1 in dry acetone, reflux for 2-10 hours, and concentrate under reduced pressure to no more than the total reaction solution One-third of the volume, put it in the refrigerator for no less than 0.5h, precipitate crystals, and filter through a Buchner funnel to obtain compound 2, whose chemical structural formula is shown in compound 2 in the synthetic route;

[0068] ② Preparation of Compound 3: Dissolve Compound 2 in acetonitrile, add di-tert-butyl dicarbonate in a molar amount equivalent to 1.1 to 3 times that of Compound 2, mix well and add dropwise in a molar amount equivalent to that of Compound 2 1. 1-3 times of N,N-diisopropylethylamine, stirred at 15°C-37°C for 24-72h, concentrated the solvent under reduced pressure, then added ether or cyclohexane to continue the concentration under reduced pressure, then added ether or cyclohexane al...

Embodiment 1

[0082] Example 1: Preparation of cysteine-functionalized hyaluronic acid conjugates

[0083] 1) Preparation of Apc: Take 10g of cysteine ​​hydrochloride, add 1000mL of dry acetone to reflux for 6h, concentrate under reduced pressure to about 200mL, put it in the refrigerator overnight, precipitate crystals, filter through a Buchner funnel, and obtain the intermediate white crystal Apc (compound 2) quality 11g, productive rate is 88%, and its proton nuclear magnetic resonance spectrum is as figure 1 shown.

[0084] 2) Preparation of Boc-Apc: Dissolve 10.9g (55mmol) of compound 2 in 250mL of acetonitrile, add 16g (73mmol) of di-tert-butyl dicarbonate, mix well and add 12.8g (99mmol) of N,N-diiso Propylethylamine was stirred at 28°C for 48h. Concentrate the solvent under reduced pressure, then add diethyl ether or cyclohexane to continue concentrating under reduced pressure, then add diethyl ether or cyclohexane, filter with diatomaceous earth, and filter the filtrate with 0.01...

Embodiment 2

[0091] Embodiment 2: the preparation of the hyaluronic acid conjugate of cysteine ​​functionalization

[0092] The preparation method of embodiment 2 is the same as embodiment 1, except that step 6) in embodiment 1 is replaced by:

[0093] Preparation of Boc-Apc-PEG-500: Dissolve 5.26g (10mmol) of polyethylene glycol (PEG-500) with a molecular weight of 500 in 5ml of acetonitrile, dissolve 840mg (10mmol) of sodium bicarbonate in 30mL of ultrapure water, and add it. Stir at 28°C, blow argon, dissolve 3.52g (11mmol) of compound 6 in 15mL of acetonitrile, add dropwise to the above reaction solution, pass argon after the dropwise addition, seal, stir and react at 28°C for 12h, TLC detection, Ellamn The color of the reagent does not show yellow, stop the reaction, concentrate the solvent under reduced pressure, extract the water phase with dichloromethane 3 times, wash the combined dichloromethane phase with water 3 times, dry over anhydrous magnesium sulfate for 2 hours, filter, a...

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Abstract

The invention discloses a cysteine functionalized hyaluronic acid conjugate, a synthetic method and an application in preparation of injectable in-situ hydrogel thereof. According to the method, a hydroxy of hyaluronic acid is modified to obtain the cysteine functionalized hyaluronic acid conjugate with a stable ether bond, and tetrabutyl ammonium hydroxide is introduced in the reaction process. The new method improves the solubility of hyaluronic acid and increases the reaction efficiency. The obtained cysteine functionalized hyaluronic acid conjugate has a sulfhydryl active group which not only improves the adhesion of hyaluronic acid, but also can be further functionalized. According to the invention, injectable in-situ hydrogel is generated by a native chemical ligation reaction or a Michael addition reaction of the prepared cysteine functionalized hyaluronic acid conjugate with a polyethylene glycol conjugate; rheological research shows that the generated hydrogel has good rheological properties, the gel performance is controllable, and the hydrogel has wide application prospects in the biological medicine field.

Description

technical field [0001] The invention relates to a cysteine-functionalized hyaluronic acid conjugate and a synthesis method thereof, as well as its application in the preparation of injectable in-situ formed hydrogel, which belongs to the field of biomedicine. Background technique [0002] Hydrogel (Hydrogel) is a network structure of hydrophilic polymers, which can absorb and retain a large amount of water, is highly swellable in aqueous solution, and has good biocompatibility. They are widely used in medical and biological fields as surgical sealants and adhesives, drug release, tissue filling, tissue repair and tissue engineering. When the hydrogel is used as a wound dressing, it is in direct contact with human tissue, which can prevent microbial infection in vitro, effectively prevent the loss of body fluids, and promote wound healing. It can also wrap drugs in the hydrogel, and the drug can pass through the gel. Release slowly into the injured area. For example, there ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C08G81/00C08B37/08A61L27/20A61L27/52
Inventor 张歆胡碧煌
Owner HAINAN UNIV
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