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What is hyaluronan or derivative?
Dec 14, 2021

Research progress of sodium hyaluronate and its derivatives

Hyaluronic acid exists in the form of hyaluronate, namely sodium hyaluronate. Natural sodium hyaluronate is easily biodegradable, has a short retention time in the organism, and is not strong enough in hardness and mechanical strength, which limits its clinical application and requires chemical modification. Sodium hyaluronate molecules can be modified with functional groups such as hydroxyl, carboxyl, acetamido, etc. The structure can be modified to overcome these shortcomings based on retaining the original biocompatibility and developing new and excellent physiological functions. Derivatives, which have a wider range of medical applications.


1 Preparation of sodium hyaluronate derivatives

1.1 Derivatives obtained through esterification

The esterification reaction of sodium hyaluronate is carried out on the hydroxyl or carboxyl group. For example, Speranza et al. obtained a novel histone deacetylase inhibitor (HA-But) through the esterification reaction of butyric acid and sodium hyaluronate. The principle of this new type of drug is that butyrate can inhibit tumor growth, but its half-life is short and it is easily metabolized out of the body. After butyrate is combined with sodium hyaluronate, it can be targeted to aggregate under the mediation of receptors. Go to the surface of tumor cells and enter the cells to exert anti-tumor effects. Paclitaxel (paclitaxel, PTX) is a highly effective anti-tumor drug, which is mostly used in the clinical treatment of ovarian cancer, breast cancer, and melanoma. PTX is a hydrophobic compound. Solvents such as ethanol are needed to dissolve PTX to make injections, but this will cause the matrix to produce high sensitivity, neurotoxicity, and other adverse reactions, and PTX itself has toxic side effects on the heart and kidneys, so it is often used as a target To preparations. Rosato et al. esterified sodium hyaluronate and PTX to prepare a water-soluble compound HA-PTX. The study found that this compound has a tumor treatment effect equivalent to PTX, and the esterified derivative is biologically water-soluble The properties and biocompatibility have been significantly improved.


1.2.1.2 Derivatives obtained by grafting reaction

The grafting reaction of sodium hyaluronate is divided into two types, one is to graft small molecules or polymers onto the molecular chain of hyaluronic acid; the other is to "trim" the long chain of hyaluronic acid molecules. Then connect to the polymer molecule. Sodium hyaluronate grafted derivatives are mostly used as drug carriers, using the properties of hyaluronic acid to bind to cell surface receptors to target drugs to their destinations. Huang et al. activated low molecular weight agarose with epichlorohydrin and grafted it with hyaluronic acid to prepare agarose-grafted hyaluronic acid, which was used as an insulin release carrier. Oldinski et al. grafted sodium hyaluronate with polyethylene to obtain a copolymer that can be used to prepare high molecular polymer materials for tissue repair.


1.2.1.3 Derivatives obtained by cross-linking reaction

There are various cross-linking reactions of sodium hyaluronate, and the groups that generally occur are on the hydroxyl and carboxyl groups. Hydroxyl cross-linking-cross-linking with epoxy compounds: Under alkaline conditions, sodium hyaluronate can react with epoxy compounds to prepare cross-linked gels. Lebreton uses 1,4-butanediol diglycidyl ether, 1,4-bis(2,3-cyclopropyl)butane, 1,4-di glycidyl butane, and other epoxy compounds to cross-link hyaluronic acid Sodium, the anti-enzymatic hydrolysis performance of the obtained derivative is much better than that of uncrosslinked sodium hyaluronate. Hydroxyl crosslinking—crosslinking with aldehydes: Sodium hyaluronate can crosslink with aldehydes to generate acetal or hemiacetal groups. The commonly used aldehyde cross-linking agent is glutaraldehyde, but glutaraldehyde is highly toxic and easily causes calcification. To avoid residual glutaraldehyde in cross-linked biological materials, Ramires et al. found an effective method to use glutaraldehyde steam as The cross-linking agent is used to prepare cross-linked polyvinyl alcohol-HA film.

Hydroxyl cross-linking-cross-linking with sulfone: Under alkaline conditions, sodium hyaluronate reacts with divinyl sulfone to make a cross-linked gel, which can be used as a scaffold material for tissue engineering.

Carboxylic cross-linking-cross-linking with carbodiimide: Sodium hyaluronate is cross-linked with carbodiimide under acidic conditions. The obtained derivatives have good cell compatibility, low cytotoxicity, and stable structure. Enhanced mechanical strength and resistance to enzymatic hydrolysis.

Hydrazide crosslinking: The amino group of hydrazide compounds can undergo crosslinking reaction with the carboxyl group of sodium hyaluronate, and it is a commonly used crosslinking agent. The hydrazides used as crosslinking agents include monohydrazide, dihydrazide and polyhydrazide. Dihydrazide and polyhydrazide have more than one amino group, so they can be cross-linked intramolecularly or intermolecularly with sodium hyaluronate, or It is further cross-linked with other small molecules and polymers, and the obtained derivatives can be used as drug carriers or tissue engineering scaffolds.

Carboxyl cross-linking—cross-linking with disulfide: Disulfide malonyl hydrazide and disulfide succinyl hydrazide can cross-link with sodium hyaluronate to obtain modified derivatives. Research has found that this derivative has good biocompatibility and a slow degradation rate.

Amino cross-linking: The amino group on sodium hyaluronate can spontaneously react with genipin to form iridoid nitrides, which are then dehydrated to form aromatic monomers, which are reacted by free radicals to form cyclic molecules The intermolecular and intramolecular cross-linked structure reacts with sodium hyaluronate to obtain cyclic cross-linked sodium hyaluronate.

Cross-linking by other methods: The above-mentioned cross-linking methods mainly use chemical cross-linking agents to cross-link sodium hyaluronate. Chemical cross-linking agents are mostly cytotoxic, and residual cross-linking agents are likely to cause damage to the human body. Researchers have found that radiation can be used to assist cross-linking to obtain high-purity and non-toxic sodium hyaluronate derivatives. Lee KY et al. found that hyaluronic acid and glycidyl methacrylate (GM) were grafted first, and then crosslinked and modified by ultraviolet light by adding photoinitiator 2959. This method successfully generated GMHA derivatives. , And successfully prepared hyaluronic acid gel under ultraviolet radiation. Based on the above research, Chen Senxue [68] used high-energy gamma rays to assist cross-linking to obtain sodium hyaluronate derivatives. High-energy gamma rays are directly used for the cross-linking of sodium hyaluronate. Due to the high energy, the molecular chain of sodium hyaluronate will generate a large number of free radicals and break, resulting in degradation. Therefore, first graft GM onto the SHA molecular chain to introduce double bonds, and then irradiate with γ-rays to prepare sodium hyaluronate derivatives. Studies have found that the derivative has high viscoelasticity and can be used as a biodegradable material.

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