Glycosaminoglycans (GAGs) are active polysaccharides containing a large number of -SO3‒ and -COO‒ groups, also known as acidic mucopolysaccharides. Depending on the composition of the disaccharide units, GAGs usually include hyaluronic acid, heparin, skin chondroitin, keratan sulfate, and chondroitin sulfate (CS). Among them, CS is mainly derived from animal cartilage and connective tissue. It forms a special fucosylated structure in sea cucumbers and exists in the form of proteoglycan in the brain cell matrix. According to the differences in structure, CS can be divided into three types: chondroitin linear polysaccharide, fucosylated chondroitin sulfate, and chondroitin sulfate proteoglycan. Since chondroitin carries a large amount of negative charge and is easily combined with K+, Na+, Ca2+, etc., metal salts are a common form of CS commercial products. CS has a wide range of sources and a variety of preparation methods. Although it has been reported that egg membrane can be used as a source of CS extraction, it is currently mainly derived from the cartilage tissue of poultry and livestock. In view of the frequent occurrence of various zoonotic diseases (such as swine flu), the safety of terrestrial animal CS has received increasing attention. Studies have shown that aquatic animals such as fish are better sources of CS than mammals. The yield of CS extracted and prepared by traditional methods such as acid hydrolysis and chemical synthesis is generally low, and the purification operation is relatively complicated. In addition, due to the emergence of environmental pollution, drug abuse in aquaculture, and antibiotic residues, the trend of microbial fermentation semi-synthesis has increased. CS produced by fermentation has the advantages of being purer, less allergenic, and having a smaller molecular weight than animal sources. CS is widely used in health foods, medical pharmaceuticals, tissue engineering, biomaterials and other fields, and therefore has great market potential. Studies have found that CS has many physiological effects such as anti-arthritis, antioxidant, improvement of metabolic syndrome, anti-coagulation and thrombosis, anti-atherosclerosis, regulation of intestinal flora, anti-tumor and cancer, anti-virus, reduction of toxic and side effects of chemotherapy drugs, protection of vision, anti-inflammation, and regulation of nerves.
Figure 1. The natural sulfation patterns of the chondroitin sulfates (CSs). (Raúl Benito-Arenas, et al.; 2019)
The main chain of CS consists of 50 to 70 disaccharide repeating units composed of β-D-glucuronic acid (GlcA) and β-D-acetylgalactosamine (GalNAc), namely "[-4-β-D-GlcA-1→3-β-D-GalNAc-1-]n" and "[-4-β-D-GalNAc-1→4-β-D-GlcA-1] n". According to the different sulphate sites on the backbone, CS is generally divided into four types: ΔDi0S (GalNAc is not substituted), ΔDi4S (CS-A, the hydroxyl hydrogen atom on carbon 4 is substituted), ΔDi6S (CS-C) and ΔDi4,6S (CS-E). The naturally occurring CS is mainly composed of 4-sulphated groups (4S) and 6S. In chondroitin from aquatic animals such as fish, the 4S/6S ratio is usually less than 1, whereas in terrestrial birds and mammals, the proportion of CS-A is higher.
Chondroitin sulphate is non-toxic and has good biocompatibility. It has excellent solubility in water. The backbone contains a large number of active groups, making it easy to achieve hydrophobic chemical modification and polymer grafting. One of the major advantages of hyaluronic acid as a drug carrier is that it can bind to the highly expressed CD44 receptor on the surface of tumor cells. Related studies have reported that chondroitin sulphate also has the properties of specific recognition and binding to CD44 due to its structural similarity to hyaluronic acid. Therefore, without the need for surface modification, the nanocarrier with hydrophilic chondroitin sulphate as the backbone itself has a certain degree of active targeting of tumor cells with high expression of CD44 receptors. At the same time, chondroitin sulphate can be degraded by hyaluronidase (Hyal-1), which is over-expressed in tumor cells, facilitating rapid cleavage of chondroitin sulphate-based nanocarriers in tumor cells and rapid drug release. Based on these advantages of chondroitin sulphate, research on nanocarriers using chondroitin sulphate as a new scaffold for tumor treatment is increasing. Chondroitin sulphate is usually used to construct nanocarriers in the following ways: (1) As a surface material, it is used to modify the surface of other particles to improve the stability and biocompatibility of nanocarriers and to enhance tumor targeting. For example, chondroitin sulfate can be modified on the surface of gold nanoparticles, iron oxide nanoparticles, magnetic nanoparticles, etc. (2) As the skeleton of nanocarriers, it is grafted with other macromolecular polymers. At present, research on chondroitin sulphate-chitosan is relatively extensive. In addition, chondroitin sulfate-polyethyleneimine (PEI) polymer can also be used as a gene carrier to achieve drug delivery. (3) As the skeleton of nanocarriers, they can be connected with small molecule drugs and hydrophobic groups through functional groups to form amphiphilic polymers, thereby constructing different types of nanocarriers, such as chondroitin sulfate-drug polymers, amphiphilic polymer nanoparticles, etc.
Alternate Names:
Thiolated chondroitin sulfate
Chondroitin sulfate-SH
Chondroitin sulfate-thiol conjugate
Chondroitin sulfate thiol derivative
Thiol-functionalized chondroitin sulfate
Chondroitin sulfate-SH conjugate
References:
1. Raúl Benito-Arenas, et al.; Chondroitin Sulfate-Degrading Enzymes as Tools for the Development of New Pharmaceuticals. Catalysts. 2019, 9(4), 322.
2. Khan AR, et al.; Chondroitin sulfate derived theranostic and therapeutic nanocarriers for tumor-targeted drug delivery. Carbohydr Polym. 2020, 233:115837.
Chondroitin Sulfate Safety and Quality
Molecules
Authors: Volpi N.
Abstract
The industrial production of chondroitin sulfate (CS) uses animal tissue sources as raw material derived from different terrestrial or marine species of animals. CS possesses a heterogeneous structure and physical-chemical profile in different species and tissues, responsible for the various and more specialized functions of these macromolecules. Moreover, mixes of different animal tissues and sources are possible, producing a CS final product having varied characteristics and not well identified profile, influencing oral absorption and activity. Finally, different extraction and purification processes may introduce further modifications of the CS structural characteristics and properties and may lead to extracts having a variable grade of purity, limited biological effects, presence of contaminants causing problems of safety and reproducibility along with not surely identified origin. These aspects pose a serious problem for the final consumers of the pharmaceutical or nutraceutical products mainly related to the traceability of CS and to the declaration of the real origin of the active ingredient and its content. In this review, specific, sensitive and validated analytical quality controls such as electrophoresis, eHPLC (enzymatic HPLC) and HPSEC (high-performance size-exclusion chromatography) able to assure CS quality and origin are illustrated and discussed.
Chondroitin sulfate-based composites: a tour d'horizon of their biomedical applications
J Mater Chem B.
Authors: Abourehab MAS, Baisakhiya S, Aggarwal A, Singh A, Abdelgawad MA, Deepak A, Ansari MJ, Pramanik S.
Abstract
Chondroitin sulfate (CS), a natural anionic mucopolysaccharide, belonging to the glycosaminoglycan family, acts as the primary element of the extracellular matrix (ECM) of diverse organisms. It comprises repeating units of disaccharides possessing β-1,3-linked N-acetyl galactosamine (GalNAc), and β-1,4-linked D-glucuronic acid (GlcA), and exhibits antitumor, anti-inflammatory, anti-coagulant, anti-oxidant, and anti-thrombogenic activities. It is a naturally acquired bio-macromolecule with beneficial properties, such as biocompatibility, biodegradability, and immensely low toxicity, making it the center of attention in developing biomaterials for various biomedical applications. The authors have discussed the structure, unique properties, and extraction source of CS in the initial section of this review. Further, the current investigations on applications of CS-based composites in various biomedical fields, focusing on delivering active pharmaceutical compounds, tissue engineering, and wound healing, are discussed critically. In addition, the manuscript throws light on preclinical and clinical studies associated with CS composites. A short section on Chondroitinase ABC has also been canvassed. Finally, this review emphasizes the current challenges and prospects of CS in various biomedical fields.
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