Hyaluronic acid (HA) is a glycosaminoglycan widely present in the human body. HA is the main component of the extracellular matrix and plays an important physiological role in the human body. In recent years, it has been used more and more widely in medical fields such as arthritis treatment, surgical operations, and drug development. HA is a natural polysaccharide composed of glucuronic acid and N-acetylglucosamine repeatedly connected by β-1, 3 and β-1, 4 glycosidic bonds. The natural HA has poor stability and a short biological half-life, which limits its application. To overcome these problems, HA can be modified to improve its stability and obtain derivatives with other excellent properties. At present, HA has become a hot spot in drug delivery research. HA and its derivatives can be used as sustained-release carriers for drugs, mainly by utilizing their high viscoelasticity, plasticity, non-immunogenicity, good biocompatibility and degradability. HA and its derivatives can specifically bind to specific cell surface receptors, such as CD44, RHAMM, LYVE-1 and HARE, etc. These receptors are widely present in certain specific tissues, such as liver, kidney, lymphatic vessels and most tumor tissues. The specific binding of HA and its derivatives to their receptors can serve as the basis for HA targeted drug delivery. HA and its derivatives can be used as delivery carriers for proteins, peptides, nucleic acids and various anticancer drugs.
Figure 1. The role of hyaluronic acid as a platform for cell and drug delivery in the IVD.(Zepur Kazezian, et al.; 2020)
HA is a natural polysaccharide. As a biomaterial, it has good biocompatibility and degradability. However, HA is sensitive to strong acid, strong base, heat, free radicals and hyaluronidase, and is easily degraded in the body and has a short biological half-life. These defects limit the application of HA in drug delivery systems. With the development of drug delivery systems and related disciplines, HA can be modified to improve its stability while retaining its excellent properties. There are currently two commonly used methods: one is to directly chemically modify HA; the other is to prepare HA gel. Before chemically modifying HA, HA with high relative molecular mass should first be degraded into oligosaccharides or oligosaccharides. The degradation can be achieved by ultraviolet rays, ultrasound, enzymatic hydrolysis and other methods. HA can introduce various functional groups by modifying the side groups. There are four sites in HA that can be chemically modified: carboxyl, hydroxyl, reducing end and N-acetylamino. For example, in order to introduce amino groups into HA, one end amino group of adipic acid dihydrazide (ADH), hexamethylenediamine (HMDA) or cystamine can be used to react with the carboxyl group of HA to form an amide bond to introduce amino groups. Currently, most of the HA derivatives with clinical value reported are modified with carboxyl groups, because the carboxyl group of HA is the recognition site of HA receptors and hyaluronidase. The biological properties of HA in vivo can be changed by modifying the carboxyl group of HA. If a cross-linking agent is used in the chemical modification of HA, the ratio of the cross-linking agent to HA should be controlled to avoid the formation of HA gel.
HA and its derivatives have good biocompatibility and degradability, and can be used as sustained-release carriers for drugs. The sustained-release effect of HA is determined by its molecular characteristics. After appropriate cross-linking of HA, the molecular chain grows, the average relative molecular mass increases, and a "supramolecular cage" is formed, thereby slowing down the release of drugs dispersed therein and achieving sustained-release of drugs. HA and its derivatives can be used as sustained-release carriers for a variety of drugs, such as anti-tumor drugs, anti-inflammatory drugs and anesthetics, etc. HA is used in various forms as a carrier for drugs. The main receptors of HA in the body are CD44, HA-mediated cell migration receptor (RHAMM), lymphatic endothelial hyaluronic acid receptor (LYVE-1) and hyaluronic acid endocytosis receptor (HARE), among which CD44 and RHAMM are mainly distributed in tumor tissues, LYVE-1 is mainly distributed in lymphatic endothelium, and HARE is mainly distributed in liver sinusoids, spleen blood sinusoids and medullary sinus of lymph nodes. By utilizing the specific binding properties of HA and its receptors, HA can be used as a carrier or targeting ligand to deliver drugs to specific organs or tissues. At present, the most applied research is the specific binding of HA to CD44.
Alternate Names:
Hyaluronan
Sodium hyaluronate
Hyaluronate
Glycosaminoglycan
Hyaluronic acid sodium salt
Polysaccharide HA
Hyaluronic acid
References:
1. Zepur Kazezian, et al.; The Role of Hyaluronic Acid in Intervertebral Disc Regeneration. Applied Sciences. 2020, 10(6257).
Hyaluronic acid in ocular drug delivery
Carbohydr Polym.
Authors: Zhang X, Wei D, Xu Y, Zhu Q
Abstract
As a naturally-occurring polysaccharide which could be found in various ophthalmic tissues, hyaluronic acid (HA) has a wide range of applications in the eye, including treatment of dry eye, vitreous substitutes and ophthalmic viscosurgical devices. Besides that, HA can be used as an effective drug carrier for ocular disease treatment due to its excellent biocompatibility, biodegradability, bioadhesion properties, viscoelasticity and receptor interaction characteristic. This review summarizes recent advances in HA-based drug delivery systems for ocular disease treatment in which it could be used as drug-polymer conjugate, drug carrier substrates, and surface modifications of the carrier. To achieve the optimum drug delivery efficacy under varied ophthalmic diseases, the molecular weight (MW) and amount of HA should be selected rationally and applied to design diverse delivery systems.
Hyaluronic acid: A review on its biology, aspects of drug delivery, route of administrations and a special emphasis on its approved marketed products and recent clinical studies
Int J Biol Macromol
Authors: Vasvani S, Kulkarni P, Rawtani D
Abstract
Hyaluronic acid (HA) is a large non-sulphated glycosaminoglycan that is an important component of extracellular matrix (ECM) and a biodegradable polymer. Due to a variation in its molecular weight, HA derivatives can be utilized to make different formulations like fillers, creams, gels and drops. HA based drug research has seen a recent surge largely due to some properties like mucoadhesion, biocompatibility and ease of chemical modification. Such properties of HA have led to applications in tissue regeneration, anti-aging and anti-inflammatory medications. HA can be conjugated, functionalized or used as a nanocarrier supplement with a definite increase in its cellular uptake and efficiency. HA when encapsulated in a nanocarrier may help to improve the ECM growth and provide a sustained release of agents. This review discusses the mechanistic behavior of HA pertaining to its biological synthesis and degradation. It also discusses the administration of some noteworthy and recent HA based formulations through different routes for application in various physiological conditions along with their ongoing clinical trial updates and approved marketed products.
Hyaluronic acid and albumin based nanoparticles for drug delivery
J Control Release
Authors: Lei C, Liu XR, Chen QB, Li Y, Zhou JL, Zhou LY, Zou T
Abstract
Albumin, a multifunctional protein, is widely used to prepare nanocarriers. Hyaluronic acid (HA) is a natural glycosaminoglycan that can specifically bind receptors, such as cluster of differentiation-44. Therefore, HA is commonly used as ligands for the surface modification of versatile nanocarriers. The combined utilization of albumin and HA as nanocarriers shows outstanding superiorities including efficient targeting, reducible particle size, pH and/or hyaluronidase sensitive drug release, combining capacity for various drugs, biocompatibility, non-immunogenicity, biodegradability and high stability. However, to the best of our knowledge, HA and albumin based nanoparticles have not been reviewed for drug delivery so far. This review involves the introduction of the essential information of HA and albumin as well as a brief presentation of the preparation methods of HA and albumin based nanocarriers. Moreover, the application of HA and albumin based nanoparticles as drug delivery carriers in tumors, joints, vitreum and skin tissue is systematically discussed with the potential and prospect in combined therapy and theranostics. In addition, the unique advantages of the HA and albumin based nanoparticles and their contributions to the improvement of drug delivery systems are further expounded in detail.
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