Over the past few years, drug delivery has evolved in ways that we've not seen before, creating advanced materials to make drugs work better, stay longer, and be more specific. One such novel material is hyaluronate tyramine (HT), a cross-reactive molecule that has the biocompatibility and bioactivity of HA with the functional flexibility of tyramine. A naturally occurring glycosaminoglycan, hyaluronic acid, is well known to act on receptors on the cell surface (specifically the CD44 receptor, overexpressed in many cancerous and inflamed tissues). Conjugate HA with tyramine, a phenolic compound that can undergo oxidative reactions and form covalent bonds, and HT molecules are given extra stability and the ability to make hydrogels or cross-linked networks. This structure has many advantages for drug delivery purposes, especially targeting cancer, tissue regeneration and inflammatory diseases. Because hypaluronate tyramine can encapsulate and control the release of drugs locally or continuously, it is now at the heart of modern drug delivery systems research. Biopolymer HA has been used in medical and pharmaceutical products for decades due to its many positive properties — biocompatibility, biodegradability, and receptor-activation on cells. Most commonly, we know of HA in connective tissues, where it is used to hydrate, lubricate and support. Because it attaches to the cell's CD44 receptor – which is overexpressed in a number of diseases, including some cancers – HA is an ideal candidate for the targeting of specific tissues and cells. Yet HA in its initial formulation has some constraints regarding mechanical stability, release control and long-term storage at the site of action. When scientists chemically reformulated HA with tyramine, a phenolic group derived from the amino acid tyrosine, the result was a more versatile substance called hyaluronate tyramine (HT). Adding tyramine to HA further chemistry the polymer to a stable hydrogels via oxidative crosslinking that can greatly enhance the controlled release of therapy and stable matrix for drug delivery. This biocompatibility and functional flexibility render HT attractive for drug delivery systems that need to be continuously, selectively and locally emitted therapies. Physiologically, hydrogels produced by HT are one of the hallmarks of hyaluronate tyramine (HT) as a delivery system. It gets this hydrogel-like property, due mainly to the oxidative coupling between the tyramine groups, which can be triggered by enzymes like tyrosinase, or by light or pH. HT can be used as a depot for encapsulating drugs, proteins, nucleic acids or other bioactives once it has gelled. This hydrogel can be modified to manipulate the release of drugs, based on the level of crosslinking, the therapeutic agent, and the environmental conditions at the site of administration. So, for example, for cancer therapy, the HT-based hydrogel could be squirted into a tumor, and it would over time breakdown and release the encapsulated drugs, providing a more localised and regulated therapy that had minimum overall toxicity. What's more, because HT is biodegradable, it will disintegrate within the body without needing to be removed or leaving any adverse long-term effects. It is because of this biodegradability, coupled with its hydrophilic nature, that HT-based systems can be utilized for a host of therapeutic needs, from wound treatment, to anti-inflammatory therapy, to gene therapy.
Figure 1. Tyramine modified HA hydrogel. (Fei Xing, et al.; 2020)
Hyaluronate tyramine is also broadly used in other drug delivery systems such as cancer treatment, regenerative medicine and inflammatory diseases. The selective target-binding by the CD44 receptor-mediated signalling is a real plus in cancer therapy. Using the HT hydrogels to pack chemotherapeutics, the drugs could be released directly at the tumor site for greater local efficacy and less systemic side effects. The process also permits the time-controlled delivery of drugs that may prevent the drug from being rapidly excreted from the body. Also, HT systems can be customised to recalcitrate against the acidic tumor microenvironment, initiating gelation, and so releasing the drug only when it reaches the targeted site, which increases treatment specificity. Regenerative medicine has been a field where HT-based drug delivery systems have been useful for tissue engineering and wound healing. Because hyaluronate tyramine is able to generate hydrogels analogous to tissues' ECM, it's an ideal material to develop scaffolds for the growth of cells and regeneration of tissue. Such hydrogels can be infused with growth factors, cytokines or other biomolecules for cell growth and tissue repair. This selective release of these biomolecules from HT scaffolds can improve wound healing, tissue repair and aid in the repair of damaged tissues in burns, diabetic ulcers or cartilage damage. In addition, HT hydrogels can be engineered to breakdown with a controlled pace so that the scaffold remains in place for optimal repair and growth of tissue for the maximum amount of time it takes to safely biodegrade. In inflammation-related conditions, HT-based drug delivery systems can deliver local, long-term administration of anti-inflammatory medication right at the source of inflammation. Rheumatoid arthritis, osteoarthritis, inflammatory bowel disease: anti-inflammatory drugs could be given to these patients on a targeted basis to avoid the need for a full-body drug and its side effects. The high sensitivity for inflammatory targets and controlled release capability of HT-based hydrogels make this technology ideal for chronic inflammatory diseases. The prolonged duration of drug action could be increased by carrying agents in HT, and hence the patients suffering from these refractory diseases could have better outcomes.
Alternate Names:
Tyramine-Modified Hyaluronate
Tyramine-Conjugated Hyaluronic Acid
Hyaluronic Acid-Tyramine Conjugate
Tyramine-Hyaluronan Complex
Tyramine-Functionalized Hyaluronate
Hyaluronate-Tyramine Adduct
Tyramine-Hyaluronate Polymer
References:
1. Fei Xing, et al.; Hyaluronic acid as a bioactive component for bone tissue regeneration: Fabrication, modification, properties, and biological functions. Nanotechnology Reviews. 2020, 9(1):1059-1079
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