Hyaluronic Acid Bioconjugates for the Delivery of Bioactive Molecules

Abstract

Hyaluronic acid (HA) has currently several therapeutic applications: in ophthalmology, osteoarthritis, wound healing, tissue regeneration, postoperative anti-adhesion and anesthetic medicine. In the last ten years, it has also been successfully investigated in the field of drug delivery, in the form of conjugates or hydrogel depot systems. HAylation, the covalent conjugation of HA to bioactive molecules, allows the overcoming of disadvantages associated with some pharmaceuticals, such as insolubility, instability and fast kidney clearance. These issues can be addressed also by covalent attachment of polyethylene glycol (PEGylation), but HA has the relevant advantages of biodegradability, high loading and specific targeting. In this review, the novel HA derivatives and the latest advances in HA-based drug delivery with a particular focus on the chemistry of conjugation will be discussed. Although, so far, there are no HA-drug conjugates on the market, several derivatives are presently under clinical investigation, and the promising results encourage further investigations and the exploitation of this versatile polysaccharide.

Hyaluronic Acid in the 3^rd Millennium

“…However, since HA has a short half-life in the blood, the majority of HA-drug conjugates have been developed for local -i.e. intraarticular, intratumoral, subcutaneous, intravesical, intraperitoneal-rather than systemic administration [179]. For instance, a variety of antinflammatory drugs, including hydrocortisone, prednisone, prednisolone and dexamethasone, have been conjugated to HA and investigated for intra-articular therapy of arthritis [166].…”

“…Hence, HA conjugated curcumin may be useful to treat diabetic wounds [182]. Finally, the most promising and thoroughly studied conjugations of active ingredients to HA involve antitumoral agents, which can be strategically carried to malignant cells by hyaluronan, as explained in the subsection 6.2 [179,183].…”

“…Hence, the receptor CD44 has been identified as potential target in cancer therapy, and hyaluronan, its primary ligand, has been recognized as powerful tool to develop targeted therapies [54,198]. Many researches have shown that HA can act as drug carrier and targeting agent at the same time, under the form of polymer-antitumoral conjugates, or delivery systems encapsulating anticancer drugs [179]. Additionally, hyaluronan can be employed to design surface-modified nanoparticles [196][197][198] or liposomes [184][185][186][187][188].…”

“…Additionally, hyaluronan can be employed to design surface-modified nanoparticles [196][197][198] or liposomes [184][185][186][187][188]. After CD44 receptor-mediated cell internalization, all these HA derivatives are hydrolyzed by intracellular enzymes and, therefore, drugs are released inside the cancer target cells [179]. This should improve the pharmacokinetic profile and the delivery process of many anticancer drugs, overcoming the limitations that reduce their clinic potential, such as low solubility, short in vivo half-life, lack of discrimination between healthy and malignant tissues, consequent off-target accumulation and side effects [54,179].…”

“…After CD44 receptor-mediated cell internalization, all these HA derivatives are hydrolyzed by intracellular enzymes and, therefore, drugs are released inside the cancer target cells [179]. This should improve the pharmacokinetic profile and the delivery process of many anticancer drugs, overcoming the limitations that reduce their clinic potential, such as low solubility, short in vivo half-life, lack of discrimination between healthy and malignant tissues, consequent off-target accumulation and side effects [54,179]. Up to now, there are no HAantitumoral conjugates and anticancer loaded carriers of HA on the market; however, the promising results of many researches and clinical trials outline their potential and encourage further studies [54,179].…”