Dottorato in SCIENZE FARMACEUTICHE

Titolo della tesi: Hyaluronan-Based Nanohydrogels as a Tool for New Applications in Drug Delivery

Polysaccharides are regarded as highly attractive and promising natural biomaterials for a wide range of biomedical applications, due to their excellent biocompatibility, biodegradability, and distinctive bioactive properties. Among them, hyaluronic acid (HA), one of the anionic polysaccharides, naturally occurs in various soft connective tissues such as synovial fluid, vitreous humour, and skin. Advances in nanotechnology have led to the rapid development of nanogels in crossing biological barriers as well as improving therapeutic effects according to effective drug delivery systems. HA-based nanogels have solicited great interest as carriers in drug delivery systems, particularly for treating cancer and other inflammation-related diseases. This is primarily due to the exceptional properties of HA-based nanogels and their ability to specifically target CD44 receptors. An optional strategy for both nanogel preparation and drug loading involves the hydrophobic modification of the HA chain. Cholesterol (CH) is a prime candidate for providing hydrophobic moieties to HA derivatives, given its favourable physicochemical properties and natural presence in the human body. The aim of this work was to develop HACH-based nanogels for effective drug encapsulation and explore their potential applications in overcoming biological barriers in both the cornea and the skin. In pursuit of further objectives, some modification of the nanogel system was also conducted. The thesis encompasses two literature reviews and three experimental studies. The structure of this thesis is outlined as follows: Chapter 1 introduces the applications of natural biomaterials in drug delivery systems, with a particular focus on HA-based carriers. This chapter also provides an overview of the objective and the outlines of this thesis. Chapter 2 summarizes recent advancements in the field of polysaccharide-based nanogels focused on overcoming key biological barriers, including mucin, cornea, skin, and the blood-brain barrier. Chapter 3 discusses the various strategies for loading therapeutics into polysaccharide-based nanogels. Chapter 4 presents experimental studies that explore the feasibility of enhancing ocular drug delivery of both hydrophilic (tobramycin) and hydrophobic (dexamethasone) drugs using HACH nanogels. Chapter 5 delves into experimental studies on HACH nanogels for application in topical dermal delivery of betamethasone, specifically for the treatment of psoriasis. Chapter 6 focuses on experimental studies regarding physicochemical property modifications of HACH nanogels, providing a strategy to modulate the stiffness of soft nanogels with the aim of enhancing drug delivery efficiency. Chapter 7 summarizes the key findings of the thesis and provides perspectives for future research directions.