Abstract
This research aimed to improve how we treat eye diseases, like, macular degeneration, diabetic retinopathies, and ocular inflammation. The focus of the thesis was on discovering improved methods to deliver medication to the eye without the need for frequent injections. The study centered on the development of new materials such
... read more
as hydrogels and micelles, to either extend the duration of drug effectiveness in the eye or reach deeper into the retina. The thesis comprised various sections discussing the creation of these new materials.
Chapter 2 highlights hydrogel formulations for intravitreal protein delivery to the posterior segment of the eye to improve therapeutic outcome and patient compliance. The rational design of intravitreally administered drug delivery systems, both preclinical and clinically investigated, is extensively discussed. The currently used polymers, crosslinking mechanisms and methods, in vitro/in vivo models, preclinical and clinical advancements are discussed together with the limitations and perspectives of these biomaterials.
Chapter 3, the Diels-Alder (DA) reaction was exploited to crosslink hyaluronic acid-bearing furan groups (HAFU) with 4-arm PEG10K-maleimide (4APM) to yield hydrogels that enable sustained release of bevacizumab, a clinically used therapeutic protein for ocular therapy to treat patients suffering from macular degeneration. The effects of polymer composition and the ratio between functional groups on the physicochemical properties of hydrogels were systematically investigated, together with intravitreal gel stability and protein release kinetics.
Chapter 4 describes the in vivo pharmacokinetic profile and ocular safety of hyaluronic acid-PEG-based DA in situ forming hydrogels for sustained intraocular delivery of bevacizumab to investigate the suitability of this formulation for ocular therapies.
Chapter 5 introduces a novel in situ forming thermosensitive hydrogel system based on two thermosensitive ABA triblock copolymers bearing either furan or maleimide moieties. The formulation was designed to rapidly form a polymer network at body temperature by physical self-assembly of the thermosensitive blocks. The rapidly formed physical network is subsequently stabilized by the DA chemical crosslinking in the hydrophobic domains of the polymer network. The sustained release of an anti-VEGF antibody fragment with or without the corticosteroid dexamethasone was investigated to get insight into the potential of the system as an intraocular drug delivery system.
Additionally, in Chapter 6, an injectable DA core-crosslinked flower-like micelle formulation was designed using previously developed thermosensitive ABA block copolymers (where A represents a thermosensitive block and B represents a permanently hydrophilic block). This design aims to enhance retinal tissue penetration and intracellular drug delivery, potentially making it useful in ocular therapy. Preliminary ocular safety and particle kinetics were evaluated in a rat eye model.
Finally, Chapter 7 provides a summarizing discussion of the findings of the research chapters of this thesis, together with recommendations for further improvements and industrial development.
This research holds significant promise as it has the potential to revolutionize the treatment of eye problems by improving how medications reach and stay within the eye. This progress marks an exciting step forward in enhancing the effectiveness of eye treatments and could significantly impact future eye care.
show less
