Silvestri, Teresa (2022) Biodegradable microparticles for the treatment of posterior eye segment diseases. [Tesi di dottorato]

	Text Silvestri_Teresa_COMPLETO.pdf Visibile a [TBR] Repository staff only Download (2MB) | Request a copy
Preview	Text Silvestri_Teresa_PARZIALE.pdf Download (2MB) | Preview

Collection description

The present research activity concerns the design and development of biodegradable microparticles (MPs), intended as controlled drug delivery systems for the treatment of posterior eye segment diseases. These pathologies, including uveitis, diabetic retinopathy, endophthalmitis, proliferative retinopathy, age related macular degeneration and glaucoma just to cite a few, are generally chronic and degenerative, leading in some cases to blindness. These diseases can be treated basically through four routes of administration: topical, systemic, intraocular, and periocular [4]. The topical, systemic and periocular routes do not allow to obtain therapeutically effective drug concentrations in the action site, due to the different biological barriers (e.g., water-blood barrier and blood-retinal barrier, tear dilution, conjunctive/choroidal blood flow and lymphatic clearance), which entail the need of high doses to achieve therapeutic drug levels in the eye. Thus, despite its invasiveness, the intravitreal (IVT) injection is the preferred route of administration to date because it allows the delivery of the therapeutic agents by the target site and the chance to achieve a more effective control of drug concentration within the intravitreal space. Nevertheless, some chronic conditions affecting the posterior chamber of the eye require repeated and frequent injections which cause serious complications such as retinal detachment, cataracts, hemorrhages and endophthalmitis, with an increasing risk of occurrence with increasing number of injections. In this scenario, research activity has been oriented towards the development of several systems for controlled drug release system based on biodegradable polymers such as gels, nanoparticles and microparticles (MPs). The latter, when introduced in the vitreous humor or in the periocular space, generally allow a sustained release of the encapsulated drug(s). Here, biodegradable microspheres based on PLGA (polylactic-co-glycolic acid) for prolonged intraocular drug delivery have been designed and developed. The main hypothesis is that long-acting drug delivery systems may help increasing the time interval between two consecutive injections, enhancing patient compliance and reduce the risk of unwanted effect insurgence. It must be highlighted that the intravitreal injection of MPs can cause their free diffusion into the intravitreal space, with a probable blurring of the visus. Also, PLGA MPs are intrinsically lipophilic, and therefore they can easily undergo aggregation, with an evident detriment of MP ability to control the release kinetics of the loaded drug(s). Therefore, MPs were externally decorated with hyaluronic acid (HA), which has been chosen as it is the main constituent of the vitreous body. The central hypothesis of this doctoral thesis is that an increase in affinity between MPs and the vitreous body discourages MP spontaneous diffusion in the eye as well as their aggregation. The MPs were produced with the double emulsion technique and, to physically bind HA to the external surface of the microdevices, the formulation procedure required the use of poloxamers as a physical bridge between lipophilic PLGA and hydrophilic HA. In a pilot phase of the work, with the intention of defining the optimized formulation, MPs were produced under different formulation conditions and loaded with BSA as a model protein. In the view of a possible translation of the production method to the industrial reality, different organic solvents to meet the regulatory requirements for human use of the MPs were evaluated. Additionally, the use of different cryoprotectants (namely trehalose, glucose, sucrose and mannitol), was investigated in the perspective of improving the re-suspension of MPs in water immediately before injection. Lastly, in vitro and in vivo biological characterization was performed with the focus on glaucoma. For this purpose, the selected formulation was loaded with palmitoylethanolamide (PEA), Citicoline (CIT) and Glial cell-derived neurotrophic factor (GDNF). These molecules were chosen for their expected neuroprotective effect on injured retina and tested in vitro on Human Retinal Pigment Epithelial Cell line (ARPE-19), and in vivo on a glaucoma animal model to assess MP safety of use and therapeutic effect.

Downloads

Actions (login required)

View Item