The doctoral dissertation in the field of Drug Research will be examined at the Faculty of Health Sciences. The public examination will be streamed online.
What is the topic of your doctoral research? Why is it important to study the topic?
Ophthalmic drug treatment is a rapidly growing field. Based on the report from WHO, overall 2.2 billion people suffer from some sort of visual impairment (WHO, 2019). A major fraction of these patients suffers from refractive errors, but a considerable number suffer from serious ocular disease that may lead to sever or permanent vision impairments. For example, the global number of patients suffering from aged related macular degeneration (AMD), diabetic retinopathy and glaucoma was 196, 146 and 76 million by 2020, respectively. Many of these like AMD or glaucoma are age related diseases which their frequency is increasing because of population aging. In order to treat many of these diseases, it is relevant to deliver the drugs to the retina. Because of tight barrier in the anterior part of the eye, the most efficient route of drug delivery for the retinal disease is intraocular injections.
My doctoral research is related to the field of ocular pharmacokinetics. Pharmacokinetics is the science to assess the journey of drug molecules in the organs after administration. It consists of four stages: absorption, distribution, metabolism, and excretion. Ocular pharmacokinetics will help us to estimate the dose of drugs and the administration intervals. In my thesis, the intravitreal pharmacokinetics of macromolecules and nanomaterials were assessed in the preclinical species. The pharmacokinetic insight provided by my thesis will be useful for development of retinal drug delivery systems.
What are the key findings or observations of your doctoral research?
Pharmacokinetics is especially important in the case of intravitreal drug administration that is used in the drug treatment of retinal diseases. In this research, we utilized non-invasive optical techniques to assess the vitreal pharmacokinetics of labelled compounds and nanomaterials in preclinical animal models. The kinetics of different labelled macromolecules and nanoparticles were studied after intravitreal injection into the eyes of rats and rabbits. In vivo luminescence imaging revealed the suitability of phosphorescence dyes in monitoring the pharmacokinetics of labelled liposomes in the eyes. Furthermore, new dyes can improve the signal-to noise ratio in autofluorescent tissues. In vivo ocular fluorophotometry was used to monitor the kinetics of intravitreally injected fluorescently labelled dextran in rats and rabbits. Based on this comparison, the same drug exposure is achieved at 2-5 times higher doses in rabbits than in the rats.
The intravitreal pharmacokinetics of fluorescently labelled peptide conjugates in the rabbit eye were also studied using fluorophotometry. These peptides bind to the components of the vitreous and this may lead to nonlinear pharmacokinetics, in which the half-life of the peptide in the vitreous is dependent on its concentration, being longer at low concentrations. The introduced computational model can be useful to study the pharmacokinetics of compounds with the specific affinity for vitreal compounds.
The intravitreal distribution and elimination of fluorescently labelled nanomaterials, such as liposomes, polymeric micelles, polymersomes and pullulan-dexamethasone conjugates, were explored with ocular fluorophotometry, fundus photography and optical coherence tomography. Pullulan-dexamethasone conjugates and small liposomes (diameter of ≈50 nm) were mainly eliminated via the anterior route. The results also revealed that the intravitreal retention was not simply dependent on particle size. For example, polymeric micelles were eliminated from the vitreous much slower than liposomes of similar particle sizes.
Simulations of drug concentrations after injection of intravitreal particles with different release rates highlighted the importance of synchronizing the particle retention and drug release rate to optimize retinal drug bioavailability. In addition, we observed that material contamination with endotoxin significantly accelerated elimination of nanomaterials from the vitreous. The measurement of endotoxin levels in intravitreal nanomaterials was a critical factor which has been almost completely disregarded in the published studies. In conclusion, we provide kinetic insights into intravitreally administered nanoparticles and macromolecules that can be used in future in the development of novel retinal drug delivery applications
What are the key research methods and materials used in your doctoral research?
In this research we applied noninvasive optical techniques to evaluate intravitreal kinetics of macromolecules and nanomaterials in periclinal animals. The applied methods were optical coherence tomography, fundus imaging and in vivo ocular fluorophotometry. Since these techniques are non-invasive, multiple measurements per subject will be possible which has advantages considering the principles of the 3Rs (Replacement, Reduction and Refinement). Moreover, since multiple measurements is possible per subject, assessments of within subject variability is also possible.
The doctoral dissertation of Amir Sadeghi Boroujeni (PharmD), entitled Characterizing Intravitreal Pharmacokinetics of Macromolecules and Nanoparticulate Systems Using Non-Invasive Fluorescence and Optical Techniques, will be examined at the Faculty of Health Sciences. The Opponent in the public examination will be Professor Francine Behar-Cohen from Université Paris Descartes, and the Custos will be Professor Arto Urtti from the University of Eastern Finland. The public examination will be held in English.
