The research within the OCUTHER consortium can be divided into three work packages. First, tools for ocular drug and delivery system design and testing is developed. Secondly, drug delivery systems are designed and tested for their pharmaceutical properties. Third, the biological properties of the delivery systems and drug candidates are being tested with preclinical models. The target diseases are retinal pathologies, which are treated in the experiments using drug administration into the vitreous of the eye, blood stream and surface of the eye. The project has progressed at all levels.
A range of different experimental and computational methods have been developed to augment ocular drug development. This includes pharmacokinetic non-invasive fluorescence methods to monitor drug and delivery system kinetics in the eyes, methods set up for the studies of expression proteins that may affect ocular distribution and elimination of drugs. Furthermore, the model structures and related mathematics of have been generated for ocular pharmacokinetics. Importantly, we have determined the dose scaling factors for intravitreal drug administration between rat, rabbit and human. The work towards pharmacodynamic test methods so far includes cell model work on autophagy in age-related macular degeneration, and methods for measuring retinal inflammation and immunological responses.
Pharmaceutical development of drug delivery systems has progressed in many respects. Delivery systems have been generated based on many technologies, including prolonged action gels, soluble polymeric conjugates, magnetic nanoparticles for topical administration, ultrasound activatable systems for targeted drug release, and nano-sized polymeric assemblies, liposomes and protein cages for cellular drug targeting. The studies have been concentrated so far on optimization of pharmaceutical properties, such as size, charge, stealth-coating , labeling, stability and drug loading to the particles. Some delivery systems have shown prolonged release, promising dosing intervals of even a year. On the other hand, some pullulan conjugates showed cell specific delivery in the retina.
Biological testing of drug delivery materials has been done using toxicological cellular methods and in some cases mobility and interactions of the particles have been investigated using ex vivo vitreal models. Polymeric assemblies (micelles, polymersomes, conjugate, magnetic nanoparticles) have been studied also in vivo in rats and rabbits and they showed prolonged retention in the vitreous after injection. New drug candidates and delivery methods have been tested using cellular methods. For example, VCP inhibitors demonstrated neuroprotective effects in retinal explant cultures.
Overview of the results. OCUTHER project has generated generalizable results that are useful for ocular drug developers at international scale (e.g. enzyme activities, kinetic parameters in different species). Furthermore, the tools of OCUTHER project will be utilized in drug development, such as inter-species dose scaling factors and pharmacokinetic models. We have developed several ocular drug delivery systems that are promising for the delivery of poorly soluble drugs, retinal cell based targeting and prolonged action and longer drug dosing intervals. New drugs for the retinal regeneration have been investigated and their efficacy was improved with the delivery systems. The project consortium includes many companies that offer potential avenues for further exploitation. Project results have been disseminated in various conferences, public events, newsletters and publications.
