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Description
Ischemic stroke is one of the major causes of death or long-term disabilities worldwide; thus, prevention and treatment of neurodegenerative diseases and stroke-related brain damage, being still largely unresolved problems of contemporary medicine, require new technologies for diagnostics and therapeutics. One of the major limitations to current neurodegenerative disease treatment is an inefficient delivery of neuroprotective drugs to the affected part of the brain due to the blood-brain barrier (BBB) that is permeable only by small, lipophilic molecules. Additionally, some of the orally delivered neuroprotective drugs may influence the whole organism, thus causing peripheral toxicity and numerous adverse reactions. Therefore, despite the progress in understanding molecular mechanisms of neuronal injury and preventing them, only few neuroprotective substances are used in the clinic and their efficiency in the treatment of stroke and neurodegenerations is still not satisfactory. The main project objective is to develop the new strategy of delivery of selected neuroprotectants by theranostic nanocarriers that can cross the blood-brain barrier without imposing side effects on its normal function. We will concentrate on developing methodology of encapsulation of neuroprotectants and fluorescent or MRI contrast agents in nanocarriers with the size below 150 nm and surfaces functionalized for targeted delivery. Immunosupressant drugs such as cyclosporine A (CsA) and FK506 are neuroprotective in animal models of brain ischemia. CsA inhibits the opening of the mitochondrial permeability transition pore, thereby maintaining mitochondrial homeostasis following brain ischemia by inhibiting calcium influx and preserving mitochondrial membrane potential. However, high systemic doses of these drugs result in undesired effects and toxicity.
Summary of project results
Prevention and treatment of neurodegenerative diseases and stroke-related brain damage are major and unresolved problems of contemporary medicine. Despite the progress in understanding the molecular mechanisms of neuronal injury and preventing them, only a few neuroprotective substances are used in the clinic, and their efficiency in the treatment of stroke and neurodegenerations is not satisfactory. One of the major limitations to current neurodegenerative disease treatment is an inefficient delivery of neuroprotective drugs to the affected part of the brain and difficulties in the diagnosis if the drug is well addressed, i.e., if it reaches the targeted organ. Theranostics is a new branch of medicine based on the joining of therapeutic and diagnostic functions in one entity. By the application of nanotechnology in theranostics, we can address the problem of developing drug carriers to simultaneously deliver therapeutic components and possess a diagnostic function, which can be used in the future in therapies for stroke and neurodegenerative diseases, like Parkinson''s, Alzheimer''s, or schizophrenia.
The main objective of the project was to develop a new strategy to deliver neuroprotectants by applying theranostic nanocarriers for neuroprotective drugs, which are able to cross the blood-brain barrier without imposing side effects on its normal function and can be detected in a given part of a brain by Nuclear Resonance Imaging (MRI).
In the project we applied various methodologies of encapsulation of neuroprotective drugs together with fluorescent or MRI contrasting agents. Additionally, we developed the silica nanostructures-based nanocarriers as well as nanoparticles with the inherent neuroprotective function. The obtained nanocarriers/nanoparticles were examined for their toxic effect, the ability to cross the model blood-brain barrier, and the possibility of carrying effective MRI or fluorescence contrast agents.
We successfully synthesized nanocarriers and nanoparticles with the required size below 200 nm. They were either polymeric nanocarriers containing selective neuroprotective drugs (Ederavone, Ebselen, and Carnosic Acid) or cerium oxide (CeO₂) nanoparticles. The in-vitro experiment demonstrated that they were non-toxic, exhibited neuroprotective activity, were able to cross the model blood-brain barrier, and could be precisely localized by the MRI or fluorescence. The fluorescently labeled nanocarriers were used in the in-vitro cell tests of neuroprotective activity of encapsulated drugs and ex-vivo test of their localization in the brain, whereas nanocarriers with MRI contrasts were aimed to be used in the in vivo tests on animal models allowing real-time tracking of drug distribution
The results of the project can contribute to the development of the basic knowledge of the efficacy, pharmacokinetic properties, and mechanism of action of selected neuroprotectants. Combining nanotechnological, neurochemical, and pharmacological approaches can provide new prototypical drug formulation with translational value for potential use in neurological clinics with potential implications for treating stroke, Alzheimer’s, and Parkinson’s disease. Moreover, the experience gained from the project can open research in various fields where the co-encapsulation technology of various compounds can find application, e.g. cosmetics, veterinary, agriculture (plant protection), etc.
Summary of bilateral results
Project was realized in collaboration between Polish and Norwegian istitutions as follow: Polish partner (ICSC) was mainly involved in the development of multilayer nanocarriers containing oil-soluble neuroprotectants, Ederavone, Ebselen (EB), and carnosic acid (CA) and their synthesis was supported with the competence of Norwegian partner (SINTEF) concerning NMR analysis of PEG grafted polyelectrolytes; SINTEF was responsible for synthesizing neuroprotective CeO2 nanoparticles and POSS-based contrast agents. The synthesized nanoparticles were characterized by Polish partners: (i) biosafety and neuroprotection by Institute of Pharmacology) and (ii) MRI contrasting properties by the Institute of Nuclear Physics. The second Norwegian (OUH) partner provided their expertise in the fluorescence staining of nanocarriers, determination of fluorescent properties and the application of confocal microscopy for in-situ detection of nanocarriers. It is stated in the report, that the application for future funding will be realized when appropriate call is announced (ERA-NET, HORIZON EUROPE, NCN)