Project 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 the 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 a few neuroprotective substances are used in the clinic, and their efficiency in the treatment of stroke and neurodegenerations is still not satisfactory. The targeted and monitored delivery of neuroprotectants with the right dosage is a crucial issue in the treatment of central nervous system disorders.

The main project objective is to develop a new strategy for the 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 a methodology of encapsulation of neuroprotectants and fluorescent or MRI contrast agents in nanocarriers with a size below 150 nm and surfaces functionalized for targeted delivery. Immunosuppressant 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. Thus, we expect that nanocarriers could be useful for the efficient delivery of CsA or other neuroprotective drugs to cerebral ischemic tissue.

The proven technique of formation of core-shell nanocarriers by sequential adsorption of nanoobjects will be applied for the encapsulation of neuroprotectants and contrast agents. The hydrophobic drugs will be placed in the nanoemulsion or biocompatible polymer core. The MRI contrast agents’ superparamagnetic iron oxide nanoparticles (SPION) or Gadolinium complexes will be mainly located in the carrier shell. The effects of the most promising neuroprotectants in the theranostic formulations on the viability of neuronal cells exposed to toxic agents and oxygen-glucose deprivation will be first examined in SH-SY5Y cell line, primary cortical neurons, and organotypic hippocampal slice culture. Then, the efficiency of the transfer of nanocarriers in the “in vitro” and ex-vivo” model of BBB will be investigated. In-vivo experiments will be performed to determine the biodistribution of nanocarriers and the efficiency of transport to the brain. At the final stage of the project, the effect of the nanocarriers containing neuroprotectants will be tested in the middle cerebral artery occlusion (MCAO) stroke model, followed by 48 h reperfusion in rats. Our approach is universal and can be used for the simultaneous encapsulation of therapeutics for other diseases (e.g., cancer) and MRI contrast agents for concurrent therapy and monitoring its efficiency. The ultimate outcome of the project will be the application of the developed concepts of neuroprotectants delivery in therapies for neurodegenerative diseases to ensure an improvement in the health condition of society.