Preventing secondary damage after brain lesion – novel macromolecular transport and membrane-anchoring systems for neuroprotective substances

• Applicant: Johanna Elter
• Subject Area: Polymer Materials
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 502192318

The long-term goal of this project is the development of nanoparticles that are able to transport GCPII (glucose carboxypeptidase II)-inhibitors through the blood-brain barrier.The inhibition of GCPII leads to a decreased expression of glutamate in the brain. An excess of glutamate in the brain can lead to excitotoxicity, that means, cell damage or cell death by continuous excitation of neurons. Different brain lesions can lead to glutamate-induced secondary brain damage, which could be prevented if GCPII-inhibitors would be used as medication. Nevertheless, the free inhibitor is not able to cross the blood-brain barrier. Therefore, suitable drug formulations have to be developed.This project aims to develop polymer-stabilized lipid nanoparticles carrying GCPII-inhibitors on their surface. Lipid nanoparticles are suitable substances to mimic natural lipoproteins that are able to pass the blood-brain barrier.A first goal in the project will be the synthesis of suitable polymers. They will be built from short, biocompatible chains with glucose attached to the repeating unit, and the GCPII-inhibitor as polymer end group. Glucose attachment can facilitate the transport of the particles to the brain due to the high requirements for nutrition of the latter. The other end group will be used to connect several chains to form short brushes. Every brush will be terminated by an "anchor", which is for example a fatty acid. The particles are formed by combining the polymer with a suitable lipid substance. The polymer acts as an emulsifier for the lipid in aqueous solutions, or later, in biological systems. The size of these transporters, which should be lower than 100 nm to enable cell uptake, will be adjusted by variation of the ratio between lipid and polymer. After formulation, the cytotoxicity, and the potential of the particles to function as GCPII-inhibitor for the free and the membrane-bound enzyme, will be tested. Upon decomposition of the particles in biological systems, the anchor of the polymer may be able to attach to a cell membrane to immobilize the inhibitor close to its target. Further, cell culture-based models of the blood-brain barrier will be used to investigate the ability of the particles to cross the latter.The particles will be optimized according to the results of the biological investigations. The goal of the project is to be able to present selected nanoparticle systems as candidates for further investigations and consideration as GCPII-inhibiting drug formulations. Additionally, the toolbox-like approach to synthesis and formulation may enable the application of the used techniques in the research field of nanomedicine in other projects.

• DFG Programme: WBP Fellowship
• International Connection: Czech Republic
• Host: Dr. Martin Hrubý