Chemo-enzymatic synthesis of multivalent dendritic architectures for the control of neurodegenerative disorders

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Alzheimers disease (AD) is a progressive neurodegenerative disease that affects more than 30 million people worldwide. Neuro inflammation, characterized by excessive glial activation and overproduction of proinflammatory cytokine and chemokines, plays a critical role in the pathogenesis of neurodegeneration in AD and related neurodegenerative disorders. One of the hallmarks of AD is the aggregation of the amyloid beta peptide, which forms amyloid plaques in the brain. Metal ions such as Cu(II) have been proposed to play a role in amyloid formation and the onset of this progressive neurodegenerative disorder. Regulation of copper homeostasis is one of the potential strategies for the design of drug candidates for the treatment of AD. Earlier studies in animals have reported that normalized or elevated Cu(II) levels can inhibit or even remove AD related pathological plaques. Another possibility to validate the regulation of copper homeostasis in an AD brain is to use appropriate chelators capable of copper ion transfer from amyloid-beta peptide to regular proteins via competitive binding and release. The ability of such ligands to behave as vehicle ligands for a monovalent binding strategy has been attempted in vitro in the literature. However, the blood brain barrier (BBB) and neurotoxicity of many traditional metal chelators has limited their utility in AD or other neurodegenerative disorders. Only 5% of the drugs listed in the Comprehensive Medicinal Chemistry database target the CNS. Therefore, the transport of Cu ions / chelators over the BBB is a critical issue for our therapeutic approach. Nanoparticle delivery systems are known to cross the blood brain barrier and this has led us to investigate whether chelators delivered conjugated to nanoparticles could act to reverse metal ion induced protein precipitation. Dendritic nanoparticles (NP) have recently been reported for the transport of Cu(II) ions across the blood brain barrier (BBB) in the laboratory of one of the collaborators (Haag, FUB). Although the copper transport was dramatically increased in an in vitro BBB model, yet the dendritic copper complex was too instable in vivo. Herein it is proposed to extend the study in multiple dimensions. We propose the design of more stable but cleavable copper complexes within nanometer sized transporters that may be beneficial because they can be tailored to optimize their properties, such as hydrodynamic size, surface charges, and conductive transport, to the area of the intended application.