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Functional Adaptive Supramolecular Systems for Medical Applications

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Title Functional Adaptive Supramolecular Systems for Medical Applications
Period 10 / 2008 - 02 / 2012
Status Completed
Research number OND1333139
Data Supplier NWO

Abstract

Unravelling disease mechanisms and therapies require multi-disciplinary research and knowledge of chemistry, biology, and medicine. Here, we propose a novel design of defined, supramolecular, bioactive, rod- and sphere-like systems operating in aqueous solution by specific interaction with proteins and cells; so-called self-organizing medicine. Two different supramolecular systems will be investigated in this chemical biology study: discotic molecules and cyclodextrins. The compounds are synthesized and modified with bioactives for specific interactions. We aim at a detailed understanding of the assembly process in water and the binding of these nano-objects with proteins and cells. The molecules will be designed in such a way that the biological interactions can be detected by imaging techniques; binding of bioactives on one nano-object with a receptor has to lead to a conformational change in the nano-object, which can be determined by Förster resonance energy transfer. These objects are defined in shape and size by steric hindrance for the discotics (incorporation of phenylalanine residues near the 1,3,5,-benzenetricarboxamide core) or by molecular templating (using monodisperse oligo(ethyleneglycol) or quaternary oligo(butyl ammonium) salts) for the threading of cyclodextrins. Furthermore, it is proposed that the objects are able to interact via multivalent interactions and that they are adaptive to the environment, i.e. specific proteins or cells, they encounter. This will lead to higher medical efficacies. Besides that, the nano-systems can also be stabilized by covalent fixation if necessary. In addition, external triggers will undo the assembly for example by a pH change after cellular take-up. We propose to investigate these systems in vitro for different diseases. In the case of obesity, specific gut bacteria might be targeted by knocking-down their metabolism. Whereas, toxic amyloid-b peptides might be scavenged in Alzheimer's disease. The supramolecular nano-objects can possibly bind advanced glycosylation end-products caused by high glucose levels, thereby lowering toxic side-effects of diabetes. Keywords: self-assembly, bioactivity, supramolecular structure, biomedical application, multivalency

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Project leader Dr. P.Y.W. Dankers

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