This proposal describes the design and development of versatile amphiphilic dendrimer-based supramolecular assemblies that disassemble in response to specific proteins as stimuli. Assembly and disassembly of macromolecules in response to a signal (or a stimulus) is an important component of most biological functions in Nature. For example, it has been shown that heparin sulfate (a natural polysaccharide) acts as the key scaffold for assembling fibroblast growth factors and transmembrane tyrosine kinase receptors that are important in several cellular processes, including cell-cell communication. Similarly, there are recent examples of receptor clustering on cell surfaces in response to artificial polyvalent ligand scaffolds. While these are examples of proteins responding to polymers, we ask here 'could we use specific proteins as signals to assemble or disassemble the supramolecular structures based on polymeric systems (more specifically dendrimers)?'This is obviously a daunting challenge. A reasonable first step towards addressing the question is to obtain a better understanding about the structural factors that control the assembly/disassembly events in response to the concentration of a specific protein. Developing such a fundamental structure-property relationship with custom-designed supramolecular assemblies could have implications in a variety of areas. For example, these assemblies could find use in controlled release applications, where the release of sequestered guest molecules (drugs) from the assembly is controlled by a stimulus. While there have been a number of reports on stimuli-responsive supramolecular assemblies, studies that use proteins as the stimuli are very limited.26,27 Exploring protein-sensitive delivery vehicles is interesting, since most of the human diseases are based on protein imbalances. The structural requirements for achieving control over these assembly/disassembly events are quite stringent. This proposal describes the first, concerted approach to achieve controlled disassembly of dendrimer based amphiphilic assemblies in response to a specific protein stimulus. We take two complementary approaches to disassemble the dendrimer assemblies through interaction with proteins: (i) where the proteins induce a covalent modification of the functionalities of the dendrimers;(ii) where the protein non-covalently binds to specific ligand functionalities in the dendrimer. Both of these approaches are backed up by significant preliminary results.

Public Health Relevance

This project describes novel strategies for stimuli-responsive disassembly of supramolecular assemblies formed from facially amphiphilic dendrimers, specifically protein-based stimulus. Since disassembly can cause concurrent guest release, this project will provide new protein-responsive drug release strategies.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Fabian, Miles
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University of Massachusetts Amherst
Schools of Arts and Sciences
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