The long term objective of this research proposal is to synthesize of peptide amphilies (PAs) with a dendritic architecture for biomedical applications. The Stupp laboratory has had much success in the area of regenerative medicine (e.g. angiogenesis, neuron growth, etc.). They have prepared PA monomers containing hydrophobic beta sheet forming regions that self-assemble into nanofiber networks displaying bioactive peptides that support cell adhesion, growth and differentation. It is of interest to investigate how the supramolecular architecture and the arrangement of the bioactive peptides on the nanostructures affects the cellular responses and the overall therapeutic effect. The branched nature of dendritic PAs allows for the attachment of multiple bioactive peptides to a single core. The coassembly of these sterically bulky branched PAs with small linear """"""""filler"""""""" PAs may result in nanostructures with domains of densely packed bioactive peptides on the surface. This is interesting because it is known that clustered multivalent ligands can induce cellular responses that are more effective than their monovalent counterparts. The steric bulkiness of the dendritic PAs may also result in the formation of smaller discrete nanostructures when assembled due to strained beta sheet formation. These discrete soluble nanostructures could potentially be used for drug delivery purposes. The synthesis of these monomers may be achieved in a stepwise divergent manner by solid phase chemistry or via a modular convergent method involving solid phase and solution chemistries. The structures can be prepared with various epitopes and degrees of branching allowing for the preparation of many different dendritic PAs using similar chemistries. The peptide based nanofibers studied by the Stupp laboratory are very promising materials for regenerative medicine applications for which no effective treatments are currently available, such as nerve damage repair. Understanding how the supramolecular architecture and arrangement of the bioactive peptides displayed on the nanostructures affects the overall therapeutic effects of the system may lead to better material design and enhanced treatment efficacy. Therefore highly branched multivalent peptides capable of assembling into nanostructures with new architectures and bioactive peptide arrangements will be prepared to determine if they induce different or enhanced biological responses. ? ? ?
| Toft, Daniel J; Moyer, Tyson J; Standley, Stephany M et al. (2012) Coassembled cytotoxic and pegylated peptide amphiphiles form filamentous nanostructures with potent antitumor activity in models of breast cancer. ACS Nano 6:7956-65 |
| Soukasene, Stephen; Toft, Daniel J; Moyer, Tyson J et al. (2011) Antitumor activity of peptide amphiphile nanofiber-encapsulated camptothecin. ACS Nano 5:9113-21 |
| Standley, Stephany M; Toft, Daniel J; Cheng, Hao et al. (2010) Induction of cancer cell death by self-assembling nanostructures incorporating a cytotoxic peptide. Cancer Res 70:3020-6 |
