(485bh) Peptide Amphiphile Micelles for Nuclear Targeting and DNA Binding
AIChE Annual Meeting
Wednesday, November 11, 2009 - 6:00pm to 8:00pm
Peptide amphiphiles can be used to create multivalent, multifunctional, self-assembled nanostructures for applications such as immunotherapy, cancer treatment, and in this case gene therapy. We have conjugated di-C16 hydrophobic tails to bZip, a thirty-eight amino acid sequence derived from the transcription factor GCN4, to promote the formation of extended micelles in solution. The peptide amphiphile headgroups adopt a high degree of alpha-helical structure in the micelle corona compared to the free peptide chains as shown by circular dichroism. The hydrophobic moiety facilitates the DNA binding of bZip amphiphiles in an orthogonal arrangement similar to the native protein, in contrast to the unmodified peptide which binds via electrostatic collapse onto DNA. The peptide amphiphiles bind DNA in a cooperative fashion but do not recognize the AP-1 sequence that GCN4 binds specifically, although further modification of the monomers may enhance their biofunctionality. To implement the DNA binding peptide amphiphiles in gene therapy applications, a nuclear targeting platform is being developed by appending a hydrophobic tail to a nuclear localization signaling (NLS) peptide. The tail enhances cellular uptake of the peptide and delivery to the nucleus of HeLa cells as observed by fluorescence microscopy. Incorporating NLS peptide amphiphiles into a mixed micelle displaying DNA binding peptides or other therapeutic agents may aid in targeted delivery to the nucleus.