Mixed α/ß-Peptides as a Class of Short Amphipathic Peptide Hydrogelators with Enhanced Proteolytic Stability.

Peptide hydrogels are a highly promising class of materials for biomedical application, albeit facing many challenges with regard to stability and tunability. Here, we report a new class of amphipathic peptide hydrogelators, namely mixed α/ß-peptide hydrogelators. These mixed α/ß-gelators possess good rheological properties (high storage moduli) and form transparent self-supporting gels with shear-thinning behavior. Infrared spectroscopy indicates the presence of ß-sheets as the underlying secondary structure. Interestingly, self-assembled nanofibers of the mixed α/ß-peptides display unique structural morphologies with alteration of the C-terminus (acid vs amide) playing a key role in the fiber formation and gelation properties of the resulting hydrogels. The incorporation of ß3-homoamino acid residues within the mixed α/ß-peptide gelators led to an increase in proteolytic stability of the peptides under nongelating conditions (in solution) as well as gelating conditions (as hydrogel). Under diluted conditions, degradation of mixed α/ß-peptides in the presence of elastase was slowed down 120-fold compared to that of an α-peptide, thereby demonstrating beneficial enzymatic resistance for hydrogel applications in vivo. In addition, increased half-life values were obtained for the mixed α/ß-peptides in human blood plasma, as compared to corresponding α-peptides. It was also found that the mixed α/ß-peptides were amenable to injection via needles used for subcutaneous administrations. The preformed peptide gels could be sheared upon injection and were found to quickly reform to a state close to that of the original hydrogel. The shown properties of enhanced proteolytic stability and injectability hold great promise for the use of these novel mixed α/ß-peptide hydrogels for applications in the areas of tissue engineering and drug delivery.

Rational design of a hexapeptide hydrogelator for controlled-release drug delivery.

The amphiphilic peptide sequence H-Phe-Glu-Phe-Gln-Phe-Lys-OH (MBG-1) is developed as a novel hydrogelator for use in controlled-drug release administration, which is the smallest tunable ionic self-complementary hydrogelating peptide reported to date making it attractive for larger scale preparation. Hydrogelation is demonstrated to result from self-assembly of the peptide into beta-sheet nanofibers that are physically cross-linked by intertwining as well as larger bundle formation. Finally, the release of two small molecule cargos, fluorescein sodium and ciprofloxacin hydrochloride, is demonstrated revealing a two-stage zero-order sustained release profile up to 80% cumulative release over eight days.