Peptide Based Conjugates for Therapeutic Delivery Applications
The effect of peptide charge on the self-assembly and gelation behaviour of three octa-peptides: VEVKVEVK (VEK2), VKVKVEVK (VEK3) and VEVEVKVE (VEK1) has been investigated and characterised. The critical gelation concentration of each peptide was found to correlate with the charge modulus carried by the peptide and to be independent of the sign of the charge. Hydrogels formed were found to be transparent and stable when the peptide charge modulus is > 1. No differences in hydrogel structure or mechanical properties, as probed by TEM and SAXS and shear rheology, were found when the peptides were at the same concentration and carried the same charge modulus. These peptides were shown to form dense fibrillar network formed by ?-sheet rich single fibre which lateral aggregation is controlled by the peptide charge modulus. The increase in fibre lateral aggregation with decreasing charge modulus was found to correlate with the increase in hydrogel mechanical properties, showing that fibre lateral aggregation pays a key role in controlling the mechanical properties of these hydrogels. The release profiles from VEK1 and VEK3 at pH 7 of two hydrophilic model drug molecules, namely napthol yellow (NY) and martius yellow (MY) was analysed using UV-Vis spectrophotometry. The incorporation of the guest molecules did not affect the self-assembly of the peptide at a molecular level but did affect the level of lateral fibre aggregation observed and therefore the mechanical properties of the hydrogels. The release of each of the model compounds was monitored over time and shown to be controlled by Fickian diffusion. The guest molecule diffusion rate D was dependent on the ratio between the overall effective charges carried by the peptide, i.e.: the fibrillar network, and the overall charges carried by the guest molecules but independent from the hydrogel concentration and mechanical properties, in the concentration and guest loading range investigated. This work shows that the rate of release of small drug molecules can be manipulated, not only by changing the charges on the guest molecules, but also by manipulating the charged state of the self-assembling peptide molecule and through it the charge state of the fribrillar network. Furthermore the VEK3 system was conjugated to a series of thermo-responsive synthetic polymers which imparted a significant change in mechanical properties, assembled structures and release profiles upon heating. Observed changes when above the polymers LCST include increased mechanical strength, fibre thickening and increased diffusion coeffcients. The synthesis, and subsequent characterisation, of these materials is the first time responsive hydrogels of OEGMA copolymers has been reported.