Understanding the structure, dynamics, and mass transport properties of self assembling peptide hydrogels for injectable, drug delivery applications

Advances in biotechnology have led to the rapid development of small protein and antibody therapeutics. However, several limitations remain in the preparation and delivery of these drugs due to the susceptibility of proteins to degrade during storage and upon administration. To address this problem, hydrogels have been used as delivery devices for these protein drugs. We have designed a class of self-assembling peptides, MAX1 and MAX8, that undergo triggered hydrogelation in response to physiological pH and salt conditions (pH 7.4, 150 mM NaCl). These peptides adopt a random coil conformation in aqueous pH 7.4 solutions and are freely soluble. However, when a physiological relevant concentration of NaCl (150 mM) is added, the peptides fold into a beta-hairpin confirmation, and subsequently, self-assemble to form a rigid hydrogel stabilized by non-covalent cross-links. For these peptides, it is possible to control the folding and assembly kinetics to form hydrogels with different mechanical rigidities. These changes affect the porous morphology (i.e., mesh size) within the hydrogel system, and subsequently influence the rate of macromolecular diffusion within the peptide fibrillar network. Another unique characteristic of these hydrogels is that under applied shear, the hydrogel will shear-thin into a low-viscosity gel; however, the gel quickly resets and recovers its initial mechanical rigidity after the applied shear is removed. This property allows hydrogels encapsulating therapeutics to be administered via syringe to target sites for eventual delivery.;The objective of this thesis work is to investigate the potential of MAX1 and MAX8 hydrogels as controlled release, drug delivery vehicles for macromolecular therapeutics. First, the differences in the folding and self assembly kinetics, as well as the resultant material properties, of MAX1 and MAX8 are assessed to yield a physical model of the nanoscale topology and dynamics of the self-assembled peptide hydrogels as a function of peptide sequence and concentration. Changes in nanoscale dynamics and structure inherently lead to substantial differences in bulk properties, such as the elastic modulus and network mesh size. Learning how the material properties of the gels influence the transport rate of therapeutics through the hydrogel is essential to the development of delivery vehicles. The remainder of the thesis focuses on correlating the mesh sizes of MAX1 and MAX8 gels to the diffusion and mass transport properties of model dextran and protein probes. Here, work is centered on how peptide charge and concentration, as well as probe structure, in particular hydrodynamic diameter and charge, dictate the temporal release of model probes from the peptide hydrogels. Experiments include self diffusion studies and bulk release experiments with model dextrans and proteins from gels before and after syringe delivery. Overall, this thesis will demonstrate the importance of understanding material properties from the nanoscale up to the macroscale for application based design. With this approach, better and specific development of self-assembling peptide materials can be achieved, allowing for the rational engineering of peptide sequences to form hydrogels appropriate for specific drug delivery applications.