| Delivery of naked drugs faces many challenges such as enzymatic and proteolytic degradation, catabolism in the liver, clearance by the kidneys, recognition by the immune system, inability to cross the cell membrane, solubility issues and nonspecific toxic effects on normal cells. Researchers have therefore been actively developing and investigating drug delivery vehicles to help therapeutics overcome these obstacles. In fact, over the past two decades, more than a dozen therapeutic products containing drug delivery vehicles have been approved by the FDA with dozens more undergoing clinical trials. The current research in this area, however, has been dominated by synthetic lipids and polymers. In order to contribute to this exciting field and potentially find a material that could improve upon current systems, this dissertation investigated amino acid-based drug delivery vehicles. Two approaches were explored. In the first approach, we focused on the Fc fragment of immunoglobulin G that has been found to increase the therapeutic lifetime of drugs via conjugation. A mathematical model was derived, and based on our model, decreasing the size of the Fc fragment and increasing its association rate with the neonatal Fc receptor, FcRn, were identified as possible design criteria for further increasing the serum half-life of Fc. Molecular modeling was then used to identify potential mutations that could satisfy the association rate design criterion. In the second approach, a novel synthetic block copolypeptide system was investigated as a potential drug carrier. Initially, a novel arginine-leucine block copolypeptide was synthesized, processed into vesicles, characterized and demonstrated to carry hydrophilic cargo into cells. The endocytosis and intracellular trafficking pathways for these block copolypeptide vesicles were then elucidated to identify design criteria for the next generation block copolypeptides. Lastly, the ability of the arginine-leucine block copolypeptide vesicles to transfect cells was systematically investigated, and there is potential for using this novel material in vitro for benchtop transfections, as well as in vivo for gene therapy. |
