| Chapter 1: The tumor microenvironment provides multiple cues that may be exploited to improve the efficacy of established chemotherapeutics furthermore, polypeptides are uniquely situated to capitalize on these signals. Peptides provide: (1) a rich repertoire of biologically specific interactions to draw upon (2) environmentally-responsive phase behaviors, which may be tuned to respond to signatures of disease (3) opportunities to direct self-assembly (4) control over routes of biodegradation (5) the option to seamlessly combine functionalities into a single polymer via a one-step biosynthesis. As development of cancer-targeted nanocarriers expands, peptides provide a unique source of functional units that may target disease. This dissertation explores potential microenvironmental physiology indicative of tumors and peptides that have demonstrated an ability to target and deliver to these signals.Chapter 2: While some amphipathic peptides interact directly with membranes, many peptides have potentially useful environmentally-responsive behavior only in aqueous solution. We developed a simple approach to modify water-soluble polypeptides via an amino terminal lysine using two palmitoyl lipids. As a model polypeptide, we used our approach to graft short elastin like polypeptide (ELPs) sequences to the surface of liposomes. High molecular weight ELPs undergo an environmentally responsive phase transition, whereby they phase separate from water above a critical transition temperature. The phase transition of free ELPs does not induce leakage of membranes however, the incorporation of two proximal lipid groups to the free amines on a terminal lysine residue were able to reversibly stabilize a lipid membrane. After developing this new strategy for grafting peptides to the surface of a liposome, we observed that these liposomes were stable near body temperature and can be triggered to release 100% of their encapsulated contents within a few minutes. This new formulation has potential as a new bioresponsive drug carrier, which may promote controlled release to cancer. |
