Design and Development of Polypeptide Materials Derived from N-Carboxyanhydride Polymerizations: From Fundamental Investigations to Nanomedical Applications

Recent decades have witnessed extensive utilization of polypeptide materials in nanomedical applications, such as serving as scaffolds for tissue engineering, matrices for drug and gene delivery, and responsive materials for biosensors, owing to their innate biocompatibility and biodegradability, multiple functionalities and precisely-defined nano- and micro-structures. This dissertation highlights the rational design and development of polypeptide-based materials for simple and easily-controlled preparations toward nanomedical applications, including full characterization studies of the compositions, structures and properties. With attractive applications in nanomedicine, such as drug and gene delivery systems, polypeptides with well-defined structures are mainly synthesized from controlled N-carboxyanhydride (NCA) polymerizations, which can serve to construct polypeptides with versatile functionalities and various molecular topologies, as well as to facilitate investigations of structure-property relationships within polypeptide materials. Therefore, in the first study, a straightforward and readily-adoptable approach to synthesize polypeptides, with controllable polymerization rates, targetable molecular weights and narrow molecular weight distributions, was developed by applying continuous N2 flow over the reaction mixture during NCA polymerizations. With the establishment of this facile synthetic method, a polypeptide-based versatile and functional nanoparticle platform with reactive and charged functionalities was synthesized from a sequential NCA polymerization and chemical transformation strategy, and the cationic nanoparticle was further investigated as a gene delivery carrier by electrostatic complexation. In addition to linear polymers, well-defined molecular brushes bearing polypeptides as side chains were constructed via a “grafting through” synthetic strategy with two-dimensional control over the brush molecular architectures by integrating NCA polymerizations and ring-opening metathesis polymerizations (ROMPs) to build polypeptide side chains and brush backbones with desirable segment lengths, independently and respectively, in controlled manners. Also, the simple copolymerization of NCAs was utilized to generate copolypeptides having a combination of ɑ-helix and β-sheet secondary structures, which could be controlled by varying the feedstock selections of NCA monomers during polymerization, and were capable of driving mechano-responsive supramolecular gel-to-gel and gel-to-sol transitions reversibly. The revealed structure-property relationships between polymer compositions, supramolecular structures and stimuli-responsive properties, were further applied to construct a polypeptide-based hydrogel system with multi-responsive properties from the statistical copolymerization of various NCA monomers, allowing for control over the release profile of encapsulated naproxen for local delivery