Synthesis and Characterization of Cyclic Polypeptoids by Organo-Mediated Controlled Zwitterionic Ring-Opening Polymerization and Development of Redox-Responsive Polypeptoid Micelles as Drug Delivery Carriers

Abstract

Peptoids are peptidomimetic polymers, which have attracted much attention over the past two decades. They have similar building blocks to peptides, and the similarity makes the backbone of peptoids hydrophilic and biocompatible.1 Two types of peptoid polymers are under development. One is sequence-defined peptoids, which exhibit excellent bioactivities.2 Another one is polypeptoids. The good biocompatibility and highly tunable side chain substituents allow polypeptoids to be used broadly in future biomedical applications. Varying polymer architectures, including linear polymers, cyclic polymers, comb-like polymers, and dendrimers can provide distinctive properties to the polymers. Cyclic polymers employ a cyclic architecture and lack chain ends, so their diffusion behaviors, aggregation behaviors, thermal transition behaviors, and crystallization behaviors are very different from the linear analogs. Facile synthetic approaches are required to expand the application of cyclic polymers into a broader scope. In chapter 1, the history of polypeptoids, the synthesis of cyclic polymers, the development of functional polypeptoids, and the cutting-edge biomedical research of polypeptoids were reviewed. In chapter 2, we reported our most recent work of the polymerization reaction of cyclic polypeptoids using a bicyclic amidine initiator. The study was described from the aspects of molecular weight control, identification of the polymerization, kinetics of the polymerization, and polymer architecture. Zwitterionic ring-opening polymerization of N-substituted N-carboxyanhydrides (R-NCA) mediated by the bicyclic amidine has been developed and well-defined cyclic polypeptoids can be synthesized. Pursuit of varying polymer architectures never ends because unique properties can be possibly discovered with the latest developed architecture. Besides cyclic polymers, linear bottlebrush polymers also attracted much attention due to their distinctive features. In chapter 3, we took one step forward and synthesized the cyclic bottlebrush polypeptoids. We then conducted a systematic study on the characterization of the cyclic bottlebrush polypeptoids and on the solution aggregation behaviors of zwitterionic cyclic polypeptoids with and without long side chains. It was revealed that zwitterionic cyclic polypeptoids tend to form clusters due to dipole-dipole interaction in methanol and even the long side chains cannot prevent this process. Another important direction of polypeptoid research, the biomedical application, was assessed in chapter 4. Redox-responsive micelles based on amphiphilic diblock copolypeptoids were prepared, and the solution stability, the morphology in dry state, the redox-responsive behaviors, drug release in vitro, and cell viability and cell inhibition activity of the micelles were completely studied.