Development of Stimuli-responsive Polyelectrolyte Block Copolymer-based Nanostructures for Drug Delivery, Regenerative Medicine, and Tissue Engineering

Abstract

For the last few decades, block copolymers have been widely investigated to prepare different nanostructures due to their unique characteristics. The block copolymers can be self-assembled to form micelles, vesicles, and hydrogel networks depending on physicochemical properties of each block. Particularly, block copolymers with stimuli-responsiveness have been of great interest for the biomedical applications because they provide unique nanostructures with special features, such as environmental sensitivity towards temperature or pH changes under physiological conditions. In chapter 1, we studied the formation of self-assembled micelles of differently charged diblock copolymers, consisting of positively or negatively charged polyelectrolytes and temperature responsive poly(NIPAM), and their capability to deliver charged molecules as models. These polyelectrolyte block copolymers were synthesized by sequential RAFT polymerization. They self-assembled into core-shell micelles depending on temperature or pH, as confirmed by DLS and turbidity measurement. We also reported the different entrapment strategies for delivery of charged model drugs, which resulted in the different release kinetics based on physical entrapment and chemical conjugation. The release mechanism of physically entrapped guest molecules generally depends on the diffusion rate and charge-charge interactions with polyelectrolytes shell. Meanwhile, the release of chemically conjugated charged molecules was triggered by hydrolysis of the conjugation bond, even though charge-charge interaction occurred. In conclusion, the polyelectrolyte block copolymer-based self-assembled micelles have great potential for advanced drug delivery applications. In chapter 2, we prepared ABC-type triblock copolymers by conjugating polyelectrolyte diblock copolymers with free thiol group at one end with methacrylated PEGs via Michael-base thiol-ene addition reaction. The oppositely charged, thermo-responsive ABC-type triblock copolymers consisted of thermo-responsive poly(NIPAM) midblock flanked by polyelectrolytes block and PEG block. The mixture of these oppositely charged ABC-type triblock copolymers at room temperature self-assembled into stable polyelectrolyte complex (PEC) micelles via electrostatic interaction. The PEC micelles consisted of neutralized PEC as the core and hydrophilic poly(NIPAM) and PEG as the shell. At an elevated temperature above their phase transition temperature, poly(NIPAM) underwent transition, forming into the hydrophobic shell layer around the PEC core while the PEG block prevented aggregation and stabilized the final micellar structures due to its hydrophilic characteristics. Thus, these self-assembled ABC-type triblock copolymer-based PEC micelles have great potential as advanced drug delivery carriers. In chapter 3, we prepared reducible ABA-type polyelectrolyte triblock copolymers by exploiting their ability to form disulfide linkage between free thiol groups at the end of the polyelectrolyte diblock copolymers. When these oppositely charged triblock copolymers were mixed, they formed polyelectrolyte complex (PEC) hydrogels via strong electrostatic interaction between the charged blocks, bridged by hydrophilic poly(NIPAM) networks. Due to the presence of thermally responsive poly(NIPAM) block, PEC hydrogels shrank and showed increased mechanical strength at body temperature, which is above the transition temperature. Additionally, disulfide bonds obtained from aminolysis and subsequent oxidation through hydrogen peroxide with potassium iodide endowed the PEC hydrogels with degradability under reduced conditions. Hence, the PEC hydrogels would have great potential as for injectable hydrogel with controlled degradation based on reduction condition for a variety of biomedical applications. In chapter 4, we developed a new class of PEC hydrogels from high concentrated mixture of oppositely charged ABC-type triblock copolymers which consisted of thermo-responsive poly(NIPAM) midblock flanked by polyelectrolyte block and PEG block. The PEG block was introduced into the PEC hydrogel network in order to stabilize the assembled nanostructures as well as to increase their biocompatibility. These PEC hydrogels were self-assembled via electrostatic interaction between polyelectrolyte blocks and hydrogen bonding between PEG blocks. These PEC hydrogels showed reversible thermal responsive behavior due to the presence of poly(NIPAM), which made their physical and mechanical properties finely controlled. In conclusion, the PEC hydrogels are promising candidates for injectable hydrogel-based biomedical applications.