Abstract

Progress in the synthesis of amphiphilic block copolymers has contributed to promising advances in the construction of smart nanocarriers for anticancer drug delivery systems. Their excellent features such as biodegradability through enzymatic hydrolysis and biocompatibility have led to tremendous applications in the biomedical field. Polylactide (PLA) is a biocompatible and FDA-approved polymer which has been used as hydrophobic core-forming block in drug delivery vehicles. However, hydrophobicity and slow degradation are the two main drawbacks that limits its usage in drug delivery systems. An introduction of stimuli-responsive degradable (SRD) platform into the design of PLA-based polymeric drug delivery systems can overcome these challenges as they can precisely tune drug release kinetics to fit the therapeutic window of the encapsulated drug. However, most of the smart PLA-based block copolymers are designed to respond to a single stimulus and therefore, multi-stimuli responsive degradable systems in which the location, number and type of degradable linkages can be varied needs to be developed.
My PhD research was focused on the studies of dual stimuli-responsive degradation (DSRD) platform to synthesize advanced PLA-based nanomaterials. They were featured with different types and location of labile linkages, that cleaved in response to biological stimuli found in cancer cells and tumor tissues. In this thesis, I had developed robust strategies that allowed for the synthesis of three novel PLA-based SRD copolymers designed with a) reduction-responsive disulfide linkage and b) an acid-labile linkage. These synthetic strategies utilized a combination of ring opening polymerization (ROP), atom transfer radical polymerization (ATRP) and facile coupling reactions. The results demonstrated the feasibility to design and synthesize smart DSRD-based block copolymers which self-assemble to form colloidally-stable micellar aggregates and encapsulate hydrophobic dyes or drugs in the hydrophobic cores. Furthermore, the SRD-driven enhanced/controlled release of loaded cargoes suggested that DSRD strategy can offer the versatility and hold great potential in the development of intracellular drug delivery nanocarriers.