Abstract

Acidic pH-responsive degradable block copolymer-based nanoassemblies that degrade through the cleavage of acid-labile linkages have gained significant attention due to their biological relevance, particularly in tumor tissues, having acidic environments (pH 4.2-6.9) due to irregular vasculatures of endothelial cells. Although they hold great potential for achieving controlled and enhanced drug release, developing a systematic understanding of the structural factors that influence their pH sensitivity remains a challenge—especially in designing effective acid-degradable, shell-sheddable nanoassemblies. This is particular for acetals and ketals, where their acid-catalyzed hydrolysis could be adjusted with the substituents attached to oxygen atoms as well as central carbon atom in acetal/ketal moieties. The relationship between the location of cleavable linkages and the drug release performance of polymeric micelles is critical in modulating their therapeutic behavior. This not only improves the biodistribution of anticancer drugs but also ensures minimal dosage, enhancing drug efficacy while reducing undesired cytotoxicity to normal tissues.
My PhD research aims at designing and synthesizing single location and dual location acid-degradable block copolymers and their nanoassemblies for controlled drug delivery. My first project (Chapter 3) evaluates single location strategy on acid-degradable shell-sheddable nanoassemblies, where the acid-labile linkage for the block junction was examined by the hydrolysis behaviour at different pH levels relevant to biological environments. The suitable candidate demonstrated that under acidic conditions, the nanoassemblies tend to form large aggregates as a result loosening the core structures, causing destabilization. My second project (Chapter 4) expands my scope of single location strategy to focus on dual location acid-responsive degradation strategy. The dual location nanoassemblies were extensively examined by assessing by the encapsulation of an anticancer drug (Curcumin) and evaluating the controlled drug release, as well as in vitro (cell) studies. My third project (Chapter 5) investigates the relationship of sensitivity to acid and stability to radical polymerizations for acetals and ketals.
Overall, my PhD thesis work provides important design principles for the synthesis of well-defined acid-degradable amphiphilic block copolymers (ABPs) with respect to acid-catalyzed hydrolysis rate and stability of acid-labile acetal/ketal, thus eventually, release rate of encapsulated drug molecules from their nanoassemblies in acidic environment.