Abstract

The efficiency of chemotherapeutic drugs has been drastically compromised by their undesired side effects. Drug delivery via amphiphilic block copolymer (ABP)-based nanoassemblies has received considerable attention as a new therapeutic method to selectively deliver chemotherapeutic drugs to tumors. Nevertheless, one of the persisting challenges for this therapeutic method is the slow degradation of the nanoassemblies and the sluggish release of encapsulated drugs in the cancer cells. To circumvent this problem, a variety of cleavable linkages have been integrated in the nanoassemblies that can be degraded in response to endogenous stimuli found in tumor environments. Particularly, tumors are known to be acidic and have higher concentrations of cytosolic glutathione (GSH) compared to normal cells.
This thesis describes the investigation of novel strategies for the synthesis of dual location acid- and dual acid/GSH-degradable ABPs for intracellular drug delivery. Various ABPs were synthesized via atom transfer radical polymerization (ATRP), reversible addition fragmentation chain transfer (RAFT) polymerization and concurrent ATRP/RAFT polymerization to study their structure-property relationships for effective intracellular drug delivery. These copolymers were designed to have acid-labile acetal or ketal groups and GSH-cleavable disulfide linkages at a junction of hydrophilic and hydrophobic blocks and in hydrophobic blocks. They self-assembled to spherical micelles with cleavable linkages at the hydrophobic core or the interface. The studies of acid or/and GSH-responsive degradation and disassembly revealed that the cleavage of acid- and GSH-cleavable linkages results in disassembly of nanoassemblies through the synergistic shedding of hydrophilic corona as well as the loss of the hydrophobic/hydrophilic balance of micelles core. The nanoassemblies were successfully loaded with Doxorubicin (a clinically used anti-cancer drug) and exhibited enhanced drug release in the presence of acidic or/and GSH stimuli. Promisingly, dual-location acid and acid/GSH degradable nanoassemblies showed biocompatibility, anti-cancer activity and cellular uptake in HeLa cancer cells.