Abstract

Design and development of smart nano-sized delivery devices for controlled drug release in response to endogenous stimuli (such as acidic pH and glutathione (GSH)) inherently found in tumor tissue is a promising platform in tumor-targeting nanomedicine. This platform allows for the maximization of therapeutic efficacy whilst reducing unwanted off-target side effects. Particularly, polymeric nanocarriers self-assembled from amphiphilic block copolymers (ABCP) have gained significant attention due of their size tunability and enhanced colloidal stability. Well-controlled ABCPs enable the formation of core-shell micelles in aqueous solutions having hydrophobic cores, enabling the physical entrapment of hydrophobic anticancer drugs, surrounded with hydrophilic coronas. Further, an incorporation of stimuli-responsive degradable (SRD) linkages in ABCPs allows for controlled micelle degradation and drug release at the site of action.
In this research, a dual location dual stimuli-responsive degradation (DL-DSRD) strategy is explored as a versatile platform for intracellular tumor-targeting drug delivery. Two ABCPs exhibiting dual acidic pH/reduction-responsive degradation are studied. The self-assembled ABCPs form colloidally stable nanoassemblies showing synergistically rapid release of encapsulated doxorubicin (a clinically used anticancer drug) at pH = 5.4 in 10 mM GSH solution caused by the cleavage of acid-labile and disulfide linkages. In addition, a new approach utilizing carbonylimidazole-hydroxyl coupling chemistry is explored to synthesize reduction-degradable poly(carbonate-disulfides) labeled with disulfide linkage on the backbones. They possess multi-functionalities as well as tunable and rapid reductive-degradation through main-chain degradation mechanism. Further, the versatility of the approach is demonstrated with the synthesis of an amphiphilic triblock copolymer exhibiting DL-DSRD responses.
Overall, the results obtained through this research contribute to the advancement of current understanding and helps guide the design of improved SRD-exhibiting ABCP-based drug delivery nanocarriers.