Development of reduction-responsive degradable polylactide-based amphiphilic block copolymers for drug-delivery applications.

Ubiquitous in nature as a result of their versatility both in their structure and properties, smart polymers have been the subject of intensive research in the design of synthetic materials in the field of biomedicine. Of notable consideration, these polymers as drug delivery vehicles offer the potential to increase the bioavailability of therapeutic molecules while reducing the side effects customarily associated with small molecule delivery. Amphiphilic block copolymers (ABPs) bear a hydrophobic block comprising the hydrophobic core of the nanostructure, and a hydrophilic block providing colloidal stability. The ABP-based micellar carriers are endowed with great advantages that include, but are not limited to, the use of biocompatible material in their synthesis, thereby avoiding adverse side effects from the use of noxious materials. Moreover, the material can be synthesized using facile synthetic methods that allow a narrow size distribution and versatility in their physicochemical properties. Furthermore, their chemical flexibility in their design allows for the incorporation of targeting ligands at the hydrophilic corona promoting active targeting into specific cells. Another point to consider is the incorporation of dynamic chemical bonds in the architecture of the delivery vehicle to promote spatio-temporal release of the encapsulated cargo. Known as stimuli-responsive degradation (SRD), this concept has been exercised to take advantage of endogenous cellular triggers such as gradients in redox potential, pH or temperature that exists among different sub-cellular organelles as well as in different cell types/states; e.g. healthy vs. cancerous cells. One such promising stimuli-responsive platform is the disulfide-thiol chemistry. In addition, polylactide, a hydroxyalkanoic acid-based hydrophobic polyester, is a promising material in the synthesis of ABPs for biomedical applications. Indeed, it is biocompatible, biodegradable, FDA-approved, and has tunable mechanical properties. However, two challenges remain to be resolved before a successful polylactide-based drug delivery system can be developed: 1) its inherent hydrophobicity; 2) its slow degradation. In this thesis, potential solutions are examined. This research is based on the development of monocleavable thiol-responsive degradable polylactide-based amphiphilic block copolymers for drug delivery applications. Different synthetic strategies for the preparation of disulfide-labeled ABPs are presented using either a methacrylate-based or an ethylene oxide-based hydrophilic block. These ABPs are synthesized by a combination of ring-opening polymerization with either atom-transfer radical polymerization or a facile coupling reaction. They are amphiphilic and thus self-assemble to form colloidaly stable micellar aggregates in aqueous solutions above their critical micellar concentration (CMC). These drug loaded ABPs were tested for drug delivery by studying the extent of drug loading and release through analytical methods. Results suggest the disulfide-labeled ABPs respond to the presence of a reducing agent by releasing the encapsulated drug providing support for their potential as delivery vehicles for the targeted release of loaded drugs in both time and space