Temperature-Responsive Injectable Hydrogels: Design, Characterization and Application as Localized Delivery Systems for Drug and Gene Therapy

In recent decades, block copolymers have found wide spread interest as drug delivery systems (DDS). Improvements in synthetic techniques, polymer engineering and nanotechnology have made it possible to design and construct a variety of DDS for emerging therapeutics, such as gene therapy. Block copolymer gene carriers have several advantages including improved biocompatibility, higher loading capacity and ease of large-scale production. However, the successful clinical application of these delivery systems has been plagued due to several shortcomings, such as poor stability in biological environment, low loading efficiency of therapeutic agents and relatively high cytotoxicity. The majority investigated block copolymer gene carriers rely on the systemic delivery of encapsulated nucleic acids to a target cell or tissue. For systemic delivery, nano-sized micelle particles are introduced into the blood stream and allowed to circulate until they reach the target site. In recent years, localized gene therapy has found increasing popularity due to its unique advantages, including reduced systemic toxicity, sustained drug bioavailability and reduced administration frequency. In-situ forming (injectable) hydrogels have attracted considerable attention as localized gene delivery vectors due to their unique features; such as minimal invasiveness (no need for surgical procedure), ability to deform and fit into defined shapes and crevices and they possess excellent biocompatibility due to their highly hydrated structures. The main hurdle in the development of injectable hydrogel for localized gene therapy is the fine balance needed between high mechanical strength and biocompatibility. To produce high modulus hydrogel, relatively toxic chemical crosslinking approaches are often needed, which has a negative effect on the biocompatibility of the system. Stereocomplexation is an attractive alternative to chemical crosslinking in the production of an injectable hydrogel with biological relevant mechanical strength. Polyester polymers such as Polylactide (PLA) are able to undergo stereocomplexation process, leading to the production of a biodegradable hydrogel matrix Additionally, the elucidation of hydrogel formation mechanism and factors that influence mechanical behavior can be utilized in design optimization of the system. Intrinsic properties of a hydrogel, such as elastic modulus, phase transition temperature, and rate of gel formation are directly influenced by the crosslinking behavior