An in-situ forming controlled release soft hydrogel-based C5a peptidase drug delivery system to treat psoriasis.

The potent pro-inflammatory cytokine, interferon gamma (IFN-γ), is an enticing therapeutic target because of its accelerator role in several acute and chronic inflammatory processes. In this work, poloxamer 407 is developed as an in-situ gelling polymer for a long-acting formulation to deliver a serine protease, C5a peptidase (ScpA) from Streptococcus pyogenes. ScpA is well known for its activity against the complement factor C5a but has also recently been shown to cleave IFN-γ in vitro into inactive fragments. A compact and uniform gel microstructure was obtained by including dextran in the gel formulation. The sol-gel transition at physiologically temperatures occurred above 19 % w/w poloxamer 407 resulting in a release profile of active ScpA for up to 8 days, with no loss in specific enzymatic activity. No cytotoxicity from ScpA before or after release from the hydrogels to a human immortalized keratinocyte cell lines was detected. Using an in vitro psoriatic skin model with IFN- γ inducing the psoriatic state, the constant and prolonged release of ScpA from this simple thermo-responsive hydrogel, administered once, restored health as effectively as two doses of free enzyme over a 5 day period. These promising results confirm the feasibility of developing ScpA as a long-acting therapeutic using a poloxamer based in-situ forming parenteral gel for local delivery.