TY - JOUR
T1 - An in-situ forming controlled release soft hydrogel-based C5a peptidase drug delivery system to treat psoriasis
AU - Patel, Pratikkumar
AU - Bhattacharjee, Promita
AU - Gedi, Vinayakumar
AU - Duarte, Francisco
AU - Tecza, Malgorzata
AU - McGourty, Kieran
AU - Hudson, Sarah
N1 - Publisher Copyright:
© 2025 The Author(s)
PY - 2025/2/25
Y1 - 2025/2/25
N2 - 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.
AB - 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.
KW - Depot delivery
KW - Hydrogel
KW - Interferon gamma
KW - Poloxamer
KW - Serine protease
KW - Thermo-responsive gel
UR - http://www.scopus.com/inward/record.url?scp=85216380630&partnerID=8YFLogxK
U2 - 10.1016/j.ijpharm.2025.125244
DO - 10.1016/j.ijpharm.2025.125244
M3 - Article
AN - SCOPUS:85216380630
SN - 0378-5173
VL - 671
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
M1 - 125244
ER -