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A Novel fusogenic lipid vesicle (FLV) based targeted delivery system displays compstatin on cell membranes and effectively reduces complement deposition in vitro
Author(s) -
Todnem Nathan D,
Goga Ledia,
Pushpakumar Sathnur,
Cramer Daniel,
PerezAbadia Gustavo,
Barker John H,
Maldonado Claudio
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.730.15
Subject(s) - complement system , in vitro , membrane , transplantation , chemistry , cell , vesicle , biophysics , microbiology and biotechnology , flow cytometry , pharmacology , immunology , biology , biochemistry , medicine , immune system
Excessive complement (C) activation due to ischemia/reperfusion following organ transplantation has been associated with graft dysfunction. Several anti complement inhibitors have been used in the past to reduce this damage however their systemic administration can leave patients vulnerable to infection. To develop a targeted therapy we created a novel method to rapidly display complement inhibitors on cell membranes by using fusogenic lipid vesicles (FLVs) containing nickel (Ni) tethers. Compstatin a C3 convertase blocker was modified with a hexahistidine (His) domain (C‐His) to bind to these tethers. The purpose of this study was to determine whether the display of C‐His was effective in reducing complement deposition in vitro. We hypothesized that cells decorated with C‐His would reduce C3b deposition after C activation. Studies were conducted in human fibroblasts and SKOV‐3 cells. Ni tethering on cell membranes was optimized by altering FLV formulation, concentration and incubation time. C‐His bioactivity was tested using hemolytic assay. Trastuzimab and human serum was used for C activation, and C3b deposition was measured using FACS analysis. We found that C‐His successfully coupled to Ni tethers on SKOV‐3 cells and reduced C3b deposition. We conclude that membrane display of C‐His is effective in reducing C deposition and that this therapy has potential in transplantation.