2013 Mediation of a non-proteolytic activation of complement component C3 by phospholipid vesicles

Authors: Klapper Y, Hamad OA, Teramura Y, Leneweit G, Nienhaus GU, Ricklin D, Lambris JD, Ekdahl KN, Nilsson B

Journal: Biomaterials, 35:3688–3696. doi:10.1016/j.biomaterials.2013.12.085


Institute of Applied Physics and Center for Functional Nanostructures (CFN), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany;

Carl Gustav Carus-Institute, Association for the Promotion of Cancer Therapy, Niefern-Öschelbronn, Germany;

Department of Immunology, Genetics and Pathology, Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden. 

Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA;

Institute of Toxicology and Genetics, Karlsruhe Institute of Technology (KIT), Eggenstein-Leopoldshafen, Germany.

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Abstract: Liposomes are becoming increasingly important as drug delivery systems, to target a drug to specific cells and tissues and thereby protecting the recipient from toxic effects of the contained drug. Liposome preparations have been described to activate complement. In this study, we have investigatedcomplement activation triggered by neutral dimyristoyl-phosphocholine (DMPC) liposomes in human plasma and whole-blood systems. Incubation in plasma led to the generation of complement activationproducts (C3a and sC5b-9). Unexpectedly, investigations of surface-bound C3 revealed contact activated, conformationally changed C3 molecules on the liposomes. These changes were characterized by Western blotting with C3 monoclonal antibodies, and by incubating liposomes with purified native C3and factors I and H. Quartz crystal microbalance analysis confirmed binding of C3 to planar DMPC surfaces. In addition, we demonstrated that DMPC liposomes bound to or were phagocytized by granulocytes in a complement-dependent manner, as evidenced by the use of complement inhibitors. In summary, we have shown that C3 is activated both by convertase-dependent cleavage, preferentially in the fluid phase, by mechanisms which are not well elucidated, and also by contact activation intoC3(H2O) on the DMPC surface. In particular, this contact activation has implications for the therapeutic regulation of complement activation during liposome treatment.