title: Contact activation of kallikrein-kinin system by superparamagnetic iron oxide nanoparticles in vitro and in vivo.
abstract: Previously we reported that plasma kallikrein and high molecular weight kininogen attach to the surface of dextran-coated superparamagnetic iron oxide nanoparticles (SPION) through the incompletely covered iron oxide core (Simberg et al., Biomaterials, 2009). Here we show that SPION also activate kallikrein-kinin system in vitro and in vivo. The serine protease activity of kallikrein was stably associated with SPION and could be detected on the nanoparticles even after extensive washing steps. The enzymatic activity was not detectable in kininogen-deficient and Factor XII-deficient plasma. The enzymatic activation could be blocked by precoating SPION with histidine-rich Domain 5 (D5) of kininogen. Importantly, the kallikrein activity was detectable in plasma of SPION-injected, but not of D5/SPION-injected mice. Tumor-targeted SPION when injected into kininogen-deficient and control mice, produced high levels of vascular clotting in tumors, suggesting that kallikrein activation is not responsible for the nanoparticle-induced thrombosis. These data could help in understanding the toxicity of nanomaterials and could be used in designing nanoparticles with controlled enzymatic activity.
authors.affiliation: Nano Tumor Center of Excellence for Cancer Nanotechnology, Moores UCSD Cancer Center, 3855 Health Sciences Drive, La Jolla, CA 92093, USA. dsimberg@ucsd.edu
authors.forename: Dmitri
authors.initials: D
authors.lastname: Simberg
authors.forename: Wan-Ming
authors.initials: WM
authors.lastname: Zhang
authors.forename: Sergei
authors.initials: S
authors.lastname: Merkulov
authors.forename: Keith
authors.initials: K
authors.lastname: McCrae
authors.forename: Ji-Ho
authors.initials: JH
authors.lastname: Park
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sailor
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000737:chemistry; D003911:Dextrans; D016503:Drug Delivery Systems; D004789:Enzyme Activation; D005290:Ferric Compounds; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D016234:Kallikrein-Kinin System / Q000502:physiology* / Q000528:radiation effects*; D008280:Magnetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D053758:Nanoparticles; D013927:Thrombosis / Q000139:chemically induced
chemical_list: D001798:Blood Proteins; D003911:Dextrans; D005290:Ferric Compounds; D005456:Fluorescent Dyes; C000499:ferric oxide; D016650:Fluorescein-5-isothiocyanate