title: Inhibition of phosphoinositol 3 kinase contributes to nanoparticle-mediated exaggeration of endotoxin-induced leukocyte procoagulant activity.
abstract: OBJECTIVE
  Disseminated intravascular coagulation is an increasing concern for certain types of engineered nanomaterials. Recent studies have shed some light on the nanoparticle physicochemical properties contributing to this toxicity; however, the mechanisms are poorly understood. Leukocyte procoagulant activity (PCA) is a key factor contributing to the initiation of this toxicity. We have previously reported on the exaggeration of endotoxin-induced PCA by cationic dendrimers. Herein, we report an effort to discern the mechanism.
  
  
  METHODS
  Poly(amidoamine) dendrimers with various sizes and surface functionalities were studied in vitro by the recalcification test, flow cytometry and other relevant assays.
  
  
  CONCLUSIONS
  Cationic dendrimers exaggerated endotoxin-induced PCA, but their anionic or neutral counterparts did not; the cationic charge prompts this phenomenon, but different cationic surface chemistries do not influence it. Cationic dendrimers and endotoxin differentially affect the PCA complex. The inhibition of phosphoinositol 3 kinase by dendrimers contributes to the exaggeration of the endotoxin-induced PCA.
authors.affiliation: Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick Inc., NCI-Frederick, 1050 Boyles Street, Building 469, Frederick, MD 21702, USA.
authors.forename: Anna N
authors.initials: AN
authors.lastname: Ilinskaya
authors.forename: Sonny
authors.initials: S
authors.lastname: Man
authors.forename: Anil K
authors.initials: AK
authors.lastname: Patri
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Clogston
authors.forename: Rachael M
authors.initials: RM
authors.lastname: Crist
authors.forename: Raul E
authors.initials: RE
authors.lastname: Cachau
authors.forename: Scott E
authors.initials: SE
authors.lastname: McNeil
authors.forename: Marina A
authors.initials: MA
authors.lastname: Dobrovolskaia
mesh_terms: D001779:Blood Coagulation Factors / Q000096:biosynthesis*; D002412:Cations / Q000737:chemistry / Q000633:toxicity; D050091:Dendrimers / Q000737:chemistry / Q000633:toxicity; D004211:Disseminated Intravascular Coagulation / Q000209:etiology; D004731:Endotoxins / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011073:Polyamines / Q000737:chemistry / Q000633:toxicity
chemical_list: D001779:Blood Coagulation Factors; D002412:Cations; D050091:Dendrimers; D004731:Endotoxins; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D000081082:Phosphoinositide-3 Kinase Inhibitors; C531249:Poly(amidoamine); D011073:Polyamines; C045071:leukocyte procoagulant activity
keywords: coagulopathy; dendrimer; disseminated intravascular coagulation; leukocyte; nanoparticle; procoagulant activity; thrombosis