Inhibition of PI3K contributes to nanoparticle-mediated exaggeration of endotoxin-induced leukocyte procoagulant activity (INC6P.340)

Abstract

Abstract Nanoparticles are increasingly used in biomedical applications due to their ability to change biodistribution, increase safety and improve efficacy of drugs. However, application of engineered nanomaterials in medicine is often halted by safety concerns. Endotoxin contamination is very common in nanomaterials and there is an increasing number of studies reporting that certain nanoparticles can exaggerate endotoxin-mediated inflammation. We studied the relationship between physicochemical properties of polyamidoamine (PAMAM) dendrimers and their ability to exaggerate LPS-induced procoagulant activity (PCA) of human leukocytes in vitro. The PCA is phospholipid-protein complex composed of tissue factor (TF) and phosphotidylserine (PS). We found that cationic but not anionic or neutral PAMAM dendrimers, increase LPS-induced leukocyte PCA. Cationic PAMAM dendrimers enhanced both LPS-induced TF expression and PS exposure on the cell surface. The mechanism of LPS-induced PCA exaggeration by PAMAM dendrimers is not mediated by the electrostatic interaction between cationic dendrimers and anionic LPS, calcium influx and secondary messengers released by dendrimer activated platelets. We hypothesize that dendrimers exaggerate LPS-mediated PCA through the inhibition of negative regulation of inflammation. Specifically, we demonstrate that cationic PAMAM dendrimers inhibit phosphoinositol-3-kinase (PI3K), a negative regulator of TF expression in response to endotoxin.