Nanoparticles and atherosclerosis : resolving the paradox
Air pollution is increasingly recognised as an important and modifiable risk factor for cardiovascular disease. Exposure is associated with a range of adverse cardiovascular events including hospital admissions with angina and myocardial infarction, and with cardiovascular death. The main arbiter of these adverse health effects appears to be combustion-derived nanoparticles that incorporate reactive organic and transition metal components. Through the induction of cellular oxidative stress and pro-inflammatory pathways, these nanoparticles exert detrimental effects on platelets, vasculature and myocardium, and can augment the development and progression of atherosclerosis. Over the last 10 years there has been remarkable progress in the development of targeted engineered nanoparticles as contrast agents to enhance cellular and molecular imaging. Ultra-small paramagnetic iron oxide (USPIO) nanoparticles (<100 nm) produce disruptions in the magnetic field of magnetic resonance imaging (MRI) scanners, and a decrease in image intensity in areas where the particles accumulate. USPIO particles are phagocytosed by cells of the monocyte-macrophage system throughout the body including within atheromatous plaques. USPIOs have regulatory approval in the United Kingdom for imaging lymph nodes in breast and prostate cancer as well as FDA approval for parenteral iron-replacement therapy in chronic kidney disease. There is great interest in developing USPIO and other nanoparticle contrast agents for imaging atherosclerosis. The delivery of engineered nanoparticles (ENPs) directly into the bloodstream to provide enhanced imaging of the unstable atheromatous plaque may assist in the diagnosis of plaque rupture and may ultimately permit targeted delivery of therapies directly to the site of vascular injury. However, these particles once blood-borne may alter monocyte-macrophage function and activate circulating platelets with adverse effects on clinical outcomes. Previously it has been shown that inhalation of combustion-derived nanoparticles results in increases in platelet-monocyte aggregation and thrombus formation in healthy volunteers. These combustion derived nanoparticles share structural similarities with engineered nanoparticles designed for intravascular infusion. This raises an obvious paradoxical question: can engineered nanoparticles designed for medical use mediate similar effects to combustion derived nanoparticles in susceptible populations? My thesis addresses this question and describes a series of complimentary experimental and clinical studies to investigate the effects of engineered nanoparticles on platelet function and thrombogenesis using commercial and clinically available nanoparticles. I found that cationic nanoparticles caused platelet activation and aggregation in vitro, whereas, anionic nanoparticles caused inflammation and up-regulated adhesion molecule ICAM-1 in monocyte derived macrophages indicating that nanoparticles have different toxicological properties in different biological conditions. Using an ex vivo model of thrombus formation, the Badimon chamber, I observed that USPIO nanoparticles added to flowing native whole blood in an extra-corporeal circuit increased platelet rich thrombus formation under high shear conditions compared to saline control in healthy volunteers. These studies were repeated in patients with abdominal aortic aneurysms who received intra-venous systemic infusions of USPIO to enhance MRI imaging. I demonstrated up-regulation in markers of platelet activation and more platelet rich thrombus formation in the Badimon chamber one hour following systemic delivery of USPIO. In summary I have demonstrated that medical nanoparticles influence platelet activation in patients with cardiovascular disease and have pro-thrombotic effects in an ex-vivo model of in both healthy persons and susceptible patients. In light of this data and to ensure the safe future development of engineered nanoparticles for medical use platelet activation assays and follow-up monitoring of patients should be considered routine in both the developmental and clinical stages of engineered nanoparticle use.