ICONS

Stroke is the first cause of acquired disability and the third cause of mortality in developed countries. Its incidence is expected to increase due to the growing aged populations. Ischemic stroke, that represents 80% of all stroke cases, is due to occlusion of a cerebral vessel by a clot, that induces neuronal loss and neurologic deficit. It also induces vascular damage leading to intracerebral hemorrhage (also called hemorrhagic transformations), a major stroke complication. Despite many efforts, at present there is only one drug approved for ischemic stroke: the recombinant tissue plasminogen activator (rt-PA), a thrombolytic that allows reperfusion of the occluded artery thereby limiting neuronal deficit. However, less than 5% of patients benefit from this treatment due to numerous contra-indications and a narrow therapeutic window. In addition, rt-PA is associated with an increased risk of hemorrhagic transformations. Beside neuroprotective strategies there is therefore also a crucial lack of vasculoprotective therapeutics for the prevention of hemorrhagic transformations in all stroke patients, without or with rt-PA treatment. Stroke is thus a major public health problem with an unmet medical need. Pathophysiology of stroke involves many mechanisms including oxidative stress that refers to imbalance between the production of radical oxygen species (ROS; e.g. superoxide anion, hydrogen peroxide and peroxynitrite) and the endogenous antioxidant systems. ROS are deleterious both for neurons and vessels but also triggers inflammation, another detrimental phenomenon in stroke, that leads to further oxidative stress. Moreover, brain reperfusion, either spontaneous or rt-PA-induced, is responsible for a burst in ROS production that enhances neuronal loss but also vascular damages thus potentiating hemorrhagic transformations. Cerium oxide nanoparticles (CNP) have antioxidant properties by reversibly binding oxygen and shifting between the Ce3+ (reduced) and Ce4+ (oxidized) forms at the particle surface. CNP have the advantage over other antioxidants to act on multiple ROS as they combine both superoxide dismutase and catalase mimetic activity and neutralize peroxynitrites. Furthermore they exhibit self-regenerating properties that may be useful for therapeutic applications. In vitro studies demonstrated that CNP protect neurons and endothelial cells against oxidative stress-related damage. Recently, one study reported the benefits of CNP for reducing neuronal death in a model of cerebral ischemia in rats. In the present project, we aim to develop a new generation of CNP capable of preventing neuronal loss but also, by using a targeted-based strategy, to prevent endothelial damage and thus hemorrhagic transformations. The consortium gathers 3 academic teams and a French start-up with expertise and know-how in different fields of science including physics, nanotechnology, in vivo imaging and animal models of stroke. The working plan will consist in 1) synthesis of innovative copolymers that once coated on CNP will improve their stability and pharmacokinetics, and labeling and physical characterization of CNP, 2) in vitro study on cultured cerebral endothelial cells for investigating their cellular internalization and antioxidant capacity, and 3) in vivo studies to evaluate the protective effects of endothelium-targeting CNP against spontaneous or rt-PA-induced hemorrhagic transformations and neuronal loss as compared to (or in combination with) non-coated CNP; experiments will be conducted on a mouse model of stroke and the effects will be assessed by a clinically relevant method (magnetic resonance imaging). The outcome of the project will be the knowledge of the potential for our innovative antioxidant CNP as therapeutic agents in stroke. Because oxidative stress is a cornerstone in many other diseases, the new particles developed here may have broad therapeutic applications in health care beyond stroke.