Cerebral Diseases
Thrombotic nanodisks to block abnormal blood vessels in brain
Dr Zhenjun Zhao
Macquarie University
Co-Investigators : Professor Marcus Stoodley, Dr Bingyang Shi, Dr Lucinda McRobb, Dr Libing Fu

Project Summary:

Brain arteriovenous malformations (AVMs) are abnormalities of blood vessels, in which direct connections form between arteries and veins. This leads to a high risk of rupture causing stroke which carries a 50% risk of death or disability in the children and young adults typically affected by AVMs.

Current treatments such as surgical removal and radiosurgery aim to prevent rupture, however each has limitations. No effective treatment is available for large and deep AVMs (one third of patients). There is an urgent need for an effective new treatment.

‘Vascular targeting’ may be an attractive approach for AVM treatment. This is the deliberate induction of blood clotting (thrombosis) in abnormal blood vessels. This technique utilises molecular differences between abnormal and normal vessels to specifically deliver drugs only to diseased vessels. Specific binding to unique molecules by antibodies linked to a clotting reagent induces thrombosis selectively in these vessels. Although unique molecules have not been identified on AVM vessels, priming with radiation has the potential to induce specific molecular changes on the surface of AVM vessels, making vascular targeting a possibility for these lesions.

In this study, we will develop nanotechnology to increase the efficiency and specificity of thrombotic agent delivery to irradiated AVM vessels. Disk shape nanoparticles (nanodisks) will be prepared that are linked with Annexin V (which targets and binds a radiation-stimulated molecule called phosphatidylserine), and thrombin (a thrombotic agent. We will test the efficacy of various formulations of these phosphatidylserine-targeting pro-thrombotic nanodisks in a flow chamber designed to artificially mimic the environment within an artery. This uses whole blood flowing over a layer of blood vessel cells to assess clotting on their surface in response to nanodisks in the presence or absence of radiation. Successful introduction of nanotechnology may improve the efficacy of our vascular targeting occlusion of AVM vessels.