Development and optimization of new sclerosing embolizing agents for vascular diseases treatment

Endovascular treatment of abdominal aortic aneurysms (AAA), a localized dilatation of the aorta, involves deploying a stent to exclude the aneurysm from the blood stream and prevent it from breaking. The clinical success of this procedure, however, is limited by the frequent persistence or recurrence of blood flow within the aneurysm, called endoleak, which can lead to aneurysmal growth and increased risk of rupture. To treat or prevent endoleaks, embolization of the sac is increasingly performed by injection of an embolic agent to occlude the blood flow that persists in entering the aneurysm. However, current embolization agents are far from ideal and clinicians are looking for new injectables. The ideal embolizing agent should be injectable with good control, effectively occlude blood flow, be biocompatible and radiopaque. The hypothesis of this thesis is that the addition of a sclerosing agent (inducing endothelial denudation) and a metalloproteinase inhibitor (to reduce the progression of the aneurysm) would better prevent endoleaks. First, we have shown that a radiopaque chitosan thermogel containing sodium tetradecyl sulphate (STS) as a sclerosing / embolizing agent, previously developed in the laboratory, tends to reduce the number of endoleaks compared to an embolizing agent without sclerosing effect (hydrogel without STS) in a canine model of endovascular aneurysm repair. However, the difference between the groups was not statistically significant, perhaps because of the small number of animals. In a second step, we assessed the feasibility of developing a sclerosing embolizing agent from a currently marketed embolic agent (Onyx) and ethanol, which could be approved more quickly for clinical use. Finally, a thermosensitive hydrogel combining the occlusive, sclerosing and inhibitory properties of MMP was developed based on chitosan and doxycycline (DOX). This gel has promising endothelial ablation and MMP inhibition properties. Short-term in vivo CH-DOX gels in the renal arteries of pork validated its injectability, good radiopacity and good initial embolization of small blood vessels, however, reopening of blood flow was observed a few minutes later embolization. We believe that increasing the amount of medication would be a good option to remove this limitation of the project, but further investigation is needed.