Occlusion of Animal Model Arteriovenous Malformations Using Vascular Targeting

The Evolution of Safe and Effective Coaguligands for Vascular Targeting and Precision Thrombosis of Solid Tumors and Vascular Malformations

“…In vivo studies subsequently demonstrated that significant occlusion of the rat model AVM vessels could be achieved with this coaguligand [46]. Although, in the latter study, both nonirradiated and irradiated AVMs showed thrombotic occlusion at high conjugate doses (potentially due to altered hemodynamics in the surgically created AVM [47]), specificity at the irradiated tissue was improved by coaguligand dose reduction, although with a concomitant reduction in efficacy [46]. These foundational studies using PS as the molecular target provided proof-of-principle that vascular infarction could be applied to the larger high flow vessels of brain AVMs using a radiation-priming approach for specific target induction as well as induction of a supportive pro-coagulatory endothelial surface.…”

“…Using a PS-targeting annexin V protein conjugated to thrombin as an effector, it was first established in vitro that rapid and selective thrombosis could be induced on an irradiated endothelial cell layer using whole human blood circulating in a parallel-plate flow system [40]. In vivo studies subsequently demonstrated that significant occlusion of the rat model AVM vessels could be achieved with this coaguligand [46]. Although, in the latter study, both nonirradiated and irradiated AVMs showed thrombotic occlusion at high conjugate doses (potentially due to altered hemodynamics in the surgically created AVM [47]), specificity at the irradiated tissue was improved by coaguligand dose reduction, although with a concomitant reduction in efficacy [46].…”

“…As described earlier, PS-targeting annexin-V coaguligands constructed with thrombin rather than TF were used to induce thrombosis in vitro as well as in vivo in an AVM rat model [40,46]. Thrombin was chosen for these proof-of-principle studies for two primary reasons: (1) early non-targeted studies using soluble, non-targeted TF induced small but not large vessel occlusion in AVMs in vivo, suggesting a more potent thrombogenic effector may be required to occlude large, high flow vessels [36]; and (2) PS-targeting ligands can neutralize TF activity [34].…”

“…Thrombin was chosen for these proof-of-principle studies for two primary reasons: (1) early non-targeted studies using soluble, non-targeted TF induced small but not large vessel occlusion in AVMs in vivo, suggesting a more potent thrombogenic effector may be required to occlude large, high flow vessels [36]; and (2) PS-targeting ligands can neutralize TF activity [34]. Gauden et al demonstrated for the first time that large vessels can be induced to form stable thrombi with targeted thrombin but also that thrombin could be safely administered by systemic infusion within certain dose thresholds [46]. Further studies to assess whether occlusion of large high flow vessels in AVMs could still be achieved with targeted tTF (using surface markers other than PS) are still required to ensure that the safest approach can be taken forward to the clinic.…”

Externalization of Mitochondrial PDCE2 on Irradiated Endothelium as a Target for Radiation-Guided Drug Delivery and Precision Thrombosis of Pathological Vasculature

“…Radiation damage sets off a cascade of cellular events in endothelial cells that can alter the molecules or proteins at the cell surface (surfaceome) [ 4 , 5 , 15 , 16 ]. Surface exposure of common inflammatory markers such as phosphatidylserine (PS), vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) have been previously investigated as radiation-stimulated targets in an AVM animal model [ 6 , 7 , 13 , 17 ]. However, their frequent exposure in response to other biological stimuli may reduce targeting specificity.…”