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

Abstract

In cardiovascular and cerebrovascular biology, control of thrombosis and the coagulation cascade in ischemic stroke, myocardial infarction, and other coagulopathies is the focus of significant research around the world. Ischemic stroke remains one of the largest causes of death and disability in developed countries. Preventing thrombosis and protecting vessel patency is the primary goal. However, utilization of the body’s natural coagulation cascades as an approach for targeted destruction of abnormal, disease-associated vessels and tissues has been increasing over the last 30 years. This vascular targeting approach, often termed “vascular infarction”, describes the deliberate, targeted delivery of a thrombogenic effector to diseased blood vessels with the aim to induce localized activation of the coagulation cascade and stable thrombus formation, leading to vessel occlusion and ablation. As systemic delivery of pro-thrombotic agents may cause consternation amongst traditional stroke researchers, proponents of the approach must suitably establish both efficacy and safety to take this field forward. In this review, we describe the evolution of this field and, with a focus on thrombogenic effectors, summarize the current literature with respect to emerging trends in “coaguligand” development, in targeted tumor vessel destruction, and in expansion of the approach to the treatment of brain vascular malformations.

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

“…PS is an abundant phospholipid that flips from the inner surface of the plasma membrane to the outer surface in response to a variety of biological stimuli, including radiation, and is most often observed in apoptotic cells [ 28 , 29 , 30 ]. The higher efficacy may reflect greater levels of PS exposure at the surface relative to PDCE2 and CRYAB or, alternatively, could reflect the relative affinity of each ligand for their respective targets [ 1 ]. A recent in vivo investigation of PS targeting in a rat AVM model revealed that both irradiated and non-irradiated vasculature could be thrombosed with a high affinity PS-targeting VTA [ 17 ].…”

“…Vascular targeting with precision thrombosis is an approach aimed at occlusion and destruction of pathological vasculature in tumors and brain arteriovenous malformations (AVMs) [ 1 , 2 , 3 ]. This approach requires the identification of discriminatory biomarkers at the luminal surface of the pathological endothelium for use as molecular targets for the focused delivery of thrombogenic agents.…”

“…This approach requires the identification of discriminatory biomarkers at the luminal surface of the pathological endothelium for use as molecular targets for the focused delivery of thrombogenic agents. To date, various endogenous markers have been identified on tumor vasculature and investigated in mouse tumor infarction models (reviewed in [ 1 ]). However, limitations to endogenous biomarker discovery in brain arteriovenous malformations (AVMs) have led to the use of ionizing radiation as a priming agent for target generation in this context [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ].…”

Erythrocyte Membrane‐Coated Invisible Acoustic‐Sensitive Nanoparticle for Inducing Tumor Thrombotic Infarction by Precisely Damaging Tumor Vascular Endothelium

“…[17][18][19] Suboptimal embolization of large tumor vessels is one of the main challenges of current treatment strategies. [8,20,21] The intensity of the induced coagulation effect in the tumor large vessels directly determines the final embolic effect, and the development of more intense and sensitive coagulation initiation modalities is an urgent requirement to further promote the development of tumor thrombosis infarction therapy. Moreover, the coagulation-cascade effect in the tumor vasculature forms thrombus after initiation, while the fibrinolytic system is also activated.…”