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Targeting of externalized αB-crystallin on irradiated endothelial cells with pro-thrombotic vascular targeting
Sinduja Subramanian1, Zhenjun Zhao1, Fahimeh Faqihi1
1Department of Clinical Medicine, Macquarie University, Sydney 2109, Australia.
Background:
Vascular targeting uses molecular markers on the surface of diseased vasculature for ligand-directed drug delivery to induce vessel occlusion or destruction. In the absence of discriminatory markers, such as in brain arteriovenous malformations (AVMs), stereotactic radiosurgery may be used to prime molecular changes on the endothelial surface. This study explored αB-crystallin (CRYAB) as a radiation induced target and pre-tested the specificity and efficacy of a CRYAB-targeting coaguligand for in vitro thrombus induction.
Methods:
A parallel-plate flow system was established to circulate human whole blood over a layer of human brain endothelial cells. A conjugate of anti-CRYAB antibody and thrombin was injected into the circuit to compare binding and thrombus formation on cells with or without prior radiation treatment (0-25 Gy).
Results:
Radiation increased CRYAB expression and surface exposure in human brain endothelial cells. In the parallel-plate flow system, the targeted anti-CRYAB-thrombin conjugate increased thrombus formation on the surface of irradiated cells relative to non-irradiated cells and to a non-targeting IgG-thrombin conjugate. Fibrin deposition and accumulation of fibrinogen degradation products increased significantly at radiation doses at or above 15 Gy with conjugate concentrations of 1.25 and 2.5 μg/mL.
Conclusions:
CRYAB exposure can be detected at the surface of human brain endothelial cells in response to irradiation. Pro-thrombotic CRYAB-targeting conjugates can bind under high flow conditions and in the presence of whole blood induce stable thrombus formation with high specificity and efficacy on irradiated surfaces. CRYAB provides a novel radiation marker for potential vascular targeting in irradiated brain AVMs.
Insights
Radiation exposure increases alphaB-crystallin (CRYAB) on brain endothelial cells. A CRYAB-targeting coaguligand effectively induces thrombus formation on these irradiated cells, offering a novel vascular targeting strategy.
Area of Science:
- Biomedical Engineering
- Vascular Biology
- Radiation Oncology
Background:
- Vascular targeting relies on molecular markers for drug delivery to diseased vessels.
- Brain arteriovenous malformations (AVMs) lack discriminatory markers, necessitating alternative strategies.
- Stereotactic radiosurgery can induce molecular changes on endothelial surfaces for targeting.
Purpose of the Study:
- To investigate alphaB-crystallin (CRYAB) as a radiation-induced target.
- To evaluate the efficacy of a CRYAB-targeting coaguligand for in vitro thrombus induction.
- To assess the specificity of CRYAB as a marker for vascular targeting post-irradiation.
Main Methods:
- Established a parallel-plate flow system with human brain endothelial cells.
- Circulated human whole blood over cells with or without prior radiation (0-25 Gy).
- Injected an anti-CRYAB antibody-thrombin conjugate to assess binding and thrombus formation.
Main Results:
- Irradiation significantly increased CRYAB expression and surface exposure on endothelial cells.
- The anti-CRYAB-thrombin conjugate demonstrated increased thrombus formation on irradiated cells versus non-irradiated controls.
- Significant fibrin deposition and degradation product accumulation occurred at radiation doses ≥15 Gy.
Conclusions:
- Surface exposure of CRYAB on brain endothelial cells is detectable post-irradiation.
- CRYAB-targeting conjugates exhibit specific and effective thrombus formation on irradiated surfaces under flow conditions.
- CRYAB serves as a novel radiation marker for potential vascular targeting in irradiated brain AVMs.
