Assessment of Aptamer-Targeted Contrast Agents for Monitoring of Blood Clots in Computed Tomography and Fluoroscopy Imaging.

Objective: Random formation of thrombi is classified as a pathological process that may result in partial or complete obstruction of blood flow and limited perfusion. Further complications include pulmonary embolism, thrombosis-induced myocardial infraction, ischemic stroke, and others. Location and full delineation of the blood clot are considered to be two clinically relevant aspects that could streamline proper diagnosis and treatment follow-up. In this work, we prepared two types of X-ray attenuating contrast formulations, using fibrinogen aptamer as the clot-seeking moiety. Methods: Two novel aptamer-targeted formulations were designed. Iodine-modified bases were directly incorporated into a fibrinogen aptamer (iodo-FA). Isothermal titration calorimetry was used to confirm that these modifications did not negatively impact target binding. Iodo-FA was tested for its ability to produce concentration-dependent contrast enhancement in a phantom CT. It was subsequently tested in vitro with clotted human and swine blood. This allowed for translation into ex vivo testing, using fluoroscopy. FA was also used to functionalize gold nanoparticles (FA-AuNPs), and contrast capabilities were confirmed. This formulation was tested in vitro using clotted human blood in a CT scan. Results: Unmodified FA and iodo-FA demonstrated a nearly identical affinity toward fibrin, confirming that base modifications did not impact target binding. Iodo-FA and FA-AuNPs both demonstrated excellent concentration-dependent contrast enhancement capabilities (40.5 HU mM-1 and 563.6 HU µM-1, respectively), which were superior to the clinically available agent, iopamidol. In vitro CT testing revealed that iodo-FA is able to penetrate into the blood clots, producing contrast enhancement throughout, while FA-AuNPs only accumulated on the surface of the clot. Iodo-FA was thereby translated to ex vivo testing, confirming target-binding associated accumulation of the contrast material at the location of the clot within the dilation of the external carotid artery. This resulted in a 34% enhancement of the clot. Conclusions: Both iodo-FA and FA-AuNPs were confirmed to be effective contrast formulations in CT. Targeting of fibrin, a major structural constituent of thrombi, with these novel contrast agents would allow for higher contrast enhancement and better clot delineation in CT and fluoroscopy.

Use of Flow Diversion for the Treatment of Distal Circulation Aneurysms: A Multicohort Study.

OBJECTIVE: The safety and efficacy of flow diversion for distal circulation aneurysms of the cerebral vasculature has not been well evaluated. The objective of this study was to assess the use of flow diversion for distal circulation aneurysms (defined as at or beyond the M1, P1, and A1 segments of the middle cerebral artery, posterior cerebral artery, and anterior cerebral artery, respectively) in an international multicenter cohort. METHODS: Clinical and radiologic records from all patients undergoing flow diversion treatment of distal circulation aneurysms at 3 academic centers (2 in the USA and 1 in Europe) from 2014 until 2017 were retrospectively reviewed. RESULTS: Forty-six patients (mean age, 58.2 years; 33 women) harboring 46 aneurysms who underwent treatment with either the Pipeline Embolization Device (Medtronic Inc., Dublin, Ireland) or the Flow Re-Direction Endoluminal Device (MicroVention, Tustin, California, USA) were included in these analyses. Thirty-four aneurysms (74%) were located in the anterior circulation and 12 (26%) were located in the posterior circulation. With a mean follow-up of 13.0 months, complete (100%) and near-complete (90%-99%) occlusion was noted in 36 aneurysms (78.2%). Angiographic evidence of side branch or perforator vessel coverage was present in 35 aneurysms (76.1%) but was not associated with failure to occlude at follow-up (P = 0.06). All patients had good functional outcomes after treatment (modified Rankin Scale score 0-2). There were 2 cases (4.3%) of perforator vessel stroke and no hemorrhagic complications. CONCLUSIONS: Flow diversion for aneurysms beyond the circle of Willis has occlusion rates comparable to alternative treatments and low morbidity. The clinical significance of flow limitation through covered side branches requires further investigation.