Timely Visualization of the Collaterals Formed during Acute Ischemic Stroke with Fe₃O₄ Nanoparticle‐based MR Imaging Probe

Abstract

Ischemic stroke is one of the major leading causes for long-term disability and mortality. Collateral vessels provide an alternative pathway to protect the brain against ischemic injury after arterial occlusion. Aiming at visualizing the collaterals occurring during acute ischemic stroke, an integrin α β -specific Fe O -Arg-Gly-Asp (RGD) nanoprobe is prepared for magnetic resonance imaging (MRI) of the collaterals. Rat models are constructed by occluding the middle cerebral artery for imaging studies of cerebral ischemia and ischemia-reperfusion on 7.0 Tesla MRI using susceptibility-weighted imaging sequence. To show the binding specificity to the collaterals, the imaging results acquired with the Fe O -RGD nanoprobe and the Fe O mother nanoparticles, respectively, are carefully compared. In addition, an RGD blocking experiment is also carried out to support the excellent binding specificity of the Fe O -RGD nanoprobe. Following the above experiments, cerebral ischemia-reperfusion studies show the collateral dynamics upon reperfusion, which is very important for the prognosis of various revascularization therapies in the clinic. The current study has, for the first time, enabled the direct observation of collaterals in a quasi-real time fashion and further disclosed that the antegrade flow upon reperfusion dominates the blood supply of primary ischemic tissue during the early stage of infarction, which is significantly meaningful for clinical treatment of stroke.

Smart diagnostic nano-agents for cerebral ischemia

“…32,33 The strong diagnostic potential of SPIONs has been recently exploited for the timely visualization of the cerebral collaterals developed during ischemic injury after middle cerebral artery occlusion in rat models. 34 Leptomeningeal collaterals are small collaterals (50-400 mm) developing during the acute phase, and play an essential role in promoting retrograde perfusion of contiguous regions; due to their small size, imaging of these collaterals by CT and MRI is particularly challenging. The possibility of monitoring in real-time the dynamic of these cerebral collaterals can be particularly relevant for undertaking strategic clinical decisions, for analyzing collateral changes during therapy, and for evaluating the hemorrhage risks after reperfusion.…”

“…Binding specificity to cerebral collaterals has been obtained by targeting the a v b 3 integrin, which is highly expressed by human brain microvascular endothelial cells and plays a critical role in post-ischemic angiogenesis. 34 Specifically, modified PEG-coated Fe 3 O 4 magnetic nanoparticles with 6.4 AE 0.4 nm diameter were covalently functionalized with a targeting peptide sequence (e.g., Arg-Gly-Asp-Cys) via click reaction. The obtained nanoprobe (Fe 3 O 4 -RGD) showed optimal targeting specificity and allowed to monitor the collateral dynamics upon reperfusion: the cerebral collaterals rapidly appeared during the acute phase of ischemia, quickly disappeared upon reperfusion (obtained by removing the occlusion 2 h after surgery), and did not recover even after 24 h. These observations indicate a relevant time window for encouraging antegrade blood flow to lower the risk of hemorrhage.…”

Imaging Characteristics of USPIO Nanoparticles (<5 nm) as MR Contrast Agent In Vitro and in the Liver of Rats

“…Magnetic resonance imaging (MRI) is widely used in clinical practice due to its advantages of nonionizing radiation, multisequencing, and better soft tissue contrast. The latest results of molecular imaging using MR scanning provide new methods for noninvasive detection or tracking of such conditions as hepatocellular carcinoma [1, 2], atherosclerotic plaque [3], collateral circulation in acute ischemic stroke [4], and glioma gene therapy [5]. It is also emerging as a kind of functional MR probe system, for example, stimuli-responsive MRI-monitored drug delivery system, including pH-responsive [6–8] or thermo-responsive [9] ones.…”

Hedgehog‐Like Gold‐Coated Magnetic Microspheres that Strongly Inhibit Tumor Growth through Magnetomechanical Force and Photothermal Effects

“…Magnetic iron oxide (Fe 3 O 4 ) nanoparticles have excellent biocompatibility and have been approved by the United States Food and Drug Administration for clinical application . As a result, Fe 3 O 4 nanoparticles have been intensively researched for use in local magnetic fluid hyperthermia, magnetically targeted drug delivery, and in vivo imaging . Tumor hyperthermia using Fe 3 O 4 nanoparticles under an alternating magnetic field (AMF) has distinctive benefits for tumor ablation in deep tissue because of the convenience of distant control and manipulation by a magnetic field.…”