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. 2018 Jan 11;8(1):450.
doi: 10.1038/s41598-017-18914-6.

Delivery of xenon-containing echogenic liposomes inhibits early brain injury following subarachnoid hemorrhage

Yi-Feng Miao  1 , Tao Peng  1 , Melanie R Moody  1 , Melvin E Klegerman  1 , Jaroslaw Aronowski  2 , James Grotta  3 , David D McPherson  1 , Hyunggun Kim  4   5 , Shao-Ling Huang  6
Affiliations

Delivery of xenon-containing echogenic liposomes inhibits early brain injury following subarachnoid hemorrhage

Yi-Feng Miao et al. Sci Rep. .

Abstract

Xenon (Xe), a noble gas, has promising neuroprotective properties with no proven adverse side-effects. We evaluated neuroprotective effects of Xe delivered by Xe-containing echogenic liposomes (Xe-ELIP) via ultrasound-controlled cerebral drug release on early brain injury following subarachnoid hemorrhage (SAH). The Xe-ELIP structure was evaluated by ultrasound imaging, electron microscopy and gas chromatography-mass spectroscopy. Animals were randomly divided into five groups: Sham, SAH, SAH treated with Xe-ELIP, empty ELIP, or Xe-saturated saline. Treatments were administrated intravenously in combination with ultrasound application over the common carotid artery to trigger Xe release from circulating Xe-ELIP. Hematoma development was graded by SAH scaling and quantitated by a colorimetric method. Neurological evaluation and motor behavioral tests were conducted for three days following SAH injury. Ultrasound imaging and electron microscopy demonstrated that Xe-ELIP have a unique two-compartment structure, which allows a two-stage Xe release profile. Xe-ELIP treatment effectively reduced bleeding, improved general neurological function, and alleviated motor function damage in association with reduced apoptotic neuronal death and decreased mortality. Xe-ELIP alleviated early SAH brain injury by inhibiting neuronal death and bleeding. This novel approach provides a noninvasive strategy of therapeutic gas delivery for SAH treatment.

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Conflict of interest statement

Drs. Klegerman, McPherson, Kim, Huang and The University of Texas Health Science Center at Houston have research-related financial interests in Zymo Pharmaceuticals, L.L.C.

Figures

Figure 1
Figure 1
Imaging of liposomes without gas loading and Xe-ELIP using IVUS and electron microscopy. (a) IVUS image of normal liposomes (without gas inside), (b) Xe-containing ELIP (white contents in the marked area indicate ultrasound reflectivity from Xe gas bubbles in Xe-ELIP), (c) Electron microscopic image of normal liposomes (without gas inside), and (d) gas-containing liposomes (gas-containing liposomes have wider lipid bilayers). Red lines refer to the region of interest where acoustic reflectivity was measured. Arrows indicate the thickness of the lipid bilayer.
Figure 2
Figure 2
Fluorescence microscopy of (a) normal endothelial cells without any treatment, (b) normal endothelial cells incubated with FITC-labeled ELIP, (c) TNF-α treated cells without any treatment, and (d) TNF-α treated cells incubated with FITC-labeled ELIP.
Figure 3
Figure 3
Effect of Xe-ELIP treatment. (a) general neurological and motor function, (b) beam walking, and (c) grid walking on day 1, day 2 and day 3 after SAH onset.
Figure 4
Figure 4
Effect of Xe-ELIP treatment on brain hemorrhage. Gross anatomy of brain hemorrhage in (a) Sham, (b) SAH without treatment, (c) Xe-ELIP, (d) ELIP, and (e) Xe solution groups. (f) Grading of the severity of SAH grade was determined as the sum of the scores from the 6 subsections. Data are shown as mean ± SEM (n = 8 animals/group).
Figure 5
Figure 5
Quantitation of hemorrhagic volume in the Sham, SAH, and Xe-ELIP groups. Hemorrhagic volume was measured using a spectrophotometer. Data are shown as mean ± SEM (n = 6 animals/group).
Figure 6
Figure 6
Immunofluorescent staining of the coronal sections of brain subcortex. TUNEL staining in (a) Sham, (b) SAH, (c) Xe-ELIP, (d) ELIP, and (e) Xe solution groups. The TUNEL-positive cells were stained with green fluorescence. Nuclei were counter stained with DAPI (blue). (f) The number of TUNEL-positive cells was calculated per mm2. Data are shown as mean ± SEM (n = 8 animals/group). (g) Colocalization of the TUNEL-positive cells (green) with the neurons (red). Arrows indicate colocalized TUNEL-positive cells. (h) Colocalization of the caspase 3-positive cells (green) with the neurons (red). Arrows indicate colocalized caspase 3-positive cells. (i) Colocalization of neutrophils (green) with blood vessel (red) in the subcortex in the SAH and Xe-ELIP groups. Arrows indicate neutrophil infiltration in the brain tissue.
Figure 7
Figure 7
(a) Schematic of the Xe delivery strategy using Xe-ELIP. Xe-ELIP can be infused intravenously and ultrasound applied over the common carotid artery for ultrasound-triggered priminary Xe release from circulating Xe-ELIP into the brain. (b) Xe-ELIP adhesion to the damaged endothelial cells to patch the hole and localize secondary release. Normal endothelium is negatively charged as the endothelium itself has an inner glycoprotein coat of negatively charged particles. After cellular damage, collagen and tissue underneath the endothelium are exposed and have positive charges. Xe-ELIP have slight negative charges and stick to the damaged vascular site to aid in repair and allow localized Xe release.
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