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. 2017 Jan 15;31(1):1-8.
doi: 10.1002/rcm.7749.

Gas chromatography/mass spectrometry measurement of xenon in gas-loaded liposomes for neuroprotective applications

Melvin E Klegerman  1 , Melanie R Moody  1 , Jermaine R Hurling  1 , Tao Peng  1 , Shao-Ling Huang  1 , David D McPherson  1
Affiliations

Gas chromatography/mass spectrometry measurement of xenon in gas-loaded liposomes for neuroprotective applications

Melvin E Klegerman et al. Rapid Commun Mass Spectrom. .

Abstract

Rationale: We have produced a liposomal formulation of xenon (Xe-ELIP) as a neuroprotectant for inhibition of brain damage in stroke patients. This mandates development of a reliable assay to measure the amount of dissolved xenon released from Xe-ELIP in water and blood samples.

Methods: Gas chromatography/mass spectrometry (GC/MS) was used to quantify xenon gas released into the headspace of vials containing Xe-ELIP samples in water or blood. In order to determine blood concentration of xenon in vivo after Xe-ELIP administration, 6 mg of Xe-ELIP lipid was infused intravenously into rats. Blood samples were drawn directly from a catheterized right carotid artery. After introduction of the samples, each vial was allowed to equilibrate to 37°C in a water bath, followed by 20 minutes of sonication prior to headspace sampling. Xenon concentrations were calculated from a gas dose-response curve and normalized using the published xenon water-gas solubility coefficient.

Results: The mean corrected percent of xenon from Xe-ELIP released into water was 3.87 ± 0.56% (SD, n = 8), corresponding to 19.3 ± 2.8 μL/mg lipid, which is consistent with previous independent Xe-ELIP measurements. The corresponding xenon content of Xe-ELIP in rat blood was 23.38 ± 7.36 μL/mg lipid (n = 8). Mean rat blood xenon concentration after intravenous administration of Xe-ELIP was 14 ± 10 μM, which is approximately 15% of the estimated neuroprotective level.

Conclusions: Using this approach, we have established a reproducible method for measuring dissolved xenon in fluids. These measurements have established that neuroprotective effects can be elicited by less than 20% of the calculated neuroprotective xenon blood concentration. More work will have to be done to establish the protective xenon pharmacokinetic range. Copyright © 2016 John Wiley & Sons, Ltd.

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Figures

Figure 1
Figure 1
Schematic diagram of apparatus for determination of equilibrium xenon solubility in water at 37°C. Xenon gas was circulated through water on a digital hotplate in a closed system. Water aliquots were sampled with a syringe and transferred to vials for GC-MS analysis.
Figure 2
Figure 2
GC-MS trace showing separation of air components from xenon and MS spectrum of the GC peak eluting at 5.323 minutes (inset).
Figure 3
Figure 3
Xenon gas GC-MS dose-response curve. Gas samples (5 μl) from mixtures of various proportions of xenon in air were manually injected. AUC for peaks were determined by auto-integration. Each point (filled circles) is the mean of 4-5 determinations ± SD; r = 0.997, y = 38.1 × – 22.3. AUC of the certified gas standard (25% Xe/75% Ar; n = 6) and its dilutions (open circles) fall around the standard curve.
Figure 4
Figure 4
GC-MS trace of the ISO 13485 QC standard, showing separation of argon and air components from xenon and MS spectra for all components (inset).
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