Perfluorocarbon Enhanced Glasgow Oxygen Level Dependent (GOLD) Magnetic Resonance Metabolic Imaging Identifies the Penumbra Following Acute Ischemic Stroke

Abstract

The ability to identify metabolically active and potentially salvageable ischaemic penumbra is crucial for improving treatment decisions in acute stroke patients. Our solution involves two complementary novel MRI techniques (Glasgow Oxygen Level Dependant (GOLD) Metabolic Imaging), which when combined with a perfluorocarbon (PFC) based oxygen carrier and hyperoxia can identify penumbra due to dynamic changes related to continued metabolism within this tissue compartment. Our aims were (i) to investigate whether PFC offers similar enhancement of the second technique (Lactate Change) as previously demonstrated for the T2*OC technique (ii) to demonstrate both GOLD metabolic imaging techniques working concurrently to identify penumbra, following administration of Oxycyte® (O-PFC) with hyperoxia.Methods: An established rat stroke model was utilised. Part-1: Following either saline or PFC, magnetic resonance spectroscopy was applied to investigate the effect of hyperoxia on lactate change in presumed penumbra. Part-2; rats received O-PFC prior to T2*OC (technique 1) and MR spectroscopic imaging, which was used to identify regions of tissue lactate change (technique 2) in response to hyperoxia. In order to validate the techniques, imaging was followed by [14C]2-deoxyglucose autoradiography to correlate tissue metabolic status to areas identified as penumbra.Results: Part-1: PFC+hyperoxia resulted in an enhanced reduction of lactate in the penumbra when compared to saline+hyperoxia. Part-2: Regions of brain tissue identified as potential penumbra by both GOLD metabolic imaging techniques utilising O-PFC, demonstrated maintained glucose metabolism as compared to adjacent core tissue.Conclusion: For the first time in vivo, enhancement of both GOLD metabolic imaging techniques has been demonstrated following intravenous O-PFC+hyperoxia to identify ischaemic penumbra. We have also presented preliminary evidence of the potential therapeutic benefit offered by O-PFC. These unique theranostic applications would enable treatment based on metabolic status of the brain tissue, independent of time from stroke onset, leading to increased uptake and safer use of currently available treatment options.

Continuous-Flow Production of Perfluorocarbon-Loaded Polymeric Nanoparticles: From the Bench to Clinic

“… 9 , 22 , 24 On the therapeutic side, PFC-based colloids show promising results in the transportation of oxygen for the treatment of cancer 1 − 3 , 5 , 6 or stroke. 7 Therefore, in the current study, after basic toxicity testing, we focused on imaging applications and the oxygen loading in vitro .…”

“…Owing to the ability to carry oxygen, PFC-loaded NPs find application in photodynamic 1 − 4 and other hypoxia-affected treatments of cancer 5 , 6 and treatment of stroke. 7 , 8 Additionally, they act as multimodal imaging agents for 19 F magnetic resonance imaging ( 19 F MRI) and ultrasound. 9 − 12 PFCs, however, have already seen a long and much more varied history of clinical use.…”

Smart diagnostic nano-agents for cerebral ischemia

“…This work represents a good example of a multifunctional nanostructure able to act as a labeling agent in two techniques used to provide information at two different levels: on one side, IVM provided insight about cellular localization of the particles, on the other one MRI provides useful information at whole organ level. 45 The last example of a label-free nano theranostic platform for cerebral ischemia has been recently proposed for the reliable identification and treatment of the hypo-perfused, metabolically active ischemic penumbra tissue, 46 the functional rescue of which significantly improves the clinical outcome. This nanoplatform is based on perfluorocarbon (PFC) oxygen carrier nanoemulsion (200 nm particle size), coupled with innovative MRI approaches allowing for oxygen change (OC) and lactate change (LC) metabolic imaging.…”

A characterization of ABL‐101 as a potential tracer for clinical fluorine‐19 MRI

“…An alternative might therefore be ABL-101 (previously known as Oxycyte), which is a third generation intravenous PFC emulsion that is currently being developed by Aurum Biosciences Ltd (Glasgow, United Kingdom) for combined diagnostic and therapeutic clinical application in acute ischemic stroke. 20,21 ABL-101 consists of perfluoro(t-butylcyclohexane) molecules in a 60% w/v concentration in saline, with egg phospholipid as an emulsifier. 22 Perfluoro(t-butylcyclohexane) consists of five magnetically inequivalent CF2 groups and a CF group on a hexane ring as well as three magnetically equivalent CF3 groups in the tertbutyl part (Figure 1a).…”

“…Its molecular formula is C10F20 and it has a molar mass of 500.08g/mol. It was initially developed for oxygen delivery after traumatic brain injury (by Tenax Therapeutics Inc, Morrisville, NC, USA), and its capacity as an oxygen carrier was among others investigated in animal models of brain injury, 20,23 and acute respiratory distress syndrome. 24 Its capacity to enhance microvascular blood flow was also investigated in an animal model of arterial gas embolism.…”