PET-MRI nanoparticles imaging of blood–brain barrier damage and modulation after stroke reperfusion

Abstract

In an acute ischaemic stroke, understanding the dynamics of blood–brain barrier injury is of particular importance for the prevention of symptomatic haemorrhagic transformation. However, the available techniques assessing blood–brain barrier permeability are not quantitative and are little used in the context of acute reperfusion therapy. Nanoparticles cross the healthy or impaired blood–brain barrier through combined passive and active processes. Imaging and quantifying their transfer rate could better characterize blood–brain barrier damage and refine the delivery of neuroprotective agents. We previously developed an original endovascular stroke model of acute ischaemic stroke treated by mechanical thrombectomy followed by positron emission tomography-magnetic resonance imaging. Cerebral capillary permeability was quantified for two molecule sizes: small clinical gadolinium Gd-DOTA (<1 nm) and AGuIX ^® nanoparticles (∼5 nm) used for brain theranostics. On dynamic contrast-enhanced magnetic resonance imaging, the baseline transfer constant K _trans was 0.94 [0.48, 1.72] and 0.16 [0.08, 0.33] ×10 ⁻³min ⁻¹, respectively, in the normal brain parenchyma, consistent with their respective sizes, and 1.90 [1.23, 3.95] and 2.86 [1.39, 4.52] ×10 ⁻³min ⁻¹ in choroid plexus, confirming higher permeability than brain parenchyma. At early reperfusion, K _trans for both Gd-DOTA and AGuIX ^® nanoparticles was significantly higher within the ischaemic area compared to the contralateral hemisphere; 2.23 [1.17, 4.13] and 0.82 [0.46, 1.87] ×10 ⁻³min ⁻¹ for Gd-DOTA and AGuIX ^® nanoparticles, respectively. With AGuIX ^® nanoparticles, K _trans also increased within the ischaemic growth areas, suggesting added value for AGuIX ^®. Finally, K _trans was significantly lower in both the lesion and the choroid plexus in a drug-treated group (ciclosporin A, n = 7) compared to placebo ( n = 5). K _trans quantification with AGuIX ^® nanoparticles can monitor early blood–brain barrier damage and treatment effect in ischaemic stroke after reperfusion.

Abstract

Blood–brain barrier damage is the next target for neuroprotection after stroke ischaemia–reperfusion. Debatisse et al. used PET-MRI nanoparticles imaging for its precise quantification. Both brain infarct and choroid plexus permeabilities were significantly increased 2 h after recanalization. Finally, they were both decreased by a single ciclosporin A injection.

Graphical Abstract

Graphical Abstract