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

Justine Debatisse (1, 2) , Omer Faruk Eker (3, 4) , Océane Wateau (5) , Tae-Hee Cho (1, 4) , Marlene Wiart (1) , David Ramonet (1) , Nicolas Costes (6) , Inés Mérida (6) , Christelle Léon (1) , Maya Dia (1, 7) , Mélanie Paillard (1) , Joachim Confais (5) , Fabien Rossetti (8) , Jean-Baptiste Langlois (6) , Thomas Troalen (2) , Thibaut Iecker (6) , Didier Le Bars (4, 6) , Sophie Lancelot (4, 6) , Baptiste Bouchier (4) , Anne-Claire Lukasziewicz (4) , Adrien Oudotte (4) , Norbert Nighoghossian (1, 4) , Michel Ovize (1, 4) , Hugues Contamin (5) , François Lux (8, 9) , Olivier Tillement (8) , Emmanuelle Canet-Soulas (1)

1 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
2 Siemens Healthcare
3 CREATIS - Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé
4 HCL - Hospices Civils de Lyon
5 CYNBIOSE SA
6 CERMEP - Imagerie du vivant
7 LU / ULB - الجامعة اللبنانية [بيروت] = Lebanese University [Beirut] = Université libanaise [Beyrouth]
8 iLM - FENNEC - iLM - Formation, élaboration de nanomatériaux et cristaux
9 IUF - Institut universitaire de France

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 V R 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] Â10 À3 min À1 , 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] Â10 À3 min À1 in choroid plexus, confirming higher permeability than brain parenchyma. At early reperfusion, K trans for both Gd-DOTA and AGuIX V R 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] Â10 À3 min À1 for Gd-DOTA and AGuIX V R nanoparticles, respectively. With AGuIX V R nanoparticles, K trans also increased within the ischaemic growth areas, suggesting added value for AGuIX V R. Finally, K trans was significantly lower in both the lesion and the choroid plexus in a drug-treated group (ciclosporin A, n ¼ 7) compared to placebo (n ¼ 5). K trans quantification with AGuIX V R nanoparticles can monitor early blood-brain barrier damage and treatment effect in ischaemic stroke after reperfusion.

Mots clés: nanoparticles; stroke; blood-brain barrier; choroid plexus; ischaemia-reperfusion damage

Domaines: Ingénierie biomédicale

Justine Debatisse, Omer Faruk Eker, Océane Wateau, Tae-Hee Cho, Marlene Wiart, et al.. PET-MRI nanoparticles imaging of blood–brain barrier damage and modulation after stroke reperfusion. Brain Communications, 2020, 2 (2), ⟨10.1093/braincomms/fcaa193⟩. ⟨hal-03060618⟩