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

Abstract

In acute ischemic stroke, understanding the dynamics of blood–brain barrier injury is of particular importance for the prevention of symptomatic hemorrhagic 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 ischemic 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 MRI, the baseline transfer constant Ktrans was 0.94 [0.48, 1.72] and 0.16 [0.08, 0.33] x10−3 min−1, respectively, in normal brain parenchyma, consistent with their respective sizes, and 1.90 [1.23, 3.95] and 2.86 [1.39, 4.52] x10−3 min−1 in choroid plexus, confirming higher permeability than brain parenchyma. At early reperfusion, Ktrans for both Gd-DOTA and AGuIX® nanoparticles was significantly higher within the ischemic area compared to the contralateral hemisphere; 2.23 [1.17, 4.13] and 0.82 [0.46, 1.87] x10−3 min−1 for Gd-DOTA and AGuIX® nanoparticles, respectively. With AGuIX® nanoparticles, Ktrans also increased within the ischemic growth areas, suggesting added value for AGuIX®. Finally, Ktrans 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). Ktrans quantification with AGuIX® nanoparticles can monitor early blood–brain barrier damage and treatment effect in ischemic stroke after reperfusion.

In vivo methods for imaging blood–brain barrier function and dysfunction

“…On another hand, PET imaging may also prove useful to evaluate the permeability of the BBB to nanoparticles with potential therapeutic perspectives as illustrated by Debatisse et al [ 270 ]. However, such application is only relevant in case of severe BBB alterations, such as in stroke, due to the fairly large size of such nanoparticles (~ 10 kDa).…”

Quantitative Tissue Pharmacokinetics and EPR Effect of AGuIX Nanoparticles: A Multimodal Imaging Study in an Orthotopic Glioblastoma Rat Model and Healthy Macaque

“…AGuIX displays free accessible DOTA moieties (1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid) at their surface enabling their radiolabeling with radioisotopes such as, 111 In (single photon emission computed tomography (SPECT), t 1/2 = 67.2 h) , [ 14 ] 68 Ga (PET, t 1/2 = 68 min), [ 43 ] or 64 Cu (PET, t 1/2 = 12.7 h) . [ 44 ] However, SPECT has low spatial resolution, while the half‐life of 68 Ga is relatively short and 64 Cu tends to deposit in the liver, which limit their use for accurately imaging the distribution of AGuIX in the tumor especially several days after injection.…”

Cortical inflammation and brain signs of high-risk atherosclerosis in a non-human primate model

“…As such, they can induce transient blood − brain barrier permeability and focal microglia activation. In stroke, blood − brain permeability leakage is an early and transient event after ischaemia and reperfusion 44 , 45 whereas TSPO activation is increased 1−3 weeks later. 46 , 47 In the cynomolgus monkey, the frontal cortex is first in line for ischaemia after middle cerebral artery occlusion 48 which could explain TSPO activation in this region.…”