Design of Gadoteridol-Loaded Cationic Liposomal Adjuvant CAF01 for MRI of Lung Deposition of Intrapulmonary Administered Particles.

Designing effective and safe tuberculosis (TB) subunit vaccines for inhalation requires identification of appropriate antigens and adjuvants and definition of the specific areas to target in the lungs. Magnetic resonance imaging (MRI) enables high spatial resolution, but real-time anatomical and functional MRI of lungs is challenging. Here, we describe the design of a novel gadoteridol-loaded cationic adjuvant formulation 01 (CAF01) for MRI-guided vaccine delivery of the clinically tested TB subunit vaccine candidate H56/CAF01. Gadoteridol-loaded CAF01 liposomes were engineered by using a quality-by-design approach to (i) increase the mechanistic understanding of formulation factors governing the loading of gadoteridol and (ii) maximize the loading of gadoteridol in CAF01, which was confirmed by cryotransmission electron microscopy. The encapsulation efficiency and loading of gadoteridol were highly dependent on the buffer pH due to strong attractive electrostatic interactions between gadoteridol and the cationic lipid component. Optimal gadoteridol loading of CAF01 liposomes showed good in vivo stability and safety upon intrapulmonary administration into mice while generating 1.5-fold MRI signal enhancement associated with approximately 30% T1 relaxation change. This formulation principle and imaging approach can potentially be used for other mucosal nanoparticle-based formulations, species, and lung pathologies, which can readily be translated for clinical use.

Quantitative Gd-DOTA uptake from cerebrospinal fluid into rat brain using 3D VFA-SPGR at 9.4T.

PURPOSE: We propose a quantitative technique to assess solute uptake into the brain parenchyma based on dynamic contrast-enhanced MRI (DCE-MRI). With this approach, a small molecular weight paramagnetic contrast agent (Gd-DOTA) is infused in the cerebral spinal fluid (CSF) and whole brain gadolinium concentration maps are derived. METHODS: We implemented a 3D variable flip angle spoiled gradient echo (VFA-SPGR) longitudinal relaxation time (T1) technique, the accuracy of which was cross-validated by way of inversion recovery rapid acquisition with relaxation enhancement (IR-RARE) using phantoms. Normal Wistar rats underwent Gd-DOTA infusion into CSF via the cisterna magna and continuous MRI for approximately 130 min using T1-weighted imaging. Dynamic Gd-DOTA concentration maps were calculated and parenchymal uptake was estimated. RESULTS: In the phantom study, T1 discrepancies between the VFA-SPGR and IR-RARE sequences were approximately 6% with a transmit coil inhomogeneity correction. In the in vivo study, contrast transport profiles indicated maximal parenchymal retention of approximately 19% relative to the total amount delivered into the cisterna magna. CONCLUSION: Imaging strategies for accurate 3D contrast concentration mapping at 9.4T were developed and whole brain dynamic concentration maps were derived to study solute transport via the glymphatic system. The newly developed approach will enable future quantitative studies of the glymphatic system in health and disease states. Magn Reson Med 79:1568-1578, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Glycopyrrolate prevents extreme bradycardia and cerebral deoxygenation during electroconvulsive therapy.

The stimulation phase of electroconvulsive therapy (ECT) induces bradycardia. We evaluated the effect of this bradycardia on cerebral perfusion and oxygenation by administration of the anticholinergic drug glycopyrrolate (Glp). Cerebral perfusion was estimated by transcranial ultrasound in the middle cerebral artery reporting the mean flow velocity (middle cerebral artery [MCA] V(mean)), and cerebral oxygenation was determined by near-infrared spectroscopy of the frontal lobe. Before ECT, heart rate (HR) was 84 beats min(-1) (66-113; median and range) and decreased to 17 (7-85) beats min(-1) during the stimulation phase of ECT (P < 0.001). Middle cerebral artery V(mean) decreased 43% (9%-71%; P < 0.001), and frontal lobe oxyhemoglobin (O(2)Hb) concentration decreased from 0.6 (0.0-25.3) to 0.1 (-1.9 to 7.6) microM, whereas the deoxyhemoglobin concentration increased from -0.2 (-13.9 to 0.8) to 0.0 (-4.2 to 0.8) microM (P < 0.001). Pretreatment with Glp largely eliminated these effects during the stimulation phase of ECT, maintaining HR at 78 (40-94) beats min(-1), MCA V(mean) at 53 (37-77) cm s(-1), and O(2)Hb at 5.6 (10.6-38.5) microM (P < 0.05). After ECT, HR, cerebral perfusion and oxygenation normalized over approximately 3 minutes, whereas the electroencephalogram was unaffected by Glp. The results demonstrate that ECT is associated with hemodynamic effects severe enough to affect cerebral oxygenation and perfusion, and that these effects can be attenuated by Glp treatment.