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![| Gadovist concentration derived from the changes in: (A) T 2 *; (B) T 1 ; (C) first 10 min of T 2 * derived Gadovist concentration in the tumour (D) expanded scale of T 1 derived Gadovist concentration of mice 3, 4, and 5; (E) first 10 min of T 2 * derived Gadovist concentration in the thalamus (F) tumour time activity curve for [ 18 F] DPA-714. For mouse 1 in (B), the maximum calculated value was ~5,000 nmol, above which the calculation failed. Mouse 1-red, mouse 2-green, mouse 3-blue, mouse 4 black and mouse 5-purple.](publication/358577874/figure/fig3/AS:1136592479621120@1647996172689/Gadovist-concentration-derived-from-the-changes-in-A-T-2-B-T-1-C-first-10.png)
| Gadovist concentration derived from the changes in: (A) T 2 *; (B) T 1 ; (C) first 10 min of T 2 * derived Gadovist concentration in the tumour (D) expanded scale of T 1 derived Gadovist concentration of mice 3, 4, and 5; (E) first 10 min of T 2 * derived Gadovist concentration in the thalamus (F) tumour time activity curve for [ 18 F] DPA-714. For mouse 1 in (B), the maximum calculated value was ~5,000 nmol, above which the calculation failed. Mouse 1-red, mouse 2-green, mouse 3-blue, mouse 4 black and mouse 5-purple.
Source publication
Efficacy of diagnostics and therapeutics for brain tumours can be modulated by vascular delivery and blood brain barrier permeability. Simultaneous dynamic gadolinium MR-PET enables independent assessment of vascular delivery and blood brain barrier integrity in a brain tumour animal model in the presence of a PET tracer.
Dual echo dynamic gadolini...
Contexts in source publication
Context 1
... tumour tissue in mice 1 and 2 both displayed dramatically enhanced T 2 * ( Figure 3A) and T 1 ( Figure 3B) derived concentration curves relative to corresponding thalamus curves (Figures 2A,B) and compared to the tumour tissue in mice 3, 4, and 5. Mice 3, 4 and 5 showed modest increases in T 2 * and T 1 derived concentrations in the tumours ( Figure 3C) compared to the normal thalamus tissue ( Figure 3E). ...
Context 2
... tumour tissue in mice 1 and 2 both displayed dramatically enhanced T 2 * ( Figure 3A) and T 1 ( Figure 3B) derived concentration curves relative to corresponding thalamus curves (Figures 2A,B) and compared to the tumour tissue in mice 3, 4, and 5. Mice 3, 4 and 5 showed modest increases in T 2 * and T 1 derived concentrations in the tumours ( Figure 3C) compared to the normal thalamus tissue ( Figure 3E). ...
Context 3
... tumour tissue in mice 1 and 2 both displayed dramatically enhanced T 2 * ( Figure 3A) and T 1 ( Figure 3B) derived concentration curves relative to corresponding thalamus curves (Figures 2A,B) and compared to the tumour tissue in mice 3, 4, and 5. Mice 3, 4 and 5 showed modest increases in T 2 * and T 1 derived concentrations in the tumours ( Figure 3C) compared to the normal thalamus tissue ( Figure 3E). ...
Context 4
... tumour tissue in mice 1 and 2 both displayed dramatically enhanced T 2 * ( Figure 3A) and T 1 ( Figure 3B) derived concentration curves relative to corresponding thalamus curves (Figures 2A,B) and compared to the tumour tissue in mice 3, 4, and 5. Mice 3, 4 and 5 showed modest increases in T 2 * and T 1 derived concentrations in the tumours ( Figure 3C) compared to the normal thalamus tissue ( Figure 3E). ...
Context 5
... extent of the dramatic increase of delivery and uptake of Gadovist in the two large tumours was not evident in the time activity curves representing the tumour uptake of [ 18 F]DPA-714 ( Figure 3F). For example, at 10 min the T2* curve for the tumour in mouse 2 is approximately 8 times the other curves ( Figure 3A), yet the TAC curve is only about double the other curves ( Figure 3F). ...
Context 6
... extent of the dramatic increase of delivery and uptake of Gadovist in the two large tumours was not evident in the time activity curves representing the tumour uptake of [ 18 F]DPA-714 ( Figure 3F). For example, at 10 min the T2* curve for the tumour in mouse 2 is approximately 8 times the other curves ( Figure 3A), yet the TAC curve is only about double the other curves ( Figure 3F). The TAC for the tumour in mouse 2 was similar in intensity to the other three tumours (Figure 3F), despite a higher bolus ( Figure 3A) and the TAC amplitude being of less than half the intensity in the thalamus compared to the other mice. ...
Context 7
... extent of the dramatic increase of delivery and uptake of Gadovist in the two large tumours was not evident in the time activity curves representing the tumour uptake of [ 18 F]DPA-714 ( Figure 3F). For example, at 10 min the T2* curve for the tumour in mouse 2 is approximately 8 times the other curves ( Figure 3A), yet the TAC curve is only about double the other curves ( Figure 3F). The TAC for the tumour in mouse 2 was similar in intensity to the other three tumours (Figure 3F), despite a higher bolus ( Figure 3A) and the TAC amplitude being of less than half the intensity in the thalamus compared to the other mice. ...
Context 8
... example, at 10 min the T2* curve for the tumour in mouse 2 is approximately 8 times the other curves ( Figure 3A), yet the TAC curve is only about double the other curves ( Figure 3F). The TAC for the tumour in mouse 2 was similar in intensity to the other three tumours (Figure 3F), despite a higher bolus ( Figure 3A) and the TAC amplitude being of less than half the intensity in the thalamus compared to the other mice. the image resolution or number of slices decreases the temporal resolution. ...
Context 9
... example, at 10 min the T2* curve for the tumour in mouse 2 is approximately 8 times the other curves ( Figure 3A), yet the TAC curve is only about double the other curves ( Figure 3F). The TAC for the tumour in mouse 2 was similar in intensity to the other three tumours (Figure 3F), despite a higher bolus ( Figure 3A) and the TAC amplitude being of less than half the intensity in the thalamus compared to the other mice. the image resolution or number of slices decreases the temporal resolution. ...
Context 10
... calculation of the two T 1 and T 2 * concentrations from the TE image pairs allows altered tissue haemodynamics and perfusion to be measured within the tissue, not in a remote vessel. Subtle BBB transport changes are discernible from T 1 changes, as observed for mice 3-5 ( Figure 3D). Areas of extreme extravasation [16], mouse 1, are indicated by T 2 * changes. ...
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Citations
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with extremely limited therapeutic options. Abnormal accumulation of misfolded and aggregated proteins in the soma of motor neurons is one of the main pathological hallmarks of ALS. Hence, reducing the burden of misfolded protein in motor neurons has emerged as a promising therapeutic approach to control the disease. Antisense oligonucleotides (ASOs) carry the potential to effectively silence proteins with gain-of-function mutations, such as superoxide dismutase 1 (SOD1). However, the extremely poor blood-brain barrier (BBB) penetration of ASOs and invasiveness of current intrathecal delivery methods, warrant the development of alternative strategies for the delivery of ASOs to the central nervous system (CNS). In the current study, we report the effective delivery of a next-generation SOD1 ASO (Tofersen) into the brain of mice using calcium phosphate lipid nanoparticles following systemic delivery. Most importantly, for the first time, we demonstrate the superior capability of transcranial focused ultrasound (FUS) with intravenously administered microbubbles to significantly improve the delivery of ASO-loaded nanoparticles into the mouse brain compared to control mice receiving FUS without microbubbles. Histological examination in combination with contrast enhanced MRI suggests that the opening of the BBB in this context is transient and without evidence of any perturbation in the neural micro environment, parenchymal injury or necrosis indicating the treatment is well tolerated. Further in vivo evaluation of this strategy could lead to the development of a promising new approach for therapeutic delivery to treat ALS in patients.
