Direct delivery of MRI contrast through skull vessel/marrow pathways into the brain guided by microCT

Rationale: The brain remains a challenging organ for drug delivery. Earlier studies demonstrated that transcranial application of small molecular therapeutics and MRI contrast such as manganese ion (Mn²⁺) could serve as a new method for delivering molecules to the brain. In this earlier work using rats, manganese-enhanced MRI (MEMRI) demonstrated that Mn²⁺ passed most effectively through regions of the skull containing suture lines or dense vessel/marrow. In the present study, the delivery of Mn²⁺ to the brain using specific skull vessel/marrow pathways has been investigated. Methods: In-vivo microCT scans of rat skull was conducted to study the intricate geometry of vessel/marrow pathways connecting the outer skull surface and meninges. Specific vessel/marrow paths were identified. MnCl₂ (500 mM) solution was pipetted directly on the skull bone surface above the target path. After 2 hr, rats were subjected to MRI. Results: High-resolution microCT images reveal that (a) there are "short paths" through the skull which have vessels on the outer surface of the skull, which directly pass through the vessel/marrow and then reach the meninges on the other side of the skull; (b) the skull above the cerebellum (interparietal bone) exhibits a significantly higher density of vessel/marrow compared to the frontal and parietal bone enabling testing whether direct application to skull enables transcranial movement and (c) thinning the skull in specific regions can lead to exposing vessel pathways from mid-skull to the meninges. Guided by microCT imaging, Mn²⁺ delivery to the brain could be accomplished as assayed with MEMRI through these different specific pathways. Two hours post pipetting MnCl₂ solution onto the top of a short path through the intact skull, Mn²⁺ could be delivered readily to levels that produce detectable brain tissue enhancement by MEMRI. A T₁ enhanced volume of 2.27 ± 1.47 mm³ was measured through the short path. Two hours post applying a MnCl₂ solution to the intact skull above the cerebellum enabled MEMRI detection of a volume of enhanced brain tissue of 2.48 ± 2.66 mm³. Finally, in areas where surface short paths are absent but a path from mid skull to meninges is present, minimal thinning of the skull led to effective Mn²⁺ delivery, enabling MEMRI detection of volume of 4.68 ± 2.70 mm³. Conclusions: MicroCT-guided transcranial delivery via vessel/marrow pathways may offer a less invasive and more localized method for administering imaging probes and therapeutics to the brain.