Dynamic dual-isotope molecular imaging elucidates principles for optimizing intrathecal drug delivery
Daniel A. Wolf, … , Jack Hoppin, Ajay Verma
Daniel A. Wolf, … , Jack Hoppin, Ajay Verma
Published February 25, 2016
Citation Information: JCI Insight. 2016;1(2):e85311. https://doi.org/10.1172/jci.insight.85311.
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Resource and Technical Advance Neuroscience Therapeutics

Dynamic dual-isotope molecular imaging elucidates principles for optimizing intrathecal drug delivery

Abstract

The intrathecal (IT) dosing route offers a seemingly obvious solution for delivering drugs directly to the central nervous system. However, gaps in understanding drug molecule behavior within the anatomically and kinetically unique environment of the mammalian IT space have impeded the establishment of pharmacokinetic principles for optimizing regional drug exposure along the neuraxis. Here, we have utilized high-resolution single-photon emission tomography with X-ray computed tomography to study the behavior of multiple molecular imaging tracers following an IT bolus injection, with supporting histology, autoradiography, block-face tomography, and MRI. Using simultaneous dual-isotope imaging, we demonstrate that the regional CNS tissue exposure of molecules with varying chemical properties is affected by IT space anatomy, cerebrospinal fluid (CSF) dynamics, CSF clearance routes, and the location and volume of the injected bolus. These imaging approaches can be used across species to optimize the safety and efficacy of IT drug therapy for neurological disorders.

Authors

Daniel A. Wolf, Jacob Y. Hesterman, Jenna M. Sullivan, Kelly D. Orcutt, Matthew D. Silva, Merryl Lobo, Tyler Wellman, Jack Hoppin, Ajay Verma

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Figure 1

Imaging the intrathecal space by MRI reveals anatomy that closely mirrors that which can be identified using classical dye-imaging techniques.

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Imaging the intrathecal space by MRI reveals anatomy that closely mirror...
(A) Sagittal high-resolution whole-body T2-weighted MRI image highlighting the intrathecal space along the rostrocaudal neuraxis of the rat (representative image from cohort of n = 6). (B) Focused MRI image of the head, outlining the cranial subarachnoid space in high detail, including major cerebrospinal fluid–containing (CSF-containing) cisterns and recesses (1, cisterna magna; 2, pituitary recess; 3, supracerebellar cistern; 4, olfactory cistern). (C) Sagittal cryosectioned head slice of a rat following lumbar puncture infusion of India ink (n = 1 experiment performed), emphasizing congruent intrathecal anatomy to that of CSF imaged by magnetic resonance (see Supplemental Video 1 for 3D reconstruction of serial sections). (D) Comparison of CSF volume measurement calculated from a 3D reconstruction of serial cryosections of a rat following lumbar intrathecal injection of India ink (n = 1) and by whole-body T2-weighted MRI (n = 1). (E) 3D rendering of the India ink, highlighting the intrathecal space within the cervical spinal column and cranium. Note the pockets of CSF branching out along cervical nerve roots, running along the ventral aspects of the brain and along lateral aspects of the supracerebellar and olfactory cisterns as well as the middle cerebral artery. (F) Sagittal whole-body cryosection of a rat following lumbar intrathecal injection of Evans blue dye (representative image from n = 2 experiments performed). (G) Cross-sectional views of the Evans blue dye–filled intrathecal space at different levels of the spinal column, as rendered from a 3D reconstruction made from serial sagittal cryosections, as in E (see Supplemental Video 2 for fly-through view of the 3D reconstruction). Note the rostral to caudal gradient of ink within the intrathecal space as well as exchange into the spinal cord interstitial fluid. Original magnification, ×1 (A and F); ×1.5 (B, C, and E); and x4 (G).