Dynamic dual-isotope molecular imaging elucidates principles for optimizing intrathecal drug delivery
Daniel A. Wolf, Jacob Y. Hesterman, Jenna M. Sullivan, Kelly D. Orcutt, Matthew D. Silva, Merryl Lobo, Tyler Wellman, Jack Hoppin, Ajay Verma
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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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 2

Noninvasive single-photon emission tomography with X-ray computed tomography imaging can be used to quantitatively track the biodistribution of molecules within the intrathecal space with high resolution.

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Noninvasive single-photon emission tomography with X-ray computed tomogr...
(A) High-resolution single-photon emission tomography with X-ray computed tomography (SPECT-CT) imaging of a rat (representative from a cohort of n = 5) 6 hours after lumbar injection of 50 μl of 123I-labeled human serum albumin (123I-HSA), showing radiotracer accumulation within cerebrospinal fluid–containing (CSF-containing) lacunes in the intrathecal space along the neuraxis, most notably adjacent to the lumbar nerve roots. (B) Quantification of radiotracer concentration along the neuraxis, within the spinal intrathecal space region of interest (ROI) from the animal shown in A. Peaks and troughs correspond to CSF pockets along anatomical nerve routes between vertebrae (anatomical locations labeled along the plots). (C) High-resolution SPECT-CT sagittal head images of 123I-HSA following a 50-μl lumbar intrathecal injection of the radiotracer (representative images from a cohort of n = 5) revealed faster kinetics of solute transport through the CSF along the ventral rather than the dorsal surface of the brain. 2 hours after injection, the tracer had flowed rostrally along the ventral surface of the brain, through the pituitary recess and toward the olfactory cisterns as well as laterally along and into the supracerebellar cistern. Later, at 6 hours after injection, the tracer appeared along the medial interhemispheric fissure of the dorsal surface of the cerebral cortex (arrow). (D) 6 hours after injection of a 50-μl bolus of 123I-HSA, tracer accumulation was observed across the cribriform plate in the nasal lymphatics and had accumulated within cervical lymph nodes (arrows). (E) Intrathecal injection of the small-molecule 111In-diethylenetriamine-pentacetic acid (111In-DTPA) (representative image from a cohort of n = 5) resulted in a similar pattern of distribution in the cranial intrathecal space 2 hours after injection. (F) Autoradiogram of a slice through the transverse plane of the head of a rat 2 hours after lumbar infusion of 111In-DTPA (n = 1 experiment performed) depicts outflow of the imaging agent from the CSF into the nasal lymphatics (arrow). (G) A 3D model of the main routes of molecule movement through the cranial CSF constructed from multiple SPECT-CT scans of lumbar intrathecally administered 123I-HSA 6 hours after injection. (blue = routes of molecule trafficking, light brown = brain parenchyma). Original magnification, ×0.5 (C); ×0.75 (D–F); and ×1 (G).