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 5

Effect of tissue affinity of a drug on rostral drug distribution following intrathecal lumbar administration.

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Effect of tissue affinity of a drug on rostral drug distribution followi...
(A) Static single-photon emission tomography with X-ray computed tomography (SPECT-CT) images of 99mTc-sestamibi 2 hours and 6 hours after intravenous infusion of the tracer into a rat (n = 1 experiment conducted). (B) Static SPECT-CT images of 99mTc-sestamibi 2 hours and 6 hours after 10-μl lumbar intrathecal bolus injection (representative image from cohort of n = 2). (C) Autoradiogram of a whole-body transverse slice through the lumbar region of the spinal column (black arrow) 2 hours after intrathecal injection of 99mTc-sestamibi (n = 1 experiment conducted). Original magnification, ×1. (D) Static SPECT-CT images of 186Re-sestamibi 2 hours and 6 hours after intrathecal bolus infusion of 40 μl of the tracer into an intrathecally catheterized rat (representative image from cohort of n = 2). (E) Microautoradiograms of transverse spinal cord sections from a separate animal that was similarly dosed intrathecally with 186Re-sestamibi via a 40-μl plus 30-μl saline flush bolus (representative image from cohort of n = 2). Top: Images of a microautoradiogram from a thoracic spinal cord section. Top left: As visualized by bright-field microscopy. Top right: As visualized by dark-field microscopy. Bottom: A section from the lumbar (left) and cervical (right) region of the spinal cord, as visualized by dark-field microscopy. WM, white matter; GM, gray matter. Scale bars: 100 μm. (F and I) Static SPECT-CT images of 111In-diethylenetriamine-pentacetic acid (111In-DTPA) (green scale) and 99mTc-sestamibi (fire scale) 0–15 minutes, 2 hours, and 6 hours after lumbar injection of a mixture of the two tracers given as either a (F) 20-μl (n = 6) or (I) 30-μl plus 40-μl saline flush bolus (n = 5). Images are from 1 representative animal from each group. Scale bars: 50 mm. Vertical dotted lines represent the rostral and caudal boundaries of the intrathecal space region of interest created for quantitative analysis. (G, H, J, and K) Quantitative distribution profiles of (G and J) 111In-DTPA and (H and K) 99mTc-sestamibi along the neuraxis from the data from the representative animals presented in F and I.