Intrathecal drug delivery in the era of nanomedicine

Abstract

Administration of substances directly into the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord is one approach that can circumvent the blood-brain barrier to enable drug delivery to the central nervous system (CNS). However, molecules that have been administered by intrathecal injection, which includes intraventricular, intracisternal, or lumbar locations, encounter new barriers within the subarachnoid space. These barriers include relatively high rates of turnover as CSF clears and potentially inadequate delivery to tissue or cellular targets. Nanomedicine could offer a solution. In contrast to the fate of freely administered drugs, nanomedicine systems can navigate the subarachnoid space to sustain delivery of therapeutic molecules, genes, and imaging agents within the CNS. Some evidence suggests that certain nanomedicine agents can reach the parenchyma following intrathecal administration. Here, we will address the preclinical and clinical use of intrathecal nanomedicine, including nanoparticles, microparticles, dendrimers, micelles, liposomes, polyplexes, and other colloidalal materials that function to alter the distribution of molecules in tissue. Our review forms a foundational understanding of drug delivery to the CSF that can be built upon to better engineer nanomedicine for intrathecal treatment of disease.

Keywords: Central nervous system; Cerebrospinal fluid; Gene delivery; Intracerebroventricular; Intracisternal; Intraventricular; Lumbar; Nanotechnology; Polymer; Subarachnoid space.

Figure 1.. Anatomy of the ventricular system.

Ventricles of a rodent brain (A) and human brain (B). Lateral ventricles (blue), 3^rd ventricle (green), and 4^th ventricle (orange) with associated choroid plexus in black. Magnified schematic of choroid plexus anatomy in the ventricles (C).

Figure 2.. CSF exchange and clearance pathways.

CSF-ISF exchanges and is cleared along arteries to cervical lymph nodes (bottom, left). CSF moves through the perivascular space and associated SAS microanatomy into the brain parenchyma (right).

Figure 3.. Mobility of nanoparticle systems in the SAS.

Solid, 100nm, fluorescently labeled polystyrene nanoparticles distribute throughout the neuroaxis to reach all CSF-exposed surfaces of the brain and spinal cord 2 hours following ICM administration in mice. (A) Delivery of nanoparticles is detected in all regions of the intact decalcified neuroaxis. Insets highlight extensive nanoparticle distribution in (B) sulci of the cerebellum, (C) cervical spinal cord, and (D) sacral spinal cord. Blue is DAPI and red is the stably labeled nanoparticle. Scale bar is 500um in (B) and 200um in (C) and (D). Figure reproduced from Householder, et al.[73]

Figure 4.. Differential fate of payload and carrier.

Free methotrexate and liposome encapsulated methotrexate experience distinct distributions within the brain following ICV administration in nonhuman primates. Cholesterol was labeled with ¹⁴C and methotrexate was labeled with ³H for quantitative scintography. A 0.5 × 0.8cm “tissue corridor” was sliced into 0.5 or 1mm sections to generate an effective line profile drug or carrier distribution from the ependymal to cortical surfaces. Methotrexate and cholesterol share a similar distribution in tissues close to the injection site, with more distal locations suggesting some release and clearance. These data are described in greater depth in the text of Section 5.1.3. Figure reproduced from Kimelberg, et al.[69]

Figure 5.. Parenchymal delivery of nanoscale colloids.

siRNA/PEI complexes achieve widespread parenchymal penetration in multiple regions of the CNS following ICV administration in mice. Blue is DAPI, green is NeuN, and red is Alexa 647-labeled siRNA complexed with PEI. White arrowheads highlight PEI-siRNA granules. Negative control shows absence of signal following administration of unlabeled PEI-siRNA. Scale bar is 20um. Figure reproduced and adapted slightly from Helmschrodt, et al.[149]