Distribution of nanoparticles throughout the cerebral cortex of rodents and non-human primates: Implications for gene and drug therapy

Abstract

When nanoparticles/proteins are infused into the brain, they are often transported to distal sites in a manner that is dependent both on the characteristics of the infusate and the region targeted. We have previously shown that adeno-associated virus (AAV) is disseminated within the brain by perivascular flow and also by axonal transport. Perivascular distribution usually does not depend strongly on the nature of the infusate. Many proteins, neutral liposomes and AAV particles distribute equally well by this route when infused under pressure into various parenchymal locations. In contrast, axonal transport requires receptor-mediated uptake of AAV by neurons and engagement with specific transport mechanisms previously demonstrated for other neurotropic viruses. Cerebrospinal fluid (CSF) represents yet another way in which brain anatomy may be exploited to distribute nanoparticles broadly in the central nervous system. In this study, we assessed the distribution and perivascular transport of nanoparticles of different sizes delivered into the parenchyma of rodents and CSF in non-human primates.

Optogenetic manipulation of neural circuits in awake marmosets

“…All images shown are from the same tissue section. grade connections, several other studies of primates have reported retrograde labeling, as well (Masamizu et al 2011;Salegio et al 2014;San Sebastian et al 2013). Similar to work in mice (Oh et al 2014;Sato et al 2014), the use of AAV constructs to transduce neurons with opsins and fluorescent proteins may be ideal for identifying pathways in the marmoset brain.…”

“…6, D and E), these results should be considered preliminary. Previous work has shown that AAV can be used to label long-range projections in mice (Oh et al 2014) and rhesus monkeys (Masamizu et al 2011;Salegio et al 2014;San Sebastian et al 2013), but there is much variability in anterograde or retrograde transport depending on the serotype (Salegio et al 2014;San Sebastian et al 2013). Although we found preliminary evidence that at least AAV9 constructs led to expression in cell bodies in the contralateral hemisphere, we were unable to confirm that viral constructs comprising the AAV5 serotype showed a similar pattern of long-range projections.…”

Strategies to enhance the distribution of nanotherapeutics in the brain

“…NP distribution in the ICS is limited by hindrances imposed by the brain extracellular matrix (ECM) that fills the space [6]. Moreover, preferable flow of NP through, and subsequent confinement within, the low-resistance, fluid-filled PVS hampers widespread distribution of NP, thereby limiting their abilities to reach target cells within the brain [5, 7]. These revelations have shed light on previously terminated CED-based clinical trials that failed to meet their primary and secondary outcomes [8, 9] and have spurred the development of the next generation of NP systems optimized for CED [10, 11].…”

Accuracy of image-guided percutaneous injection into a phantom spinal cord utilizing flat panel detector CT with MR fusion and integrated navigational software

“…A similar technique as above was used for a second pass during a different procedural session. However, instead of a spinal needle, a custom step design cannula for CED with a 200 µm inner diameter tip and 3 mm step design (figure 3),25 was advanced to the target and 0.1 mL of gadolinium was manually delivered with a 1-cc gastight syringe over 5 min. For this pass, the inter-laminar spinal cord target was three vertebral levels distal from the spinal needle injection pass to avoid any potential overlap from the two injection sites.…”