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

Ernesto A Salegio, Hillary Streeter, Nikhil Dube, Piotr Hadaczek, Lluis Samaranch, Adrian P Kells, Waldy San Sebastian, Yuying Zhai, John Bringas, Ting Xu, John Forsayeth, Krystof S Bankiewicz, Ernesto A Salegio, Hillary Streeter, Nikhil Dube, Piotr Hadaczek, Lluis Samaranch, Adrian P Kells, Waldy San Sebastian, Yuying Zhai, John Bringas, Ting Xu, John Forsayeth, Krystof S Bankiewicz

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.

Keywords: AAV; CSF; gene delivery; liposomes; perivascular; thalamo-cortico.

Figures

FIGURE 1
FIGURE 1
Transgene distribution after AAV2 and AAV6 delivery. (A–F) Unilateral injection into the thalamus of adult rats of either AAV2 or AAV6 resulted in widespread expression of GFP transgene in the neocortex and in pre-frontal regions distal to the site of injection. Scale bars: A,D = 5 mm; B,C,E,F = 1 mm.
FIGURE 2
FIGURE 2
Early parenchymal distribution of fluorescently labeled liposomes. (A–E) Acute survival time-point for liposome-infused animals revealed the rapid spread of fluorescently labeled liposomes 30 min after delivery into the thalamus. Spread of fluorescence reached approximately 2.4 mm rostral and 1.6 mm caudal from the site of infusion, suggesting efficient movement of these particles throughout the brain after CED. Scale bar: B–D = 5 mm.
FIGURE 3
FIGURE 3
Perivascular transport of liposomes. (A–F) Examination of parenchymal tissue 2 mm rostral from the site of infusion showing the presence of fluorescently labeled liposomes surrounding the lumen of blood vessels, indicating effective transport of these particles along perivascular spaces. Scale bars: A,E = 5 mm; C,D = 500 μm; B,F = 1 mm.
FIGURE 4
FIGURE 4
Expansion of perivascular spaces after CED. PBS-infused tissue was processed for EM and revealed the expansion of perivascular spaces after CED. These spaces ranged in size from 11 μm (width) × 3 μm (height; black arrows; A) and 2.0 μm (w) × 11.5 μm (h; B), as compared to non-infused, naïve control tissue (C). BV = blood vessel lumen. Scale bar: 1 μm.
FIGURE 5
FIGURE 5
Perivascular transport and pattern of transgene expression. (A–F) Immunostaining against GFP and blood vessels (CD31; endothelial marker) revealed the presence of GFP-positive cells surrounding blood vessels. Transgene expression was frequently observed to form rosette-like patterns in white matter, as demonstrated in cross-sectional views of blood vessels (B,C,E,F), indicative of perivascular transport of AAV particles irrespective of the serotype. Scale bars: A,B,D,E = 500 μm; C,F = 250 μm.
FIGURE 6
FIGURE 6
Early distribution of micelles. (A–D) Cisternal injection of fluorescently labeled micelles (shown in green) indicate the rapid transport of these particles within different regions of the NHP brain. These micelles filled the perivascular space of blood vessels throughout the brain, particularly in the brainstem (BS), cerebellum (CB), ventral tegmental area (VTA), and amygdala (AM). Note that these micelles are shown in green (white arrows) and presence of autofluorescent lipofuscin is shown in red. Scale bars: A,D = 500 μm; B,C = 250 μm.

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