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Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain
Benjamin A. Plog, … , Douglas H. Kelley, Maiken Nedergaard
Benjamin A. Plog, … , Douglas H. Kelley, Maiken Nedergaard
Published October 18, 2018
Citation Information: JCI Insight. 2018;3(20):e120922. https://doi.org/10.1172/jci.insight.120922.
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Resource and Technical Advance Neuroscience Therapeutics

Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain

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Abstract

Despite the initial promise of immunotherapy for CNS disease, multiple recent clinical trials have failed. This may be due in part to characteristically low penetration of antibodies to cerebrospinal fluid (CSF) and brain parenchyma, resulting in poor target engagement. We here utilized transcranial macroscopic imaging to noninvasively evaluate in vivo delivery pathways of CSF fluorescent tracers. Tracers in CSF proved to be distributed through a brain-wide network of periarterial spaces, previously denoted as the glymphatic system. CSF tracer entry was enhanced approximately 3-fold by increasing plasma osmolality without disruption of the blood-brain barrier. Further, plasma hyperosmolality overrode the inhibition of glymphatic transport that characterizes the awake state and reversed glymphatic suppression in a mouse model of Alzheimer’s disease. Plasma hyperosmolality enhanced the delivery of an amyloid-β (Aβ) antibody, obtaining a 5-fold increase in antibody binding to Aβ plaques. Thus, manipulation of glymphatic activity may represent a novel strategy for improving penetration of therapeutic antibodies to the CNS.

Authors

Benjamin A. Plog, Humberto Mestre, Genaro E. Olveda, Amanda M. Sweeney, H. Mark Kenney, Alexander Cove, Kosha Y. Dholakia, Jeffrey Tithof, Thomas D. Nevins, Iben Lundgaard, Ting Du, Douglas H. Kelley, Maiken Nedergaard

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Figure 2

Plasma hypertonicity increases CSF influx in anesthetized mice.

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Plasma hypertonicity increases CSF influx in anesthetized mice.
(A) Fluo...
(A) Fluorescent BSA-647 was delivered into the cisterna magna (CM) of anesthetized mice. Mice received isotonic saline (KX), hypertonic saline (+HTS), or hypertonic mannitol (+Mannitol) i.p. at the onset of the CM injection. (B) Representative time-lapse images of BSA-647 influx over the immediate 30 minutes following CM injection in the KX, +HTS, and +Mannitol groups. Images (8-bit pixel depth) are color coded to depict pixel intensity (PI) in arbitrary units (AU). Scale bar: 2 mm. (C) Representative front-tracking analysis of CSF tracer influx over the imaging session for all groups. Fronts are time coded in minutes. (D) Quantification of the influx area over time (mean ± SEM; n = 6–7 mice/group; repeated-measures 2-way ANOVA, Sidak’s multiple comparisons test; ****P < 0.0001 KX vs. +HTS and +Mannitol). (E) Tracer influx speed maps (μm/min) and (F) quantification of mean influx speeds for all groups (mean ± SEM; n = 6 mice/group; 1-way ANOVA, Tukey’s multiple comparisons test; *P < 0.05, ***P = 0.001). (G) Representative ex vivo conventional fluorescence images of intact brains upon removal from the cranium (scale bar: 2 mm) and after coronal sectioning (scale bar: 1 mm) from all groups. Coronal sections were imaged with high-powered confocal laser scanning microscopy to evaluate perivascular tracer (scale bar: 50 μm). (H) Quantification of ex vivo coronal section fluorescence MPI (mean ± SEM; n = 5–7 mice/group; 1-way ANOVA, Tukey’s multiple comparisons test; **P < 0.01, ***P = 0.003). Total brain uptake of CSF-delivered (I) 3H-dextran (40 kDa) or (J) 14C-inulin (6 kDa) in all 3 groups (mean ± SEM; n = 5 mice/group; 1-way ANOVA, Tukey’s multiple comparisons test; **P = 0.001, ***P = 0.0009, ****P < 0.0001) expressed as percentage injected dose (%ID). The KX data set is the same that is used in Figure 1.

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