Intranasal delivery of imaging agents to the brain

Abstract

The potential of intranasal administered imaging agents to altogether bypass the blood-brain barrier offers a promising non-invasive approach for delivery directly to the brain. This review provides a comprehensive analysis of the advancements and challenges of delivering neuroimaging agents to the brain by way of the intranasal route, focusing on the various imaging modalities and their applications in central nervous system diagnostics and therapeutics. The various imaging modalities provide distinct insights into the pharmacokinetics, biodistribution, and specific interactions of imaging agents within the brain, facilitated by the use of tailored tracers and contrast agents. Methods: A comprehensive literature search spanned PubMed, Scopus, Embase, and Web of Science, covering publications from 1989 to 2024 inclusive. Starting with advancements in tracer development, we going to explore the rationale for integration of imaging techniques, and the critical role novel formulations such as nanoparticles, nano- and micro-emulsions in enhancing imaging agent delivery and visualisation. Results: The review highlights the use of innovative formulations in improving intranasal administration of neuroimaging agents, showcasing their ability to navigate the complex anatomical and physiological barriers of the nose-to-brain pathway. Various imaging techniques, MRI, PET, SPECT, CT, FUS and OI, were evaluated for their effectiveness in tracking these agents. The findings indicate significant improvements in brain targeting efficiency, rapid uptake, and sustained brain presence using innovative formulations. Conclusion: Future directions involve the development of optimised tracers tailored for intranasal administration, the potential of multimodal imaging approaches, and the implications of these advancements for diagnosing and treating neurological disorders.

Keywords: brain imaging; imaging modalities; intranasal administration; neuroimaging agents; nose-to-brain.

Figure 1

Pathways of intranasal drug delivery and associated imaging modalities: This illustration depicts the IN administration of imaging agents through the nasal cavity and their subsequent pathways to the brain. It highlights two primary routes: the olfactory (purple) and trigeminal (blue) pathways and the secondary systemic circulation route across the BBB. Various imaging techniques are employed to trace these agents: MRI, OI, FUS, SPECT, and PET are color-coded to represent the respective IN route that each imaging technique monitors. [created with BioRender.com].

Figure 2

Timeline of development for imaging modalities and neuroimaging agents in INDD. [created with BioRender.com].

Figure 3

Gamma scintigraphy images of rats 30 min post-administration/injection. A: [^99mTc]diazepam solution post-IV injection. B: [^99mTc]diazepam solution post-IN administration. C: [^99mTc]diazepam-NP post-IN administration. Redrawn from . [created with BioRender.com].

Figure 4

SPECT/CT fusion images of mice following IN administration of [¹²³I]R8-YAβ(25-35)-PEI. A: displays the maximum intensity projection view. B: shows the sagittal view, marking 'B' for brain, 'Bl' for bladder, 'N' for nose, 'T' for thyroid and 'S' for stomach. Adapted with permission from , copyright 2022 Elsevier.

Figure 5

Presents lateral views of the brain following IN administration of (A) [¹⁸F]FDG and (B) [¹⁸F]fallypride. In both images, arrows point to the olfactory region. Additionally, the basal ganglia are indicated in the image (B) of [¹⁸F]fallypride. Adapted with permission from , copyright 2018 Elsevier.

Figure 6

Brain PET/MRI images for rhesus macaque post IN administration (A) [¹¹C]CH₃-Orexin A tracer and (B) [¹¹C]raclopride. (A) Images showing no detectable brain uptake in unaffected regions. (B) Images show uptake concentrated in the striatum, highlighting dopamine D2/D3 receptor binding. Adapted with permission from , copyright 2018 American Chemical Society.

Figure 7

A) Ex vivo fluorescence images and B) Analysis of fluorescence intensity in mouse brains prior to and at 1, 6, 12, and 24 h following IN administration of CB-Gd-Cy5.5 or BSA-Gd-Cy5.5. C) Fluorescence microscopy of brain slices from mice 1 h post-IN administration of CB-Gd-Cy5.5 or BSA-Gd-Cy5.5, with white arrows highlighting areas of CB-Gd-Cy5.5 presence. 1-4 representative fluorescence images of brain sections from mice at 1 h post-IN administration CB-Gd-Cy5.5 or BSA-Gd-Cy5.5. Adapted with permission from , copyright 2019 Wiley.

Figure 8

Illustrating the ex vivo brain fluorescence tomography. It depicts the brain images at different time intervals (0.5 h, 1 h, and 3 h) following the IN administration of IR780-labelled CHC-loaded NPs (panel A) and IR780-loaded conjugated NPs (panel B), along with a separate column representing negative controls. "Adapted with permission from copyright 2021 ELSEVIER".

Figure 9

Demonstrate the Gd³⁺-NE distribution within the brain regions. An illustrative image highlights the spread of the Gd agent in various distinct areas of the rat brain map following IN administration (A). Gd³⁺-NE Distribution of in primary brain areas at 25-30 min post-administration, in contrast to Magnevist and the control (B). Distribution of Gd^3+-NE in significant brain areas 55-60 min after administration, in comparison to both Magnevist and the control (C). Adapted with permission from copyright 2019 American Society for Pharmacology and Experimental Therapeutics.

Figure 10

T1 MRI scans of mouse brains are displayed, taken at both 0 h and 1 h, before and after administration. The upper row (A) features images with CB-Gd-Cy5.5, while the lower row (B) presents those with BSA-Gd-Cy5.5. A red arrow highlights signal enhancement in the hippocampus. Adapted with permission from , copyright 2019 Wiley.

Figure 11

MRI images of MPIOs-MSCs migration in mice post-IN administration. Panel (A) presents coronal MRI images where images a and b serve as control showing absence of MSCs and tumour, thus no detectable signal. Images c and d show the migration pathway of MSCs in a nonirradiated, tumour-bearing mouse, while e through g display the migration in an irradiated mouse, all through T1-weighted imaging. T2-weighted images h, i, and j from an irradiated mouse highlight both the migrating MSCs, indicated by red arrows, and the tumour, pinpointed by a yellow arrow in j. Panel (B) illustrates axial T1-weighted brain images of an irradiated, tumour-bearing mouse from a to e, with red arrows denoting the direction of MSC movement. These images were captured on the second day following IN administration of MPIOs-MSCs, providing insight into the MSCs' behaviour and their potential therapeutic trajectory towards the tumour site. Adapted with permission from , copyright 2014 Elsevier.

Figure 12

Demonstrating FUS+IN administration of NP and the potential pathways from nose-to-brain. "Reproduced with permission from , copyright 2018 ELSEVIER".

Figure 13

Demonstrates CT images depicting the uptake of AuNPs in the brain. The images compare three scenarios: (A) an untreated rat, (B) a resveratrol transferosome capped with AuNPs treated rat, and (C) a resveratrol NE AuNPs treated rat. The red arrow points to the observed uptake of AuNPs in the brain. Adapted with permission from , copyright 2019 Taylor & Francis.

Figure 14

Diagram of literature search based on PRISMA-S guidelines.

Figure 15

Comparative analysis of the imaging modalities in INDD to the Brain. This figure presents six pie charts, each representing a different imaging modality utilised to track the migration of specific tracers from the nasal cavity to the brain. Each chart details the tracer used, highlighting its unique pathway through the olfactory and trigeminal nerve routes. These visualisations underscore the diverse mechanisms and efficiency of nose-to-brain delivery pathways across different imaging agents. [created with BioRender.com].