Abstract
Intranasal administration provides a non-invasive drug delivery route that has been proposed to target macromolecules either to the brain via direct extracellular cranial nerve-associated pathways or to the periphery via absorption into the systemic circulation. Delivering drugs to nasal regions that have lower vascular density and/or permeability may allow more drug to access the extracellular cranial nerve-associated pathways and therefore favor delivery to the brain. However, relative vascular permeabilities of the different nasal mucosal sites have not yet been reported. Here, we determined that the relative capillary permeability to hydrophilic macromolecule tracers is significantly greater in nasal respiratory regions than in olfactory regions. Mean capillary density in the nasal mucosa was also approximately 5-fold higher in nasal respiratory regions than in olfactory regions. Applying capillary pore theory and normalization to our permeability data yielded mean pore diameter estimates ranging from 13–17 nm for the nasal respiratory vasculature compared to <10 nm for the vasculature in olfactory regions. The results suggest lymphatic drainage for CNS immune responses may be favored in olfactory regions due to relatively lower clearance to the bloodstream. Lower blood clearance may also provide a reason to target the olfactory area for drug delivery to the brain.
Highlights
(perivascular, perilymphatic or perineural) associated with the trigeminal and/or olfactory nerves to reach the brain[2,3,8,9]
Preferentially targeting a region of the nasal passage that has a lower blood vessel density and/or more restrictive capillary permeability characteristics would help minimize delivery to the systemic circulation and enhance access to the cranial nerve-associated extracellular pathways leading to the brain[3]; previous work has shown that intranasal application of a vasoconstrictor can significantly increase peptide delivery to the olfactory bulbs through a reduction in the systemic absorption rate[13]
Evans blue extravasation studies have demonstrated that nasal mucosal blood vessels are fairly permeable when compared to the non-permeable blood vessels of the brain[17] and have provided some indication that there may be vascular permeability differences between respiratory and olfactory regions of the nasal mucosa[16]; a detailed, quantitative comparison of vascular properties across multiple nasal mucosal regions using a range of well-characterized vascular tracers has not yet been described
Summary
(perivascular, perilymphatic or perineural) associated with the trigeminal and/or olfactory nerves to reach the brain[2,3,8,9]. Evans blue extravasation studies have demonstrated that nasal mucosal blood vessels are fairly permeable when compared to the non-permeable blood vessels of the brain[17] and have provided some indication that there may be vascular permeability differences between respiratory and olfactory regions of the nasal mucosa[16]; a detailed, quantitative comparison of vascular properties across multiple nasal mucosal regions using a range of well-characterized vascular tracers has not yet been described Such a comparison is necessary to reveal size-dependent permeability properties of the nasal vasculature that may critically inform and guide nasal drug delivery, e.g. to provide an explanation for which particular locations of the nasal passage might be targeted for greater brain delivery (with lower systemic absorption) and to better anticipate the disposition of larger biologics. The findings reveal important differences in mucosal vascular properties between nasal respiratory and olfactory regions that provide guidance on the region of the nasal passage that might be targeted to maximize intranasal drug delivery to the brain and that we speculate may have significance for physiological processes such as the efficiency of lymphatic drainage to regional lymph nodes
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