Direct nose to the brain nanomedicine delivery presents a formidable challenge

Abstract

This advanced review describes the anatomical and physiological barriers and mechanisms impacting nanomedicine translocation from the nasal cavity directly to the brain. There are significant physiological and anatomical differences in the nasal cavity, olfactory area, and airflow reaching the olfactory epithelium between humans and experimentally studied species that should be considered when extrapolating experimental results to humans. Mucus, transporters, and tight junction proteins present barriers to material translocation across the olfactory epithelium. Uptake of nanoparticles through the olfactory mucosa and translocation to the brain can be intracellular via cranial nerves (intraneuronal) or other cells of the olfactory epithelium, or extracellular along cranial nerve pathways (perineural) and surrounding blood vessels (perivascular, the glymphatic system). Transport rates vary greatly among the nose to brain pathways. Nanomedicine physicochemical properties (size, surface charge, surface coating, and particle stability) can affect uptake efficiency, which is usually less than 5%. Incorporation of therapeutic agents in nanoparticles has been shown to produce pharmacokinetic and pharmacodynamic benefits. Assessment of adverse effects has included olfactory mucosa toxicity, ciliotoxicity, and olfactory bulb and brain neurotoxicity. The results have generally suggested the investigated nanomedicines do not present significant toxicity. Research needs to advance the understanding of nanomedicine translocation and its drug cargo after intranasal administration is presented. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials

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“…On the other hand, in the olfactory mucosal pathway region, the drug is directly delivered through the olfactory route or reaches the brain through diffusion. [ 53,54 ] The intranasal instillation offers the advantages of noninvasiveness, and self‐administration, allowing the drug to bypass the blood−brain barrier by migrating from the nasal mucosa. [ 55,56 ] However, nasal drug delivery is subject to certain limitations.…”

Versatile Nanoparticulate Systems as a Prosperous Platform for Targeted Nose–Brain Drug Delivery

“…It is worth mentioning that there are three pathways that contribute to the nose-to-brain drug delivery, namely, olfactory nerve, trigeminal nerve, and respiratory pathway as demonstrated in Figure . The delivery of actives from the nose to the brain is achieved through two main mechanisms, namely, the intracellular and extracellular absorption which include paracellular and transcellular pathways . Intracellular pathways represent the delivery of different molecules through endocytosis or pinocytosis, where molecules are engulfed and moved throughout olfactory or trigeminal neural axons to finally reach the CNS. , On the other hand, in paracellular mechanism, the drug passes through tight junctions between the epithelial cells.…”

Nose‐to‐brain delivery of nanotherapeutics: Transport mechanisms and applications

“…Therefore, the efficiency of reaching the brain via extracellular routes is low. Intracellular pathways occur mainly through olfactory neurons or through supporting intracellular pathways involving endocytosis and exocytosis as well as receptor‐mediated transcytosis (RMT), carrier‐mediated transcytosis (CMT), and adsorption‐mediated transcytosis (AMT; Vetter & Wagner, 2022; Yokel, 2021) (Figure 3). A number of studies have been conducted to design nano‐drugs for nose‐to‐brain application based on the above intracellular and extracellular transport modes, which are summarized below.…”