Nose-to-brain drug delivery: from bench to bedside

Abstract

There is increasing interest in nose-to-brain delivery as an innovative drug delivery strategy for neurodegenerative disorders such as Parkinson's or Alzheimer's disease. The unique anatomy of the nose-brain interface facilitates direct drug transport via the olfactory and trigeminal pathways to the brain, bypassing the blood-brain barrier. Different administration techniques as well as advanced drug formulations like targeted nanoparticles and thermoresponsive systems have been explored to improve the delivery efficiency and the therapeutic efficacy. This review provides an up-to-date perspective on this fast-developing field, and discusses different studies on safety and pharmacokinetic properties. A thorough evaluation of preclinical and clinical studies reveals both promises and challenges of this delivery method, highlighting approved drugs for the treatment of epilepsy and migraine that successfully utilize intranasal routes. The current landscape of research on nose-to-brain delivery is critically discussed, and a rationale is provided for ongoing research to optimize therapeutic strategies.

Keywords: Alzheimer's; Intranasal; N2B; Nanoparticle; Neurodegenerative disease; Parkinson's.

Fig. 1

a General anatomy of the nose-to-brain interface and potential transport pathways for nose-to-brain delivery. The olfactory epithelium is composed of bipolar olfactory neurons, sustentacular cells, Bowman's glands, basal cells and its underlying lamina propria, which contains blood and lymph vessels. Axonal processes of olfactory neurons are arranged in bundles known as the fila olfactoria, which traverse the cribriform plate and reach the olfactory bulb. Potential pathways for drug delivery from the olfactory mucosa to the brain are illustrated in dark blue. ➀ Intracellular pathway: drugs are transported within olfactory neurons via axonal transport and endocytosis. ➁ Extra/paracellular transport along cranial nerves: drugs are transported within the perineural space, either to the cerebrospinal fluid in the subarachnoid space, or to the lamina propria, and subsequently to the blood or lymph vessels. ➂ Transcellular transport: drugs are transported through cells to the lamina proria with further transport to lymphatic vessels that are connected with the cervical lymph nodes or to blood vessels following entry to the systemic circulation. b Innervation of the nasal region by the olfactory nerve and branches of the trigeminal nerve. The olfactory nerve bundles, originating from the olfactory bulb, traverse the cribriform plate and provide innervation to the olfactory region of the nasal mucosa. The trigeminal nerve leaves the brainstem at the level of the pons and divides after the trigeminal ganglion into its three main divisions: V₁, ophthalmic nerve; V₂, maxillary nerve; V₃, mandibular nerve. Only V₁ and V₂ send branches to the nasal epithelium, thereby innervating the respiratory mucosa and thus participating in the process of nose-to-brain delivery

Fig. 2

Factors influencing nose-to-brain delivery

Fig. 3

Preclinical studies using nose-to-brain drug delivery in different rodent models of PD. The Thy1-aSyn mouse model overexpresses human alpha-synuclein under the Thy1 promoter, while the A53T mouse model overexpresses the A53T-mutant human alpha-synuclein under the mouse prion protein promoter. Models generated by injection of different toxins include 6-hydroxydopamine (6-OHDA), which is a synthetic monoaminergic neurotoxin. Haloperidol is an antipsychotic medication that has been observed to induce parkinsonism as an adverse effect. Rotenone is an isoflavonoid that is typically utilized as an insecticide and acaricide. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that selectively targets dopaminergic neurons

Fig. 4

Approved drugs using nose-to-brain delivery for the treatment of neurological diseases