Evidence of nose-to-brain delivery of nanoemulsions: cargoes but not vehicles

Abstract

The nose-to-brain pathway has been proven to be a shortcut for direct drug delivery to the brain. However, whether and to what extent nanoparticles can be delivered through this passage is still awaiting validation with evidence. In this study, nose-to-brain transportation of nanoparticles is tracked via fluorescence bioimaging strategies using nanoemulsions (NEs) as model carriers. Identification of NEs in biological tissues is based on the on → off signal switching of a new type of environment-responsive embedded dyes, P2 and P4, and two conventional probes, DiR and coumarin-6 (C6), are embedded to represent the cargoes. Evidence for the translocation of NEs was collected either via live imaging or ex vivo histological examination in rats after nasal administration. Results suggest that NEs with a particle size of about 100 nm, either naked or coated with chitosan, have longer retention duration in nostrils and slower mucociliary clearance than larger ones. P2 signals, representing integral NEs, can be found in mucosa and trigeminal nerves for all size groups, whereas only weak P2 signals are detected in the olfactory bulb for chitosan-coated NEs of 100 nm. Confocal microscopy further confirms the translocation of integral 100 nm NEs in nasal mucosa and along the trigeminal nerve in decremental intensity. Weak signals of the P4 probe, also representing integral NEs, can be detected in the olfactory bulb but few in the brain. NEs as large as 900 nm cannot be transported to the olfactory bulb. However, the DiR or C6 signals that represent the cargoes can be found in significant amounts along the nose-to-brain pathway and finally reach the brain. Evidence shows that integral NEs can be delivered to the olfactory bulb, but few to the brain, whereas the cargoes can be released and permeated into the brain in greater amounts.

Pharmacotechnical Development of a Nasal Drug Delivery Composite Nanosystem Intended for Alzheimer’s Disease Treatment

“…SPC/cholesterol liposome formulations are widely found in the literature, and the particle size properties obtained are comparable to ours results [44,45]. The nose-to-brain passage of nanoemulsions has been studied through live imaging or ex vivo histological examination in rats after nasal administration by Ahmad et al [46]. This study demonstrated that nanoparticle size plays a determinant role, by directly influencing their in vivo fate.…”

Biodistribution, Clearance, and Long‐Term Fate of Clinically Relevant Nanomaterials

“…Currently, efforts are concentrated on bypassing the very selectively permeable blood–brain barrier (BBB) and thereby delivering drugs directly into the brain . However, the efficacy of this route is yet to be experimentally proven . In comparison, most of the research into the buccal administration route is performed in order to increase retention time and to increase mucoadhesion so as to prevent the drug from being washed away by saliva .…”

“…Another possibility is the clearance of the nanomaterials via the lymph system. After extravasation of nanomaterials from the blood system, they face the dense interstitial space and ECM, a network of collagen, proteins, and elastic fibers that provide the structural integrity to the tissue . Diseases such as cancer and liver fibrosis reveal an altered ECM and an increased number of fibroblasts, which affect the penetration of nanomaterials through the tissue .…”

Intranasal Delivery of Nanoformulations: A Potential Way of Treatment for Neurological Disorders

“…Therefore, to address the low drug delivery problem, scientists are conducting experiments with nanoparticulate formulations like nanoemulsions, lipids, or polymer particles, which offer enhanced penetration and a longer residence time within the nasal cavity [156,[168][169][170][171][172][173][174][175][176] (Table 2). It has been found that 100 nm nanoemulsion particles penetrated the olfactory bulb and reached the brain to a small extent, whereas 900 nm particles could not penetrate the brain, which indicated that a particle size cut-off may be operational for the delivery of nanoformulations beyond the olfactory bulb [168]. A transformational effect is known to occur on the level of drugs detected in the brain following intranasal delivery when it is converted from solution to particulate formulation [177].…”