Investigation of the Transport Pathways Associated with Enhanced Brain Delivery of Peptide Drugs by Intranasal Coadministration with Penetratin

Abstract

We previously found that coadministering peptides and proteins with the cell-penetrating peptide L-penetratin intranasally significantly increased transport to the brain and enhanced pharmacological effects. The present study aimed to clarify the mechanisms of nose-to-brain drug delivery enhancement by L-penetratin coadministration. First, we compared the concentrations of Exendin-4 in plasma and brain after intranasal and subcutaneous administration and suggested that coadministration with L-penetratin facilitated the direct nose-to-brain transport of Exendin-4. Second, we demonstrated that L-penetratin did not stimulate the transport of Cy7-labeled Exendin-4 and insulin through the trigeminal nerves but shifted their distribution to the olfactory mucosal pathway. Third, we investigated the distribution of insulin into the deeper regions of the brain after delivery via the olfactory pathway and suggested that insulin had entered the olfactory bulb, bottom part of the brain, and perivascular space through the cerebrospinal fluid and had diffused throughout the brain. We further demonstrated that intranasally delivered insulin with L-penetratin specifically accumulated on the hippocampus neuronal cells. Thus, this study suggested that administrating peptide drugs intranasally with L-penetratin allows direct transport to the olfactory bulb, bottom part of the brain, and perivascular space of the cerebral artery. This technique also potentially allows targeting of specific brain areas.

Rapid and Widespread Distribution of Intranasal Small Extracellular Vesicles Derived from Mesenchymal Stem Cells throughout the Brain Potentially via the Perivascular Pathway

“…The delivery of MSC-sEVs from the entry point to other distant brain areas after intranasal administration subsequently brought a question: how can this kinetic characteristic be achieved? Researchers have suggested that the perivascular pathway was mostly important to the rapid and widespread distribution of macromolecules in CNS following intranasal delivery [25,26,40], confirmed by the fact that fluorescence-labeled dextrans (3 or 10 kDa), peptide (<10 kDa), or IgG (150 kDa) was rapidly distributed to cerebral PVS. Lochhead et al have shown that the concentration of IgG in PVS of major cerebral arteries at 30 min was higher than that in corresponding brain regions, but consistent with that in the OB and trigeminal nerves [26].…”

Research progress in brain-targeted nasal drug delivery

“…Cell-penetrating peptides are short peptides that can penetrate the cell and/or nuclear membrane to guide any connected peptides, proteins, or other bioactive molecules into cells ( Kamei, 2017 ). Although the precise transmembrane mechanism of cell-penetrating peptides is not fully understood, the effects are likely mediated via signal transduction pathways and endocytosis ( Kamei et al, 2021 ).…”

Validation of the Absorption-Enhancing Ability of Oligoarginines Grafted onto a Backbone of Hyaluronic Acid through Animal Studies from Rodents to Primates

“…53 Such comparison is often used; however, if there are no data of intravenous administration, the activation of the route by delivery tools coadministered intranasally with drugs can be predicted using the alternative way: comparison between the ratio of the brain concentration to the plasma concentration under tool-present conditions and that under tool-free conditions. 54 In this case, when the route of the nose-to-brain delivery works well, the ratio (the brain concentration/the plasma concentration) under delivery tool-present conditions is expected to be larger than that under tool-free conditions. The brain collection was performed along with the blood collection from mice whose data of drug concentrations in the plasma were described in Figure 1.…”