Therapeutic Potential of Intranasal Drug Delivery in Preclinical Stroke Studies

At a glance

Intranasal drug delivery presents a promising noninvasive method for delivering drugs directly to the brain, effectively bypassing the blood-brain barrier (BBB). After application to the nasal mucosa, drugs can either reach the olfactory bulb (olfactory pathway) or brainstem (trigeminal pathway) and then rapidly distribute throughout the brain parenchyma. Intranasal delivery of various therapeutic compounds including neuroprotective agents, therapeutic antibodies, and even stem cells has proven to be very effective in bypassing the BBB and has led to some important advances in translational research for stroke.

As a leading stroke research provider, Ace Therapeutics offers comprehensive nasal drug delivery system development services to pharmaceutical companies in the field of stroke. Working together, our professionals can optimize nasal drug delivery systems and develop new drug formulations to make stroke drugs suitable for intranasal delivery.

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Main Physiological Pathways of Intranasal Administration in the Brain

The intranasal delivery system is crucial in bypassing the BBB. Studies show that the INA delivery system primarily uses two main routes to transport drugs to the brain:

Neural Pathways

This route allows drugs to enter the brain via the olfactory and trigeminal nerves, which are located beneath the nasal mucosa. The olfactory nerve connects directly to the olfactory bulb, while the trigeminal nerve leads to the brainstem. By utilizing these neural pathways, drugs can bypass the BBB and directly reach the brain, providing a more direct and efficient route for drug delivery.

Vascular Route

In this route, drugs first enter the systemic circulation by crossing the capillaries in the nasal mucosa. Once in the bloodstream, they can cross the BBB through various mechanisms, eventually reaching the brain. This pathway relies on the circulatory system to deliver drugs to the brain.

Fig. 1 A schematic illustration of drug uptake via the intranasal route. Fig. 1 Schematic representation of drug uptake by the intranasal route. (Marcello, et al., 2023)

Advantages and Disadvantages of Intranasal Drug Delivery

Advantages	Disadvantages
Non-invasive and comfortable: Intranasal delivery bypasses the need for injections. Bypasses the BBB and first-pass metabolism: This approach avoids the BBB and hepatic metabolism, which are major obstacles for oral drug administration. Targeted CNS delivery: Drugs can directly enter the CNS rather than the systemic circulation, reducing peripheral tissue drug exposure. Rapid brain absorption: Intranasal delivery allows for faster absorption into the brain, making it suitable for conditions requiring quick intervention, such as seizures. Higher drug concentration: Compared to intravenous administration, more intact drug can be delivered into the brain due to bypassing plasma protein binding. No need for formulation changes: Intranasal delivery does not necessarily require modifications to therapeutic agents.	Limitations for hydrophilic agents: Hydrophilic drugs, which require larger doses to be effective, are not suitable for IN delivery. Risk of enzymatic degradation: Nasal enzymes and mucociliary clearance may degrade drugs, reducing their effectiveness. Small surface area: The olfactory epithelium has a limited surface area compared to the BBB, which may limit the efficiency of drug delivery. Slow axonal transport: The transport process across the olfactory nucleus is slow, which may hinder the delivery of drugs to deeper brain regions. Limited diffusion distance: The diffusion distance in the nasal cavity is restricted, which may make it challenging to deliver drugs to areas of the brain, such as penumbral tissues. Slightly acidic nasal environment: The nasal epithelium's acidic pH might create conditions unfavorable for some drugs.

Advantages

Disadvantages

Non-invasive and comfortable: Intranasal delivery bypasses the need for injections.
Bypasses the BBB and first-pass metabolism: This approach avoids the BBB and hepatic metabolism, which are major obstacles for oral drug administration.
Targeted CNS delivery: Drugs can directly enter the CNS rather than the systemic circulation, reducing peripheral tissue drug exposure.
Rapid brain absorption: Intranasal delivery allows for faster absorption into the brain, making it suitable for conditions requiring quick intervention, such as seizures.
Higher drug concentration: Compared to intravenous administration, more intact drug can be delivered into the brain due to bypassing plasma protein binding.
No need for formulation changes: Intranasal delivery does not necessarily require modifications to therapeutic agents.

Limitations for hydrophilic agents: Hydrophilic drugs, which require larger doses to be effective, are not suitable for IN delivery.
Risk of enzymatic degradation: Nasal enzymes and mucociliary clearance may degrade drugs, reducing their effectiveness.
Small surface area: The olfactory epithelium has a limited surface area compared to the BBB, which may limit the efficiency of drug delivery.
Slow axonal transport: The transport process across the olfactory nucleus is slow, which may hinder the delivery of drugs to deeper brain regions.
Limited diffusion distance: The diffusion distance in the nasal cavity is restricted, which may make it challenging to deliver drugs to areas of the brain, such as penumbral tissues.
Slightly acidic nasal environment: The nasal epithelium's acidic pH might create conditions unfavorable for some drugs.

Methods to Improve Brain-Targeted Nasal Mucosal Drug Delivery Using Biomaterials

The effectiveness of brain-targeted nasal drug delivery is influenced by several factors, which determine how much of the administered drug reaches the CNS or is absorbed into the systemic circulation. These factors include:

Penetration Enhancers	Pz-peptidase: Promotes drug permeability by reversibly opening tight junctions. Cell-penetrating peptides: Facilitate drug entry into cells via endocytosis or signal transduction pathways. Chitosan: Enhances epithelial permeability and acts as a mucosal adhesive. Cyclodextrins: Forms inclusion complexes to enhance drug solubility, stability, and absorption.
Mucosal Adhesives	Chitosan and hydroxypropyl methylcellulose: Extend drug retention in the nasal cavity. Receptor–ligand interactions: Surface modifications with ligands (e.g., lactoferrin, lectins) enhance mucosal adsorption.
Novel Drug Delivery Systems	Liposomes: Encapsulate drugs for increased bioavailability and reduced enzymatic degradation. In situ gel preparations: Provide extended drug retention via phase transitions in the nasal cavity. Microspheres: Protect drugs from enzymatic degradation and extend nasal retention time. Emulsions: Carry both lipophilic and water-soluble drugs while preventing degradation. Nanoparticles: Enable direct nose-to-brain drug transport and protect drugs from degradation.

Common Experimental Methods Used in Intranasal Drug Delivery Research

Cerebellomedullary Cistern Puncture (Single-Point Puncture Method)

This method involves extracting cerebrospinal fluid (CSF) from the cerebellomedullary cistern after drug administration. The drug content in the CSF is quantified, but due to issues with maintaining normal intracranial pressure and difficulty in tracking drug distribution over time, it is less commonly used. This method provides limited data on brain tissue distribution and requires a large number of animals for experimentation.

Brain Tissue Homogenization Method

In this method, the whole brain is collected, and specific tissues such as the olfactory bulb and cerebellum are separated for drug content analysis. While it offers insights into the drug distribution in brain tissue, it requires large sample sizes to account for individual animal variability. Despite this limitation, it remains one of the most widely used techniques.

Radionuclide Labeling Method

Using isotope labeling, this method allows for sensitive detection of drug content in tissues without the need for extensive drug extraction. However, it cannot distinguish between the drug, its degradation products, and conjugates, making it challenging to accurately determine the drug concentration.

Brain Microdialysis Method

This technique offers high temporal and spatial resolution for determining drug concentrations in the CNS without affecting normal physiological functions. It allows continuous sampling and quantification in a single animal, making it ideal for studying brain-targeting drugs. However, it requires high-cost instruments and may not be suitable for large-scale studies.

Pharmacodynamic Evaluation Method

In cases where drug concentration is difficult to measure, this method assesses the pharmacological effects of the drug to indirectly infer its absorption into the brain. This approach relies on the known effects of the drug to evaluate its brain delivery and action.

Intranasal Therapy for Stroke

Intranasal delivery of various proteins and genes has been investigated as therapeutic agents in experimental animal models of ischemic stroke.

Insulin-Like Growth Factor-1 (IGF-1)	Erythropoietin	Osteopontin
Transforming Growth Factor (TGF)	Mesenchymal Stem Cells (MSCs)	deferoxamine

Although intracerebral hemorrhagic (ICH) is less studied than ischemic stroke, intranasal delivery of therapeutics has shown promise in experimental ICH models. Studies have investigated intranasal delivery of rat HP-BMSCs in a collagenase-induced ICH mouse model. HP-BMSCs reached the ipsilateral cortex, perivascular spaces, and perihematoma region within 6 hours. Increased protein levels of GDNF, VEGF, and BDNF were observed.

Fig. 2 The improved therapeutic effects for ischemic stroke achieved using intranasal temperature-sensitive hydrogels containing an inclusion complex of edaravone and borneol. Fig. 2 Enhanced the treatment of ischemic stroke through intranasal temperature-sensitive hydrogels of edaravone and borneol inclusion complex. (Teng, et al., 2024)

References

Marcello, E., & Chiono, V. (2023). Biomaterials-enhanced intranasal delivery of drugs as a direct route for brain targeting. International Journal of Molecular Sciences, 24(4), 3390.
Teng, C., et al. (2024). Enhanced the treatment of ischemic stroke through intranasal temperature-sensitive hydrogels of edaravone and borneol inclusion complex. International Journal of Pharmaceutics, 651, 123748.
Huang, Q., et al. (2024). Research progress in brain-targeted nasal drug delivery. Frontiers in Aging Neuroscience, 15, 1341295.