The brain is protected by something called the blood-brain barrier that makes it hard for drugs to reach the brain from the bloodstream.
But new research shows that delivering drugs through the nose could be an effective way to bypass the blood-brain barrier and get drugs to the brain to potentially treat brain disorders like Alzheimer’s disease and Parkinson’s disease.
Key Facts:
- The blood-brain barrier blocks over 98% of drugs from reaching the brain from the bloodstream. This makes treating brain disorders very challenging.
- Delivering drugs through the nose and into the nasal cavity could allow the drugs to bypass the blood-brain barrier and enter the brain directly.
- Nanoparticles loaded with drugs and delivered through the nose show promise for improving drug delivery to the brain compared to conventional drug delivery methods.
- Lipid-based nanoparticles like liposomes and nanoemulsions are being studied as nasal drug delivery systems to the brain because they are low toxicity and stable.
Source: Frontiers in Cell and Developmental Biology (2023 Aug 22)
The Nasal Cavity is the Gateway to the Brain
The nasal cavity is the large space behind and above the nose where air passes on its way to the lungs.
The nasal cavity is lined with a thin mucous membrane that can absorb drugs quickly.
Researchers believe drugs delivered into the nasal cavity can enter the brain directly through three pathways:
- Through the olfactory nerve pathway – olfactory nerve cells in the upper part of the nasal cavity can transfer molecules directly into the brain.
- Through the trigeminal nerve pathway – the trigeminal nerve in the nasal cavity has branches that extend into the brain.
- Through the circulatory system – drugs absorbed into blood vessels in the nasal cavity can enter the brain by crossing the weaker blood-brain barrier present in these vessels.
So the nasal cavity works as a gateway for rapidly delivering drugs from the nose to the brain, bypassing the protective blood-brain barrier that blocks drugs delivered through the bloodstream.
Nano Drug Delivery Systems Are Ideal for Nose-to-Brain Transport
But simply spraying drugs into the nose has limitations.
The nasal cavity is lined with mucus that traps foreign particles and rapidly clears them away.
Most drugs get trapped in the mucus and don’t reach the brain.
That’s where nanoparticles come in. Nanoparticles are tiny particles ranging from 1 to 100 nanometers in size.
They are similar to the viruses and particles the body is exposed to everyday.
This makes them ideal drug delivery vehicles.
When drugs are loaded into nanoparticle carriers:
- The nanoparticles protect the drugs from getting trapped in nasal mucus.
- The nanoparticles prevent the drug from being metabolized and degraded before reaching the brain.
- Nanoparticles can cross cell membranes easily and enter the olfactory and trigeminal nerves to access the brain.
- Coating the nanoparticles with ligands helps target them to receptors on the olfactory nerves and cells.
- Nanoparticles release drugs slowly over time for a sustained effect.
- Small nanoparticle size allows faster drug absorption into the nasal cavity.
Together, these advantages allow more of the drug loaded in nanoparticles to reach the brain compared to the drug administered alone.
Lipid Nanoparticles Are A Promising Nano Carrier
Among the different nanoparticle platforms, lipid-based nanoparticles show particular promise for nose-to-brain drug delivery.
Lipids are fat-like molecules that are naturally found in the body.
This makes lipid nanoparticles low toxicity and biocompatible.
The different types of lipid nanoparticles being explored are:
Liposomes:
- Liposomes are spherical nanoparticles made from a lipid bilayer shell with an aqueous core. The drug is encapsulated in the core or within the lipid shell.
- Liposomes fuse readily with cell membranes to deliver the drug inside cells.
- Hydrophilic and lipophilic drugs can be loaded into liposomes.
- The liposome coating protects the drug from degrading in the nasal cavity.
- Liposomes provide sustained release of drugs over hours to days.
Nanoemulsions:
- Nanoemulsions are emulsified droplets of oil in water stabilized by a surfactant coating.
- The oil core allows loading of lipophilic drugs.
- Nanoemulsions allow large-scale production and delivery of poorly water-soluble drugs.
- Adding polymers like chitosan helps nanoemulsions stick to the nasal cavity lining for longer durations.
Solid Lipid Nanoparticles (SLNs):
- SLNs have a solid lipid core stabilized by a surfactant coating. This allows controlled drug release.
- The solid matrix protects against drug degradation.
- SLNs are easy to scale up for industrial manufacture.
- However, SLNs have limited drug loading capacity and can show ‘burst release’.
Nanostructured Lipid Carriers (NLCs):
- NLCs prevent drug expulsion by using blended solid and liquid lipids in the core.
- NLCs allow higher drug loading and prevent burst release.
- But NLCs show poor loading of hydrophilic drugs.
- Making NLCs using physiological lipids enhances biocompatibility.
Lipid nanoparticles show great promise for nose-to-brain delivery because of their biocompatibility, ability to encapsulate both hydrophilic and lipophilic drugs, sustained drug release, and capacity for surface modifications.
Recent Research Examples of Lipid Nanoparticles for Brain Drug Delivery
Here are some recent examples that demonstrate the potential of using lipid nanoparticles administered through the nose to deliver drugs directly to the brain:
Treating Alzheimer’s disease:
Researchers developed liposomes loaded with an Alzheimer’s drug called imatinib mesylate.
Compared to oral delivery, the liposomes delivered 7 times more drug to the brain when given intranasally.
The liposomes released the drug slowly over 4 days.
This shows the potential of liposomes to improve imatinib delivery and retention in the brain.
Treating brain cancer:
Liposomes containing two anti-cancer agents – lomustine and n-propyl gallate – were designed.
These liposomes could enhance the anti-cancer effect compared to the free drugs when applied to brain tumor cells growing in the lab.
This liposome formulation will next be studied in animals and humans.
Treating Huntington’s disease:
A nanoemulsion formulation was made to deliver an anti-Huntington’s drug called tetrabenazine through the nose.
The nanoemulsion increased the amount of the drug absorbed across a tissue barrier by 1.68 times compared to the plain drug.
The nanoemulsion was also better tolerated by nerve cells compared to the free drug.
Treating Parkinson’s disease:
Solid lipid nanoparticles containing the Parkinson’s drug rotigotine were prepared using the hot melt emulsification method.
The nanoparticles had sustained drug release over 30 hours.
This long-acting nanoformulation could reduce the dosing frequency needed for managing Parkinson’s symptoms.
Treating anxiety disorders:
Nanostructured lipid carriers coated with chitosan polymer were developed to deliver the anti-anxiety medication buspirone to the brain.
Chitosan helped the nanoparticles stick to the nasal cavity.
These nanoparticles increased the amount of drug delivered to the brain 3-fold compared to intravenous injection.
The Future is Bright for Intranasal Drug Delivery
As the examples above show, lipid-based nanoparticles are emerging as promising carriers to facilitate nose-to-brain delivery of drugs to potentially treat a wide variety of brain diseases.
Though more research is still needed, this non-invasive delivery approach could improve treatment outcomes and quality of life for the millions affected by brain disorders worldwide.
Ongoing research is focused on:
- Identifying new lipids and lipid combinations to optimize drug encapsulation, release and delivery.
- Exploring alternate polymers and ligands for surface modification and targeting nanoparticles to the brain.
- Combining imaging molecules with therapeutics for tracking nano delivery and drug release.
- Developing nanocarriers for delivering biomolecules like genes, proteins, antibodies.
- Designing nanocarrier systems tailored to an individual drug’s structure and properties.
- Testing safety and efficacy in animal models of human brain diseases.
- Gaining better understanding of nanoparticle transport mechanisms into the brain.
The nose-to-brain route leverages the unique access the nasal cavity provides to the brain.
Coupled with specially engineered lipid nanoparticle carriers, it is poised to enable a new generation of therapies for combatting debilitating brain disorders.
References
- Study: Lipid-based nanoparticles via nose-to-brain delivery: a mini review
- Authors: Yang Xinchen et al. (2023)
