The blood-brain barrier (BBB) prevents the passage of foreign substances from the blood to the brain’s extracellular fluid. Several drugs that permeate through the BBB are compromised, and only an insufficient amount reaches the targeted tissues. Nanoparticle-based systems present a wonderful opportunity to beat the challenges related to drug administration via the intranasal route.

Study: On a highway to the brain: A review on nose-to-brain drug delivery using nanoparticles. Image Credit: Kateryna Kon/Shutterstock

Scientists have recently reviewed research articles related to the applying of inorganic nanoparticles in delivering drugs to the brain through the intranasal route. This review is on the market in Applied Materials Today.

The role of blood-brain barrier within the central nervous system

BBB and cerebrospinal fluid separate the central nervous system from systemic blood circulation. It further maintains homeostasis and protects the brain from external injuries. In a healthy person, BBB ensures proper brain functioning by stopping the influence of external blood materials within the brain’s extracellular fluid.

BBB comprises a monolayer of tightly connected endothelial capillary cells that allows selective penetration of hormones and nutrition. Moreover, this membrane also resists the entry of poisons, pathogens, and foreign bodies like drugs. BBB impairs the entry of enormous and low-weight molecules; nonetheless, it allows the passage of smaller and highly lipophilic substances.

The compounds present in oral or systemic drugs must first go through the BBB to achieve the CNS. Drugs reach the brain through mechanisms comparable to passive diffusion and lively transport. BBB comprises specific transporter proteins and receptors that allow the entry of essential substances, comparable to insulin receptor, glucose transporter GLUT1, and transferrin receptor TfR. The presence of efflux transporters on the endothelial cells restricts the uptake of several molecules into the brain and forces drugs to re-enter systemic circulation.

For the treatment of CNS disorders (e.g., multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, neurocysticercosis, and meningitis), optimal drug concentration must reach the brain. CNS disorders are related to a wide selection of pathological symptoms as a result of impaired neural function and damaged neural structures. Several drugs used for the treatment of CNS disorders are related to unintended effects that negatively impact patients’ quality of life.

Benefits and challenges of intranasal drug administration

The nasal cavity is split into three regions, namely, the respiratory region, the vestibular region, and the olfactory region. The Intranasal (IN) route of drug administration is an efficient method to realize high drug levels within the brain. Subsequently, it is taken into account another drug administration route.  

The nasal cavity presents a minimally invasive route for drug delivery with rapid motion. The olfactory region of the nasal cavity provides direct access to the brain. Moreover, the IN cavity comprises high-density microvasculature, which is related to drug absorption and distribution.

Drug delivery through the IN route aids within the reduction of systemic unintended effects. This route also avoids the issues related to drug degradation within the gastrointestinal tract. The IN route can achieve direct drug delivery through the sensory neuronal pathway or indirect delivery via the passage across the BBB from the systemic circulation.

A few of the challenges related to nasal-based formulations include small volume formulation that might be introduced to the nose and the presence of a mucus layer and native enzymes that may inactivate drugs or minimize their absorption. The nasal mucosal layer, coupled with ciliary movement, can limit the retention time of the drug dosage and resist the movement of drug molecules towards the CNS.  

Nanoparticle-based nasal drug delivery system

Nanoparticle-based drug delivery systems have proved to be promising tools to deliver and accumulate therapeutic agents within the CNS by enhancing the permeability across the olfactory region. Their unique characteristic size and functions, comparable to reactivity, strength, surface area, and solubility, aid in crossing the BBB.

The important thing factor that should be controlled in IN formulations is the scale of nanoparticle-based systems since it impacts the drug loading, release, stability, and targeting towards the CNS. The nanoparticle size also impacts the pharmacokinetics of nanocarriers, including absorption, circulation time, and biodistribution. Small particle size with greater surface area promote enhanced drug solubility, stronger interaction with mucosa, and higher permeation than drug solution.

The nanocarrier’s surface charge also influences drug performance post IN administration. Positive zeta potentials offer higher interaction with the negatively charged mucin residues and favor higher retention of the nanoformulations within the nasal mucosa for an extended period. IN-based nanoformulations revealed higher drug uptake, permeability, and absorption within the olfactory region and promoted accumulation within the CNS. 

Proteins with receptors within the olfactory region (e.g., lectins) are considered the gold standard for lively brain targeting. Hence, incorporating other strategies, comparable to adding mucoadhesive agents, in nanoparticulate-based systems promotes the next degree of selective drug delivery to the brain.

Biodegradable and biocompatible polymer nanoparticles, comparable to poly(caprolactone) (PCL), poly(lactic acid) (PLA), lipid-based nanocarriers, nanovesicular particles, gold nanoparticles, magnetic nanoparticles, and silica nanoparticles, are related to IN drug delivery to CNS.