Understanding How and What Drug Can Cross the Blood-Brain Barrier?

Approximately 98% of all small-molecule drugs and nearly 100% of larger therapeutics are unable to cross the blood-brain barrier (BBB). Understanding what drug can cross the blood-brain barrier is critical for developing effective treatments for neurological diseases like Alzheimer's and Parkinson's.

Quick Summary

The ability of a drug to cross the blood-brain barrier depends on its physicochemical properties or its interaction with specialized transport systems. Highly lipid-soluble compounds can use passive diffusion, while nutrients and certain modified drugs use carrier- or receptor-mediated transport. Specialized efflux pumps can also prevent drug entry.

Key Points

• Passive Diffusion: Small, lipid-soluble molecules like alcohol, nicotine, and many psychoactive drugs cross the BBB by passively diffusing through the endothelial cell membranes.

• Carrier-Mediated Transport (CMT): Certain drugs, such as L-DOPA for Parkinson's disease, mimic natural nutrients and use dedicated protein carriers to cross the barrier.

• Receptor-Mediated Transcytosis (RMT): Larger molecules, including peptides and engineered 'Trojan horse' proteins, can bind to specific receptors on the BBB surface to be actively transported into the brain.

• Efflux Transporters: Efflux pumps like P-glycoprotein actively pump many drugs out of the brain, a major challenge that researchers must overcome when designing new CNS therapies.

• Modern Drug Delivery Systems: Non-invasive methods like focused ultrasound combined with microbubbles and targeted nanoparticles are being developed to temporarily and safely open the BBB or transport drugs across it.

• Brain Cancer Treatments: Some chemotherapy drugs, like temozolomide, lomustine, and carmustine, are capable of crossing the BBB, making them viable options for treating brain tumors.

The Gatekeeper of the Central Nervous System

The blood-brain barrier (BBB) is a highly selective membrane separating the blood from the brain's extracellular fluid. It's formed by endothelial cells with tight junctions, preventing substances from leaking into the brain and protecting it from pathogens and toxins. This barrier, while protective, is a significant challenge for delivering drugs to treat neurological disorders.

Mechanisms of Crossing the Blood-Brain Barrier

Passive Diffusion

Small, lipid-soluble molecules can cross the BBB by passive diffusion through the endothelial cell membranes. Drugs with high lipid solubility, such as heroin, nicotine, anesthetics, and other psychoactive drugs, can quickly enter the brain via this method. Molecular size is also a factor, with molecules under 400-600 daltons often having a better chance of diffusing passively, although efflux can still be a barrier.

Carrier-Mediated Transport (CMT)

Essential nutrients use specific transport proteins to cross the BBB. Some drugs mimic these nutrients to utilize these transporters. L-DOPA, for example, a Parkinson's drug, uses the large neutral amino-acid transporter (LAT1) to enter the brain. Gabapentin also uses LAT1.

Receptor-Mediated Transcytosis (RMT)

Larger molecules can cross via receptor-mediated transcytosis, binding to specific receptors on endothelial cells and being transported in vesicles. This "molecular Trojan horse" approach, using proteins like insulin and transferrin that have their own transport systems, is being explored for drug delivery.

Efflux Transporters

Efflux transporters, like P-glycoprotein (P-gp), actively pump many compounds, including small, lipophilic drugs, out of the brain. This system significantly impacts drug efficacy by limiting their accumulation in the brain.

Examples of Drugs Crossing the BBB

Examples of drugs that cross the BBB include temozolomide, lomustine, and carmustine for brain tumors, many psychotropic medications, alcohol, and caffeine. The ability of a drug to cross the BBB depends on properties like lipid solubility and molecular size, which determine if it primarily uses passive diffusion, specialized transport, or is affected by efflux pumps. For a detailed comparison of drug properties and BBB permeability, you can refer to {Link: Drug Permeability: From the Blood-Brain Barrier to the Peripheral ... https://pmc.ncbi.nlm.nih.gov/articles/PMC10465108/}.

Modern Strategies to Overcome the Blood-Brain Barrier

New methods are being developed to deliver drugs across the BBB. These include focused ultrasound (FUS) with microbubbles, nanoparticle delivery systems, molecular Trojan horses (using RMT), and prodrugs that are modified for better BBB passage.

Conclusion

The ability of a drug to cross the blood-brain barrier relies on its properties and the barrier's transport systems. Overcoming the BBB is crucial for treating brain diseases. New strategies like focused ultrasound, nanoparticle delivery, and molecular Trojan horses are providing innovative ways to bypass the barrier and deliver therapies to the brain.

Brain drugs can now cross the once impenetrable blood–brain barrier

Frequently Asked Questions

Why is it so difficult for most drugs to cross the blood-brain barrier?

The blood-brain barrier (BBB) is a protective network of blood vessels with very tight cell junctions, preventing many substances from leaking into the brain. In addition, specialized proteins called efflux pumps actively push potential toxins and many medications back out of the brain.

How do highly lipid-soluble drugs, like heroin, cross the BBB?

Highly lipid-soluble molecules, like heroin, are able to dissolve in the fatty lipid membranes of the BBB's endothelial cells and passively diffuse across them. Once in the brain's environment, they can then produce their pharmacological effects.

What is carrier-mediated transport and how is it used for drugs?

Carrier-mediated transport (CMT) uses specific transporter proteins, usually meant for essential nutrients like glucose or amino acids, to carry substances into the brain. Some drugs, such as L-DOPA, are designed to mimic these nutrients to gain entry via the same transporters.

What is the 'molecular Trojan horse' strategy?

The 'molecular Trojan horse' is a strategy that uses receptor-mediated transcytosis (RMT) to deliver drugs. A therapeutic drug is attached to a molecule (the 'Trojan horse') that naturally binds to a receptor on the BBB, causing it to be actively transported across the barrier into the brain.

Do all chemotherapy drugs cross the blood-brain barrier for brain cancer?

No, most chemotherapy drugs are not able to cross the BBB. A few, such as temozolomide, lomustine, and carmustine, are known to have good BBB penetration, which is why they are used to treat certain brain tumors.

What are the latest non-invasive methods being developed to improve BBB crossing?

Advanced methods include using focused ultrasound (FUS) combined with microbubbles to temporarily and locally increase the barrier's permeability. Another is designing nanoparticles that are engineered to encapsulate drugs and cross the barrier using various mechanisms.

What role do efflux pumps like P-glycoprotein play in preventing drug entry?

Efflux pumps act as bouncers at the BBB, actively pushing many small, lipid-soluble drug molecules back into the bloodstream. This mechanism has a significant impact on drug efficacy for CNS disorders, limiting the accumulation of many potential therapies in the brain.