Proper delivery is pivotal in nearly every part of life, from jokes to packages, but there are few instances where it is more important than in the case of pharmaceutical drugs. Delivering medicines or therapeutics to the right targets, at the right dosage and at the right time, is a key focus in every indication. But some drugs are harder to deliver than others, either because of their targets or their formulations. And of such targets, the brain has to be one of the biggest culprits in complicating drug delivery, thanks to the blood-brain barrier.
This barrier protects the central nervous system by serving as a gatekeeper for all substances from the blood into the brain; harmful or unfamiliar substances are blocked while safe substances, such as nutrients and oxygen, pass through. Most drugs fail to successfully pass the blood-brain barrier in high enough levels to have a therapeutic effect, and trying to increase doses enough to get such an effect can come with unwanted side effects.
There is one potential opening, however—the blood-brain barrier expresses a number of transporters that serve to ferry safe substances and nutrients from the blood into the brain. And a research team at the University of Eastern Finland recently published results in Scientific Reports detailing a method for harnessing one such transporter.
The transporter in question is L-Type Amino Acid Transporter 1 (LAT1), which is highly expressed within the brain. As explained on the University’s website, LAT1 “is essential for the transport of large neutral amino acids such as phenylalanine and leucine from extracellular fluids into the cells. Additionally, it transports amino acid-containing drugs such as gabapentin, L-DOPA and baclofen across the blood-brain barrier (BBB). In normal cell membranes, LAT1 is expressed only in blood-brain and blood-placenta barriers. Much of its appeal as a drug carrier is due to its relative high abundance at the BBB versus other tissues. Besides having an important role in brain delivery, LAT1 is significantly up-regulated in several human cancer types including e.g., glioma.”
Adjust Professor Kristiina Huttunen of the University of Eastern Finland’s School of Pharmacy leads a group of researchers that have been studying this transporter for years. Their research has shown that LAT1 can be used for brain targeting and the delivery of drugs across the blood-brain barrier, and this most recent work has demonstrated that LAT1 can be used for intrabrain-targeted drug delivery after the blood-brain barrier has been bypassed. According to a University of Eastern Finland press release, this study also proved for the first time that LAT1 is expressed not only on the surface of neurons, but also in supporting cells, astrocytes and microglia.
The most interesting aspect of LAT1 is that by temporarily converting some drugs into prodrugs, those prodrugs can use LAT1 to enter cells, thereby enabling greater drug delivery. This was demonstrated with the prodrugs of compounds such as ketoprofen (an anti-inflammatory drug) and ferulic acid (an antioxidant), which saw improved cellular uptake versus the parent drugs.
“We were also able to identify structural requirements for the prodrugs that could enable targeting between the different brain cell types in future," noted first author of the study, PhD student Johanna Huttunen.
On the website of the University of Eastern Finland’s Drug Targeting Research Group, which is led by Prof. Huttunen, it was noted that in addition to higher drug accumulation, this approach “is expected to decrease simultaneously unpleasant adverse [e]ffects that rise from unselective drug delivery and distribution of drugs to off-target organs.” Other transporters of interest to the group include “Organic Anion Transporting Polypeptides (OATPs), Monocarboxylate Transporters (MCTs), Organic Cation Transporters (OCTs) and Organic Anion Transporters (OATs),” all of which “are highly and/or selectively expressed on the blood-brain-barrier, and in certain brain cells, such as neurons, astrocytes and microglia or in activated immune cells.”
“By this approach it is possible to multiply the exposure of target cells to the drugs with therapeutically relevant concentrations and solve one of the main hurdles in CNS-drug development; lack of efficacy has been the greatest single reason (46%) for CNS-drug failure in clinical trials in the past … Moreover, this study shows that by careful prodrug design that takes into account transporter selectivity, brain cell selective drug delivery and targeting between neurons, astrocytes or microglia can be obtained in future, which can lead to improved efficacy and safety of neuroprotective drugs within the brain,” the authors concluded.