While the blood-brain barrier is notoriously stringent, it occasionally allows the passage of small molecules, in the right circumstances, almost as though these molecules are capable of the biochemical equivalent of uttering, “open sesame.” Like Ali Baba’s cave, the blood-brain barrier provides a temporary opening, permitting free passage.

Finding the right invocation has preoccupied scientists, who have been determined to find the least disruptive means possible of transporting drugs across the blood-brain barrier. These scientists hope to improve on alternative transport aids, such as convection-enhanced delivery and ultrasound-mediated delivery, which can be relatively invasive. If Ali Baba’s cave could be accessed without the aid of a jackhammer, why should therapeutic carriers resort to rough means of reaching the brain?

Such was the thinking of researchers at the Mayo Clinic, who have demonstrated in a mouse model that their recently developed synthetic peptide carrier is a potential delivery vehicle for brain cancer chemotherapy drugs and other neurological medications. The carrier, called K16ApoE, mimics a ligand-receptor system and generates transient blood-brain barrier permeability. In the Mayo Clinic’s study, this permeability was used for noncovalent delivery of chemotherapeutics and other neurological medications to the brain.

The results of this study appeared in PLOS One May 21, in an article entitled, “Peptide Carrier-Mediated Non-Covalent Delivery of Unmodified Cisplatin, Methotrexate and Other Agents via Intravenous Route to the Brain.” Besides cisplatin and methotrexate, the molecules transported across the blood-brain barrier included include cisplatin, methotrexate, cetuximab, three different dyes, and synthetic peptides Y8 and I-125.

“Not only have we shown that we can transport eight different molecules, we think this method will be less disruptive or invasive because it mimics a normal physiological process,” said Mayo Clinic neuroscientist Gobinda Sarkar, Ph.D., the corresponding author of the study. In addition, it was possible to transport the drugs without modifying any of the molecules involved.

The synthetic peptide K16ApoE, once injected into a vein, binds to proteins in the blood to create entities that can pass for near-normal ligands to some receptors present on the blood-brain barrier. The “pseudo-ligand” receptor interaction creates what the researchers believe to be transient pores through which various molecules can be transported to the brain.

In their article, the researchers emphasize that their ligand receptor system can transport “various proteins and immunoglobulins across the blood-brain barrier in a noncovalent manner,” avoiding the complications of covalent linking strategies, which include the need for expertise in linkage chemistry, necessity of purification after linkage, and evaluation of functionality after purification.

The researchers say their method, which has been successfully demonstrated in mice, meets three of five requirements for a usable therapy: It's feasible as a repeated procedure; it should be relatively easy to introduce into medical practice; and it would work for any size or location of brain tumor. More research will need to be done to prove effectiveness and determine any adverse effects.

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