Targeted drug delivery after TBI works via short peptide sequence of amino acids

By Liz Meszaros, MDLinx
Published July 5, 2016

Key Takeaways

A new technology centered on a peptide sequence of amino acids may help deliver treatments to injured areas of the brain in patients sustaining traumatic brain injuries (TBIs), according to study results from researchers at the Sanford Burnham Prebys Medical Discovery Institute, San Diego CA, and Orland, FL, published June 28 in the journal Nature Communications.

“We have found a peptide sequence of four amino acids, cysteine, alanine, glutamine, and lysine (CAQK), that recognizes injured brain tissue,” said senior author Erkki Ruoslahti, MD, PhD, distinguished professor in SBP’s NCI-Designated Cancer Center. “This peptide could be used to deliver treatments that limit the extent of damage.”

Lead author Aman Mann, PhD, postdoctoral researcher in Dr. Ruoslahti’s lab added: “Current interventions for acute brain injury are aimed at stabilizing the patient by reducing intracranial pressure and maintaining blood flow, but there are no approved drugs to stop the cascade of events that cause secondary injury.”

Currently, researchers are studying—in preclinical trials—over 100 compounds that are designed to minimize or even prevent brain damage after TBI. These compounds were designed to block those events that cause secondary damage such as inflammation, high free radical levels, neuronal over-excitation, and signaling that could cause neuronal cell death.

Drs. Ruoslahti and Mann and fellow researchers identified a short peptide (sequence CAQK) which they identified using in vivo phage display screening in mice with acute brain injury. The CAQK peptide selectively binds to injured mouse and human brains. More specifically, it binds to components of the meshwork surrounding chondroitin sulfate proteoglycans, which are increased after injury, and are known to inhibit axon regeneration after spinal cord injury.

“Not only did we show that CAQK carries drug-sized molecules and nanoparticles to damaged areas in mouse models of acute brain injury, we also tested peptide binding to injured human brain samples and found the same selectivity,” added Dr. Mann.

“This peptide could also be used to create tools to identify brain injuries, particularly mild ones, by attaching the peptide to materials that can be detected by medical imaging devices,” said Dr. Ruoslahti. “And, because the peptide can deliver nanoparticles that can be loaded with large molecules, it could enable enzyme or gene-silencing therapies.”

Future applications of this technology are now being studied in animal models of central nervous system injuries, including multiple sclerosis and spinal cord injury.

This work was done in collaboration with the laboratories of Dr. Tambet Teesalu, the University of Tartu, Estonia; Prof. Michael Sailor, the University of California, San Diego; and Prof. Sangeeta Bhatia, the Broad Institute of Harvard and MIT. The work was supported by the Defense Advanced Research Projects Agency (DARPA) under Cooperative Agreement HR0011-13-2-0017, as well as grants from the European Research Council, Wellcome Trust, and the National Multiple Sclerosis Foundation. The findings and views expressed are those of the authors and do not reflect the official policy or position of the Department of Defense or the U.S. Government.

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