A group of researchers at Sanford Burnham Prebys Medical Discovery Institute has found a new drug delivery method for brain injury treatment which is capable of delivering drugs directly to the injured part of  the brain. The technique, called CAQK coupling, will utilize a peptide called CAQK that targets, and selectively binds, to damaged brain areas once it is systematically administered. Drugs, or treatments such as siRNA complexes, can now be coupled to CAQK peptide for effective targeted delivery.

This technique has been licensed by a biotech research and technology startup company, AivoCode, which was recently awarded a Small Business Innovation Research (SBIR) grant from the National Science Foundation for further development and commercialization.

The study, conducted due to high prevalence of Traumatic Brain Injury (TBI) victims,  forced researchers set out to investigate various peptides that would recognize specific molecular changes at the locations of traumatic injury in the brain, and improve delivery of therapeutic chemicals to these sites. The researchers previously employed in vivo phage display as a powerful and unbiased method to probe tissues in tumors and wounds. The goal of this approach was to explore an alternative to local delivery of therapeutics, which is invasive and can add complications to the injury. The study was published on June 28, 2016 in Nature.

The researchers described the short peptide sequence, CAQK which was identified in vivo phage display screening in mice with acute brain injury. The CAQK peptide selectively binds to injured mouse and human brains. Systemically-injected CAQK specifically attaches to sites of brain injury in mouse models called chondroitin sulfate proteoglycans, which increase in case of brain injuries. These CAQK chemicals have the ability to carry drugs and nanoparticles to the injury site of the brain.

The hindering factor in treating brain diseases is the blood-brain barrier, due to which localized delivery of drugs has been closely examined by many scientists over the years but has significant limitations in clinical environments. In several cerebrovascular diseases, the blood-brain barrier is disrupted.  Due to a lack of binding proteins that get washed out of the blood barrier, the therapeutic efficiency of drugs becomes extremely weakened.

The peptide sequence could also be used to detect brain injuries and invent detection tools by attaching the peptide to materials that can be detected by medical imaging devices. This is due to the fact that the peptide can deliver nanomolecules that can be loaded with larger nanoparticles and can enable genetic engineering therapies or enzyme therapies.

The researchers tested the peptides area of effect by inducing non-penetrative brain trauma injury in mice. The scientists tested peptide homing in a controlled cortical impact injury (CCI) model. Without any penetrative injury, the model showed symptoms of cortical tissue loss, axonal injury, concussion and BBB dysfunction similar to TBI.

The peptide targeted the injured area of brain in this model. However, the peptide binding was only limited to the area of injury particularly and not to other areas as no peptide accumulation was detected in perforating injuries inflicted on the liver and skin. Hence the peptide targeting was limited to the area of injury in the model at least.

Traumatic Brain Injury (TBI)

Traumatic Brain Injury (TBI), also known as intracranial brain injury, occurs when an external force injures the brain. TBI is a major health problem which can lead to early death and other brain diseases such as dementia and depression.

According to Centers for Disease Control and Prevention (CDC), of the 1.7 million who sustain TBI each year in the United States; 52,000 die, 275,000 are hospitalized, and 1.365 million are treated and released from an emergency department. Since there are limited treatments available to treat TBI and many TBI injuries are penetrative, making diagnosis even more complicated, the researchers took it upon themselves to increase the mortality of TBI patients..

Blood-brain barrier (BBB) disharmony is an important indicator for BTI, with therapies to restore BBB functionality currently under investigation for neuroprotection. Since BBB injuries are localized to the upper region of the body, the delayed onset of a second injury provides an effective method for medical interventions. Research suggests the duration of the BBB impairment is at least up to 5 days which provides ample time for such a treatment method. The results show enhancement as high as 35 times in the accumulation of systemically administered imaging agents and therapeutic chemicals at and around the site of injury.

The peptide targeting was observed for up to 5 days after the injury, facilitating precise targeting. Furthermore, the peptide was more successful at targeting the area of injury via intravenous injections as compared to draining blood vessels near the brain and relieving intracranial pressure to minimize injury.

The high accuracy of such targeting is likely accounted for by two factors — the peptide can access and bind to its target that allows accumulation of the payload and causes retention at the site of injury. The impairment of the BBB allows all circulating substances to enter the injury area. And, if the peptide receptor is in sufficient volume compared to the volume of the peptide-drug compound, the binding of the peptide to the receptor can assist payload accumulation beyond the BBB drainage.