Drug delivery
“It is estimated that only 2% of developed drugs are able to cross the blood-brain barrier, and for this reason, the delivery of drugs to the brain is an unmet clinical need,” says Vera Neves, whose work centres around finding drug delivery systems to bypass the barrier. Research teams have been searching for ways to overcome the blood-brain barrier for some time, but with advances in the field of peptides – short chains of amino acids that serve as building blocks for proteins – some believe we can use ‘peptide shuttles’ to sneak active pharmaceutical ingredients past it, effectively tricking the cells that form the blood-brain barrier into letting them use the same pathway that ferries nutrients to where they’re needed.
Peptide shuttles
Proponents of peptide shuttles believe they could be used to improve the treatment of a wide range of neurological conditions, such as Alzheimer’s, Parkinson’s and brain tumours, by facilitating the delivery of therapeutic agents to the brain. Neves explains that peptides serve an important role in transporting drugs across the blood-brain barrier. “In simple terms, it’s like having a key that recognises a blood-brain barrier property (the lock) in the cells. For instance, peptides (the key) can be used to enable transport using overexpressed receptors, such as transferring receptor (TfR), in a mechanism designated Receptor Mediated Transport (RMT).”
Peptides can mediate the delivery of drugs using the unique properties of cell components (lipids, glycolipids, or glycoproteins), in a mechanism called adsorptive mediated transport (AMT), says Neves. “In AMT, positively-charged peptides induce interactions with the blood-brain barrier cell membrane, which will culminate with vesicular transport across it,” she adds. “These types of mediated transports are particularly important for the delivery of large therapeutics, such as antibodies, that have been successfully used to treat diseases like cancer in other parts of the body, but have very limited application in the brain.” As well as enabling a treatment pathway that could open the door for new therapeutics, advantages to using peptide shuttles over traditional drug delivery methods include them being more cost-effective and scalable, since they’re small and can easily be synthesised. They can also be designed to specifically target certain areas, reducing the need for unnecessary off-target therapy and the side-effects that can result. However, as with any potential drug delivery method, there are challenges associated with developing peptide shuttles for the brain, as Stacy Blain, chief science officer of Concarlo Therapeutics and professor at SUNY Downstate
World Pharmaceutical Frontiers /
www.worldpharmaceuticals.net Successful shuttles
In a paper for the journal Pharmaceutics, researchers Macarena Sanchez-Navarro and Ernest Giralt, discuss the different types of peptides that have effectively been used as shuttles, including cell-penetrating peptides, receptor-specific peptides, and brain-targeting peptides. Examples of successful drug delivery peptide shuttles include: ■ Delivery of insulin-like growth factor-1 (IGF-1) to the brain: A receptor-specific peptide shuttle was developed that could bind to the insulin receptor on the blood-brain barrier and transport IGF-1 across the barrier. The peptide shuttle successfully delivery IGF-1 to the brain and protected against ischemic damage in a mouse model.
■ Delivery of neuropeptide Y (NPY) to the brain: A cell-penetrating peptide shuttle was developed that could transport NPY across the blood-brain barrier. The peptide shuttle successfully delivered NPY to the brain and reduced brain injury in a rat model of traumatic brain injury.
■ Delivery of doxorubicin to brain tumours: A brain-targeting peptide shuttle was developed that could bind to receptors on the surface of brain tumour cells and transport doxorubicin across the blood-brain barrier. The peptide shuttle successfully delivered doxorubicin to brain tumours and improved survival in a mouse model of brain cancer.
Source: Peptide Shuttles for Blood-Brain Barrier Drug Delivery
Medical Center, explains: “There are many safety concerns or even cost issues, but neurological diseases are so difficult to treat that cost is less of an issue. The bar is quite low. Any drugs that we can get across the blood-brain barrier would be a benefit, regardless of price.” In terms of safety, it’s important to remember that the peptide shuttles are just that: shuttles. “They are not the drug themselves, they’re just a modality to get another medicine across the barrier,” says Blain. “So, we will have to take into account the inherent safety to your cost of what the peptide shuttles are transporting.”
“There are many safety concerns or even cost issues, but neurological diseases are so difficult to treat that cost is less of an issue. The bar is quite low.”
Stacy Blain, chief science officer of Concarlo Therapeutics
Beyond cost and safety, there’s also efficacy to consider – and here, too, there are many other potential complications. “The major challenge associated with peptide shuttles is their short lifespan in vivo, due to the abundance of peptidases in the digestive system (which limits oral administration), blood, liver, the blood-brain barrier,” says Neves. “As a consequence, the use of peptide shuttles might result in lower effectiveness.” Nevertheless, it has been proposed that modifications to peptides might increase their time in the blood. Such modifications include the use of unnatural amino acids, as well as cyclisation and glycosylation – two chemical modulation techniques that can improve bioavailability and
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