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Peptide-based drug delivery to target the brain

Identifying peptides that overcome the blood-brain barrier as a powerful approach to deliver therapeutics to brain cells

The blood-brain-barrier (BBB) is a protective membrane that shields the brain from pathogens, toxins and large water-soluble molecules. Blood vessels throughout the body are lined by endothelial cells that allow some materials to flow from the blood stream into the surrounding tissues. In the brain however, the endothelial cells are more tightly coupled to prevent material from easily permeating the brain tissue, and they express efflux pumps that rapidly remove any molecules that manage to pass through this barrier. Supporting brain cells including pericytes and astrocytes wrap around the blood vessels, inducing the endothelium to create an even stronger shield against the free flow of molecules. Naturally, the barrier is selectively penetrable as water, gases like O2 and CO2 and small fat-soluble molecules, including hormones, alcohol, nicotine, caffeine, and a limited number of drugs like barbiturates, can diffuse or cross the membrane. Molecules needed for cell function are able to overcome the barrier via transporters, channels, pumps and specific receptors located at the endothelial cell surface. Many life-saving drugs and molecules, such as therapeutic antibodies, cannot permeate the BBB and thus cannot effectively be used for treating brain diseases and neurological disorders. Additionally, development of more effective and safer therapeutics calls for specific targeting of the cells of interest in order to bypass debilitating side effects from their non-specific delivery to the whole body.

Scientists at the Wyss Institute for Biologically Inspired Engineering have combined their human BBB Chip with phage-display peptide technology to identify short peptides that can preferentially cross the BBB. The Chip, pioneered at the Wyss as an organ model in a dish, contains all the necessary human cells in a cell architecture that replicates the BBB. This approach has been used to screen billions of peptides to identify universal BBB shuttles that can be linked chemically to antibodies, drugs, or nanoscale drug containers to carry these therapeutic cargoes across the BBB and to the brain tissue. Multiple rounds of selection identified unique small peptides that exhibited ~ 500-fold enhancement in their ability to cross the human BBB model without causing defects in its normal function.

Our group is utilizing powerful synthetic biology platforms coupled to our human organs-on-chips to rapidly discover shuttle peptides that can preferentially transit drugs across the human blood-brain barrier for delivery of CNS therapeutics.

Donald Ingber

In vivo work confirmed that these peptides enable the delivery of fluorescent nanoparticles across the BBB of living mice with a higher brain accumulation than previously seen with the published transport peptide Angiopep-2. More studies are ongoing to determine how efficient these peptides are for carrying small molecules, antibodies and antibody fragments, as well as nanomedicines in the form of drug-carrying nanoparticles and liposomes, across the BBB and into the brain. These peptides can also be tested in other human organ chips such as liver, lung, and kidney to identify shuttles that prefer binding only to BBB and not to other organs, and thus to make drug delivery brain-specific.

The Wyss team is currently evaluating the applications of these shuttle peptides for development of novel brain-specific therapeutics through internal research programs. In addition, they are interested in collaborating with pharmaceutical and biotechnology companies to further explore the capabilities of this system for central nervous system (CNS)-targeted drug development.

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