Blood Brain Barrier
Our central nervous system (CNS), the highly complex and sensitive brain and spinal cord organs, regulate the functions of our bodies and perform an amazing range of actions. The work of our CNS enables us to do everything from speach, to creating mathematical models of the early universe. To protect these essential and incredible capabilities and maintain healthy function, this tissue must be supplied with essential nutrients and allowed to remove waste via the blood. Chemicals, proteins, and cells in the blood that are not safe or necessary for healthy function are prevented from entering the CNS by a tightly bound layer of specialized cells collectively called the Blood Brain Barrier (BBB). This security system creates a problem for the treatment of disorders and diseases within the CNS because therapeutic compounds are both excluded from entering the brain and rapidly expelled back to the blood by the BBB. Generally, small chemical drugs must be carefully engineered to enter the brain, and biologic drugs cannot accumulate in the brain at high enough concentrations to be effective.
Modern biological drugs are delivering treatments for previously incurable diseases because they offer unparalleled specificity and affinity to a wealth of druggable targets. However, surface charges and their large size prevents biologic drugs like antibodies and oligonucleotides from freely crossing the BBB, limiting their usefulness for CNS disorders despite their huge potential and the high unmet needs of these disorders.
Routes of Entry
There are currently no technologies available to doctors to delivery drugs consistently throughout the whole CNS. The most successful approach to date has been the engineering of small molecule drugs to fit size, charge and lipophilicity properties, these can require extensive modification of the active compound to increase its passive uptake. Like absorptive-mediated-transcytosis, small molecule engineering is not targeted and must balance effective CNS drug concentrations with systemic toxicity effects due partly to higher uptake in other tissues.
Physical engineering solutions with direct injection, drug wafers, and convection-enhanced delivery can achieve localized effective drug concentrations but require invasive surgery risking injury to the brain. Short term disruption of the blood brain barrier can be achieved with drugs and ultrasound at the expensive of exposing CNS tissue to infection and long term damage of the BBB.
The ideal drug delivery system (DDS) targets the BBB with selective ligand(s) to enhance uptake specifically for the CNS without modification of the active form of the pharmaceutical compound. Additional targeting of specific cells within the CNS, and limited uptake in peripheral tissues further enhance the utility of this ideal CNS DDS. Receptor-meditated-transcytosis dependent technologies using ligands against Transferrin, Low Density Lipoprotein, and Insulin receptors show promise in development. None of these display the specificity of CNS targeting, greatly increased drug accumulation, and limited drug interaction offered by Braizon’s B-Smarter™ platform.