Howard Curler Distinguished Professor
3631 Engineering Hall
1415 Engineering Drive
Madison, WI 53706
Ph: (608) 262-1092
Fax: (608) 262-5434
Chemical and Biological Engineering
Non-invasive delivery of small molecule pharmaceuticals and biopharmaceuticals (protein pharmaceuticals) to the brain is hindered by the presence of the blood-brain barrier (BBB). This impermeable barrier, comprised of endothelial cells, separates the bloodstream from the interstices of the brain. Unless a molecule satisfies the dual criteria of having a small molecular size of less than 600 daltons and a high degree of lipid solubility, it will not cross the BBB. Because of these constraints, greater than 98% of small molecule pharmaceuticals do not cross the BBB and no biopharmaceuticals can cross this barrier. We are focused on overcoming this barrier through the development of non-invasive delivery methods that target drugs to the brain for the treatment of neurological diseases.
Traditionally, the design of neuropharmaceuticals has been chemistry-driven and has relied on the manipulation of small molecule compounds to satisfy the size and lipid solubility requirements. However, molecular engineering techniques allow us to take a more robust approach and employ endogenous transport mechanisms present at the BBB as a means to shuttle drug cargo from the blood to the brain. These cellular transport systems can be targeted using the exquisite specificity of antibodies that are in turn linked to a drug payload that can include small molecule pharmaceuticals, biopharmaceuticals, or even DNA therapeutics. We are therefore interested in the discovery of novel transport systems and cognate antibody targeting molecules, and we design high throughput selections that serve this purpose. Along these lines, we are also working to optimize the process for producing large amounts of therapeutic antibodies and proteins to meet the eventual demands of clinical application.
We are also interested in developing an in vitro model of the BBB that accurately mimics the in vivo characteristics of the BBB. An in vitro BBB model would permit the combinatorial screening of drug candidates and drug-targeting strategies, a process that is not amenable to an in vivo system. When the endothelial cells that make up the BBB are cultured in vitro, however, changes in gene and protein expression occur thereby altering the permeability characteristics and integrity of the in vitro model. We investigate these changes using genomics and proteomics techniques in an attempt to understand how gene and protein expression must be modulated to yield properties representative of the in vivo BBB. We then work to leverage this information for the development of novel in vitro models that possess more in vivo-like qualities.