Assistant Professor
Department of Chemical Engineering
University of Michigan

ABSTRACT

"Molecular Engineering of Advanced Imaging Agents and Therapeutics:
Using ChE principles to aid in design"


Traditionally, drug development has proceeded in a linear fashion from optimizing target affinity, validating in cell culture, testing in animal models, and moving to the clinic. For some drugs, such as small molecules, extensive data are available to define empirical ‘rules’ to help guide development of early screening hits to avoid attrition at later stages. However, for new, more advanced therapeutics, sufficient data are not available for empirical guidance. Because of their more complex structures, many of these agents have transport limitations within the body. These include the transient kinetics of an imaging agent reaching its target and washing out of the background or a macromolecular therapeutic trying to navigate its way through the tumor microenvironment and bind a receptor, either inside or outside the cell.


Our lab uses predictive computational transport simulations to guide the design of these agents without the need for a priori data. I will outline several examples where these transport limitations give rise to counter-intuitive results. These include i) the design of antibody-drug
conjugates, where lower potency can result in higher tumor killing, ii) directed evolution of stabilized alpha helical peptides where lower cellular efficacy can more efficiently hit currently ‘undruggable’ targets in the body, and iii) use of high charge density to improve oral
absorption and targeting of a ‘disease screening pill.’ By incorporating these predictive, multiscale simulations – from the molecular level to the whole organism scale – we can use molecular engineering to help design novel therapeutics and imaging agents rather than develop them through costly trial-and-error.