Speaker: Howard Levine
Title: A Mathematical Feasibility Argument for the Use of Aptamers in Chemotherapy and Imaging
Affiliation: Iowa State University
Date: Friday, March 20, 2009
Place and Time: Room 101, Love Building, 3:35-4:30 pm
Refreshments: Room 204, Love Building, 3:00 pm

Abstract. A central challenge for drug design is to create molecules with optimal function that also partition efficiently into appropriate in vivo compartments. This is particularly true in cancer treatments because cancer cells upregulate their expression of multi drug resistant transporters, which necessitates application of higher concentrations of extracellular drugs to enable cell killing. We prove in principle with a mathematical model based on chemical kinetics that mobile intracellular drug receptors such as RNA aptamers can increase the effective intracellular concentration of a drug by "pulling" the drug in. We evaluate the use of cell-expressed aptamers with affinity for the drug to increase the efficiency of drug transport across the cell membrane and to increase the intracellular concentration of drug. This outcome will occur if the aptamer diffuses throughout the cytoplasm and away from the cell periphery. The ability of the aptamer to increase the intracellular concentration of its target molecule could also be used for imaging cells. Simulations show that an intracellular aptamer can be enlisted for an integrated approach to both increase drug effectiveness and image aptamer-expressing cells.

An important finding is the identification of the role of diffusion of the aptamer or other drug receptor in moving a drug from the membrane into the cell interior. The study predicts that the efficiency of drug action will be higher if the drug target molecule diffuses rather than being sequestered in an intracellular location such as is true for many enzymes and other cellular protein drug targets.