A mathematical feasibility argument for the use of aptamers in therapy in therapy and imaging

Karen Ames Lecture Series

Dr. Howard Levine

Department of Mathematics
Iowa State University


September 5, 2008

109 Shelby Center
3:00 PM (Refreshments at 2:30)

Abstract

A central challenge for drug design is to create molecules with optimal function that also partition efficiently into appropriate exit{in vivo} compartment(s). 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.

colloq LevineBiographical Sketch

Dr. Howard Levine is a Distinguished Professor of Liberal Arts and Sciences and a former Chairman of the Department of Mathematics at the Iowa State University. He received his Ph.D. from Cornell University in 1969. His research interests are Partial Differential Equations, Mathematical Biology, and Applied Mathematics and Mathematical Modeling.

Dr. Levine is members of Sigma Xi Scientific Honorary Society and Phi Kappa Phi Honorary Society. He is also an Associate Editor for Mathematical Methods in the Applied Sciences, Journal of Mathematical Analysis and Applications, and Communications in Applied Analysis.