A mathematical feasibility argument for the use of aptamers in chemotherapy and imaging.
A challenge for drug design is to create molecules with optimal functions that also partition efficiently into the appropriate in vivo compartment(s). This is particularly true in cancer treatments because cancer cells upregulate their expression of multidrug resistance transporters, which necessitates a higher concentration of extracellular drug to promote sufficiently high intracellular concentrations for cell killing. Pharmacokinetics can be improved by ancillary molecules, such as cyclodextrins, that increase the effective concentrations of hydrophobic drugs in the blood by providing hydrophobic binding pockets. However, the extent to which the extracellular concentration of drug can be increased is limited. A second approach, different from the 'push' mechanism just discussed, is a 'pull' mechanism by which the effective intracellular concentrations of a drug is increased by a molecule with an affinity for the drug that is located inside the cell. Here we propose and give a proof in principle that intracellular RNA aptamers might perform this function. The mathematical model considers the following: Suppose I denotes a drug (inhibitor) that must be distributed spatially throughout a cell, but that tends to remain outside the cell due the transport properties of the cell membrane. Suppose that E, an enzyme that binds to I, is expressed by the cell and remains in the cell. It may be that the equilibrium E+I[right arrow over left arrow]{k(-1)k(1)}P is not sufficiently far enough to the right to drive enough free inhibitor into the cell to completely inhibit the enzyme. Here we evaluate the use of an intracellular aptamer with affinity for the inhibitor (I) to increase the efficiency of inhibitor transport across the cell membrane and thus drive the above equilibrium further to the right than would ordinarily be the case. We show that this outcome will occur if: (1) the aptamer neither binds too tightly nor too weakly to the inhibitor than the enzyme and (2) the aptamer is much more diffusible in the cell cytoplasm than the enzyme. Thus, we propose and show by simulation that an intracellular aptamer can be enlisted for an integrated approach to increasing inhibitor effectiveness and imaging aptamer-expressing cells.
Boushaba
Khalid
K
Department of Mathematics, Iowa State University, Ames, IA 50011, USA. boushaba@iastate.edu
Levine
Howard
H
Hamilton
Marit Nilsen
MN
D000277:Adjuvants, Pharmaceutic / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology*; D000465:Algorithms; D052157:Aptamers, Nucleotide / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology*; D001693:Biological Transport, Active; D003198:Computer Simulation; D003952:Diagnostic Imaging / Q000379:methods; D004358:Drug Therapy / Q000379:methods; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D004798:Enzymes / Q000378:metabolism; D005057:Eukaryotic Cells / Q000378:metabolism; D055459:Facilitated Diffusion; D006801:Humans; D007700:Kinetics; D008954:Models, Biological
D000277:Adjuvants, Pharmaceutic; D052157:Aptamers, Nucleotide; D004791:Enzyme Inhibitors; D004798:Enzymes