Assessing CDK5 as a Nanomotor for Chemotactic Drug Delivery

Enzyme chemotaxis is a thermodynamic phenomenon in which enzymes move along a substrate concentration gradient towards regions with higher substrate concentrations. Mathematical models have been developed to understand and define this phenomenon using Michaelis-Menten kinetics and substrate binding coefficients. One key application of this phenomenon is in the field of drug delivery, where chemotaxis can steer nanovehicles towards targets along natural substrate concentrations. Such gradients exist throughout the body, including around the blood-brain barrier, and thus targeted nanovehicles can bring therapeutics through such a gradient and target themselves at a given toxic species. In patients with Alzheimer’s disease, a gradient of tau protein forms in the bloodstream, and this protein is a substrate of the enzyme CDK5, a tau protein kinase that catalyzes the phosphorylation of tau protein. Through chemotaxis, CDK5 can travel along the tau protein gradient towards increasing concentrations of tau tangles and amyloid-beta proteins that are the cause of neuronal cell death in Alzheimer’s patients. In order to create the momentum necessary to propel a nanovehicle along the substrate concentration gradient, an enzyme’s binding affinity towards its substrate must overcome obstacles such as Brownian motion. We hypothesized that CDK5 would be able to overcome these barriers and developed a quantitative model using Michaelis-Menten kinetics to define the necessary parameters to confirm and characterize CDK5’s chemotactic behavior to establish its utility in drug delivery and other applications. Our results found that CDK5’s movement significantly outpaced random motion and characterized its movement for usage in drug delivery system design.