A Target-Oriented Approach for Materials Design

Many drugs bind their biological targets selectively and reversibly with characteristic binding constants and on/off-rates. These same targets can serve as depots for drug loading, and be used as building blocks for the construction of new drug delivery materials. For example, self-assembling a given biological target should afford a material with a tunable copy number of selective binding sites that can house and subsequently release drug at predictable rates. We demonstrate feasibility of this approach by preparing gel networks by self-assembling amphiphiles containing the drug target of the antibiotic vancomycin. This drug kills bacteria by reversibly binding to the dAla-dAla dipeptide found within bacteria, inhibiting cell wall biosynthesis. Gel networks formed by dAla-dAla assembly serve as selective depots for vancomycin and provide sustained release of drug over months <i>in vivo</i>. Biophysical experiments and release simulations using mathematical models of mass transport dynamics indicate that drug release is largely dependent on the on/off-rates defining the reversible binding event between drug and target. Lastly, we demonstrate that the gel can be reloaded multiple times by simple tail-vein injection after releasing its cargo.