A novel microbial infection-responsive drug release system

The aim of this study was to construct a novel drug delivery system suitabl e for controlled release of antibiotics. There is a need for devices that r elease antibiotics only during microbial infection, because prophylactic or prolonged use of antibiotics leads to serious problems, such as renal and liver toxicity and the emergence of drug-resistant bacteria (e.g., meticill in-resistant Staphylococcus aureus). We found previously that Staphylococcu s aureus-infected wound fluid showed high thrombin-like activity; therefore , in this study we designed an antibiotic release system triggered by throm bin activity. We synthesized an insoluble polymer-drug conjugate in which g entamicin was bound to poly(vinyl alcohol) hydrogel through a newly develop ed thrombin-sensitive peptide linker. The conjugate released gentamicin whe n it was incubated with Staphylococcus aureus-infected wound fluid, with th rombin and leucine aminopeptidase, or with human plasma and Ca2+, whereas n o biologically active gentamicin was released when the conjugate was incuba ted with noninfected wound fluid, with leucine aminopeptidase alone, with t hrombin alone, or with plasma. Furthermore, the conjugate reduced the bacte rial number in an animal model of Staphylococcus aureus infection. These re sults demonstrated that the conjugate has sufficient specificity and excell ent potential as a stimulus-responsive, controlled drug release system.