Development of a Thrombin-Sensitive Recombinant Silk, "Smart" Drug Delivery System

North Dakota State University, Fargo ND

Investigators

Abstract

? DESCRIPTION (provided by applicant): The rise in antibiotic resistant bacterial strains is quickly outpacing drug discovery, imposing an enormous economic burden on the world's healthcare systems with estimates reaching $20 billion in direct healthcare costs. Listed by the World Health Organization as one of the top 3 threats to global public health, more than 2 million Americans suffer from an antibiotic-resistant infection with over 23,000 succumbing annually (according to the Centers for Disease Control, USA). Combating multidrug resistance necessitates a paradigm shift away from exclusive drug discovery efforts toward smart, infection-responsive drug delivery systems for current therapeutics. These observations culminate in the following global hypothesis: a bioinspired copolymer containing a thrombin-sensitive linker chemically grafted to a biomimetic recombinant silk peptide will provide a self-assembling nanocapsule drug delivery vehicle that will only release its drug payload in the presence of up-regulated thrombin-like activity associated specifically with S. aureus and P. aeruginosa infections. To address this hypothesis, fabrication, analysis and testing of this new smart drug delivery system will be pursued via the following specific aims: 1) Chemically graft a thrombin-responsive peptide to a recombinant silk peptide; 2) Determine the proteolytic stability of the newly created thrombin sensitive silk-based biomimetic polymer to S. aureus and P. aeruginosa thrombin-like activity; 2) Assess the size, polydispersity, and tobramycin encapsulation efficacy of thrombin-sensitive silk biopolymer nanoscale micelles. Achievement of these aims will yield a new infection responsive drug delivery system that will only release its drug payload in the presence of up-regulated thrombin activity. Everything is currently in place to successfully execute these aims and provide a powerful platform to proceed to more extensive in vivo testing, ultimately, controlling the rising tide of multidrug resistant S. aureus and P. aeruginosa infections.