Development of a Targeted Nanotherapeutic Approach to the Treatment of Biofilm-Associated Staphylococcus aureus Infection

Infections caused by Staphylococcus aureus represent a major health concern, as S. aureus is a leading cause of both hospital-acquired and community-acquired infections. Specifically, S. aureus is a leading cause of implant-associated infection, owing to the ability of S. aureus to form biofilms. As biofilm formation results in inadequate responses to conventional antibiotics, infections associated with biofilms, particlulary orthopaedic infections, often necessitate surgical intervention. This subjects patients to increased risk and financial strain. Thus, biofilm formation represents an enormous burden on the healthcare system and demonstrates the need for novel therapeutic approaches. Nanotechnology is an emerging topic in medicine and provides new materials with unique properties and scale for the development of novel therapeutic approaches. Nanoparticles (NPs) have been employed as drug delivery vehicles in a number of clinical settings. Additionally, many types of NPs exhibit the ability to convert light energy into heat to achieve thermal killing of target cells. These photothermal (PT) effects have been employed in pre-clinical models of both cancer and infectious disease. We therefore sought to design a system exploiting the apparent multiple beneficial aspects of NPs to target and selectively eradicate bacterial biofilms. This dissertation describes the development and optimization of a novel nanotherapeutic system comprised of core elements including gold nanocages, a polymer coating, targeting antibodies, and antibiotics loaded for controlled release. We demonstrated the ability to achieve complete eradication of S. aureus planktonic cultures and biofilms through combined synergistic effects of PT killing and controlled antibiotic release. We then assessed the potential optimization of our system by evaluating the relative activity of antibiotics in the context of established biofilms, which could inform the choice of antibiotic to be loaded into our nanotherapeutic system. Finally, we demonstrated the versatility of our design with the substitution of various components as well as demonstration of activity against biofilms formed by diverse bacterial pathogens including S. aureus and Pseudomonas aeruginosa. These results demonstrate the successful design of a novel nanotherapeutic approach for the treatment of infectious diseases and potentially pave the way for the future development of successful treatments for the eradication of established bacterial biofilms.