Bone-targeting lipid-polymer hybrid nanoparticles for less invasive, injectable local antibiotic treatment of bone infections by methicillin-resistant Staphylococcus aureus (MRSA).

Effective treatment of osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA) requires sufficiently high antibiotic concentrations at the infected bone sites. Local drug therapy such as antibiotic-impregnated beads or cement is a valuable option but requires invasive surgical procedures for implantation and sometimes removal. In this study, lipid-polymer hybrid nanoparticles decorated with alendronate, known as bone-targeting nanoparticles (BTN), were tailored for local antibiotic treatment of MRSA-osteomyelitis in a bone-targeting fashion. BTN loading linezolid demonstrated size around 100 nm in diameter that remained stable in serum- or calcium- supplemented medium, encapsulation efficiency around 60 % and controlled drug release properties, and were shown to be significantly more effective than free linezolid against MRSA both in their biofilm and intracellular forms. Significant bone-targeting affinity was demonstrated in hydroxyapatite screening (5.5-fold enhancement over no-alendronate nanoparticles) and ex vivo porcine bone model. BTN injected into animal legs resulted in lasting local bone-accumulation of nanoparticles with minimal distribution to most remote organs, leading to up to 34.9-fold antibiotic level enhancement at the injected bone legs over free drug group. In animal osteomyelitis model, BTN groups achieved multiple log10 scale reduction (p < 0.01) in bacteria CFU counts post-treatment with less blood platelet count reduction (p < 0.05) when compared with free drug group. Overall, this study highlights the excellent potential of a more active, less invasive nanodelivery-based approach for targeting those poorly accessible MRSA pathogens of osteomyelitis.