High-resolution bimodal imaging and potent antibiotic/photodynamic synergistic therapy for osteomyelitis with a bacterial inflammation-specific versatile agent

Abstract

Unsatisfactory diagnosis and therapy of osteomyelitis are still common but challenging issues for clinicians. To overcome these problems, a bacterial inflammation-specific multifunctional agent, denoted bovine serum albumin-manganese dioxide-ubiquicidin_29-41-indocyanine green (ICG) -gentamicin (BMUIG), was synthesized for combined high-resolution bimodal imaging and antibiotic/photodynamic therapy for osteomyelitis. BMUIG binding affinity and antibacterial ability were assessed by using Staphylococcus aureus (S. aureus). Photoacoustic/magnetic resonance imaging was performed on a mouse model of acute osteomyelitis after intravenous injection of BMUIG. Then, myelitis-bearing mice were treated with antibiotic/photodynamic combination therapy. BMUIG specifically targeted S. aureus in comparison with non-targeted agents. In the osteomyelitis model, the infection area was identified accurately and quickly through ICG-based photoacoustic imaging and Mn²⁺-based T₁ magnetic resonance imaging after injection of BMUIG. Furthermore, the manganese dioxide in BMUIG reacted with the locally produced hydrogen peroxide under acidic inflammatory conditions, continuously generating oxygen for enhanced photodynamic therapy. In combination with low-dose gentamicin, a synergistic antibacterial effect was observed and bone infection was resolved. In summary, a non-invasive accurate diagnosis and effective synergistic therapy for osteomyelitis was successfully developed using a bacterial inflammation-specific versatile agent, which would provide a sound theranostic strategy for common infectious diseases. STATEMENT OF SIGNIFICANCE: Osteomyelitis is one of the most serious consequences in orthopedics. However, its inaccurate diagnosis and low-effective antibiotic treatment are still common but challenging issues for clinicians. To overcome these problems, we uniquely designed a bacterial inflammation-specific multifunctional nanoagent, bovine serum albumin-manganese dioxide-ubiquicidin_29-41-indocyanine green-gentamicin (BMUIG), for high-resolution bimodal imaging and antibiotic/photodynamic combined therapy of osteomyelitis. Herein, high-resolution imaging technologies refer to classic magnetic resonance imaging and emerging photoacoustic imaging. Photodynamic therapy is subtly introduced because of its safe and effective killing mechanism, which can synergize the bactericidal effect of antibiotics. As a result, we successfully realize non-invasive accurate diagnosis and effective synergistic therapy for osteomyelitis by virtue of the bacterial inflammation-specific versatile agent, which will serve as a promising candidate for sound theranostics in common infectious diseases.

Keywords: Antibiotic/photodynamic therapy; Bacterium specificity; Manganese dioxide; Osteomyelitis; Photoacoustic/magnetic resonance imaging.