Development of a Rifapentine-Loaded Alendronate-Conjugated PLGA-PEG Nanosystem: A Novel Bone-Targeted Strategy for Osteoarticular Tuberculosis Treatment with Enhanced Drug Delivery and Bone Regeneration.

BACKGROUND: The treatment of osteoarticular tuberculosis (TB) remains a significant clinical challenge, primarily due to inadequate drug delivery to bone tissues, severe bone destruction, and delayed repair processes. Conventional pharmacological therapy has limited efficacy and often necessitates surgical intervention. Thus, we developed a bone-targeted nanosystem by integrating rifapentine (RPT) and alendronate (ALN) to improve drug delivery, mitigate TB-induced bone destruction, and facilitate bone regeneration. METHODS: In this study, ALN was conjugated to PLGA-PEG-COOH utilizing the DCC/NHS method and subsequently loaded with RPT through premix membrane emulsification, resulting in the formation of the RPT/ALN-PLGA-PEG nanosystems. The physicochemical properties of the nanosystems were characterized, and its antibacterial activity, cytotoxicity, and impact on osteogenic/osteoclastic differentiation were evaluated in vitro. Bone-targeting efficacy and biodistribution were assessed using in vivo experiments. A rabbit spinal TB model was used to assess therapeutic efficacy based on inflammatory and bone turnover markers, bone mineral density (BMD), and histopathological analyses. RESULTS: The RPT/ALN-PLGA-PEG nanosystems exhibited a uniform size of 89 nm, excellent stability, and sustained drug-release characteristics. In vitro, the nanosystems demonstrated excellent antibacterial activity, low cytotoxicity, and the ability to suppress osteoclastogenesis while promoting osteoblast differentiation. In vivo imaging and tissue distribution studies have demonstrated that the RPT/ALN-PLGA-PEG nanosystem achieved a drug concentration in bone tissue at least 3-fold higher than that of the non-targeted nanosystem. In vivo, the bone-targeted nanosystem effectively alleviated inflammation, stabilized levels of bone resorption markers, and improved BMD, accompanied by elevated levels of osteogenic markers. Histological scores revealed complete bone regeneration in the RPT/ALN-PLGA-PEG group, whereas fibrous tissue formation was observed in the other groups. CONCLUSION: The RPT/ALN-PLGA-PEG nanosystems demonstrated remarkable bone-targeting capability, sustained and potent antibacterial efficacy, and mitigation of bone destruction, coupled with the promotion of bone repair. These findings provide an innovative approach for addressing osteoarticular TB.