OSTEOMYELİT GÖRÜNTÜLEME VE TEDAVİSİNDE KULLANILMAK ÜZERE RADYOİŞARETLİ FUSİDİK ASİT VE LEVOFLOKSASİN İÇEREN LİPOZOM FORMÜLASYONLARININ GELİŞTİRİLMESİ VE ETKİNLİĞİNİN İZLENMESİ

Abstract

ABSTRACT Taş A., Development and Evaluation of Radiolabeled Liposomal Formulations Containing Fusidic Acid and Levofloxacin for Imaging and Treatment of Osteomyelitis, Hacettepe University, Graduate School of Health Sciences, Radiopharmacy Doctoral Programme, Doctoral Thesis, Ankara, 2026. Osteomyelitis is a disease characterized by inflammation and swelling of bone tissue. Compared to other infection models, significant challenges are encountered in the diagnosis and effective treatment of osteomyelitis. Laboratory tests, microbiological analyses, and radiological imaging techniques are used in the diagnosis. The administration of antibiotics using drug delivery systems enables therapeutic efficacy at very low concentrations while significantly reducing side effects and allowing the combined delivery of two different drugs. Liposomal systems, one of the most widely used delivery platforms, offer advantages such as enhanced bioavailability of drugs, the ability to specifically target tissues, and being biocompatible and non-toxic. Within the scope of this study, PEGylated, nanosized theranostic liposomes actively targeted to bone via DPPE-Asp conjugation and radiolabeled with Gallium-68 (⁶⁸Ga) through DOTA-Bn-DSPE synthesis were formulated for the diagnosis and treatment of osteomyelitis. These liposomes co-encapsulated fusidic acid and levofloxacin as a combined drug therapy, and their characterization, in vitro stability, in vitro antimicrobial activity, and in vivo efficacy were evaluated. Asp-Lipo/LEV/FA liposomes were developed in the nanoscale range (220.31 ± 2.40 nm) and showed encapsulation efficiencies (8.62 ± 1.27% for levofloxacin and 31.20 ± 2.04% for fusidic acid). The highest ⁶⁸Ga radiolabeling efficiency for Asp-Lipo/LEV/FA was obtained at 60 °C, pH 4.5, within 5 minutes. All liposomal formulations remained stable at 4 °C for 30 days. Asp-Lipo/LEV/FA demonstrated significantly lower minimum inhibitory concentration (MIC) values against both E. coli and S. aureus strains compared to Lipo/LEV/FA and single-drug-loaded liposomes. 68Ga-labeled Asp-Lipo/LEV/FA showed greater uptake than 68Ga-labeled Lipo/LEV/FA formulations and was more effective in terms of treatment efficacy than the LEV/FA solution due to MicroPET/CT imaging and biodistribution studies. In conclusion, both 68Ga-labeled Asp Lipo/LEV/FA and 68Ga-labeled Lipo/LEV/FA have potential for use in the imaging and treatment of osteomyelitis. Keywords: Osteomyelitis, Bone targeting, Fusidic acid, Levofloxacin, 68Ga Radiolabeling, Theranostic liposomal systems. Supported by: H.U.BAP Project No: 19200 and H.U.BAP Project No: 21978.