Yijia Zhang1, Zhenshan Jia1, Hongjiang Yuan1, Anand Dusad1, Ke Ren1, Xin Wei1, Edward V Fehringer2, P Edward Purdue3, Aaron Daluiski3, Steven R Goldring3, Dong Wang4,5. 1. The Departments of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, Nebraska, 68198-6025, USA. 2. The Departments of Orthopaedic Surgery and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA. 3. Hospital for Special Surgery, New York, New York, 10021, USA. 4. The Departments of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, Nebraska, 68198-6025, USA. dwang@unmc.edu. 5. The Departments of Orthopaedic Surgery and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA. dwang@unmc.edu.
Abstract
PURPOSE: To evaluate the therapeutic efficiency of a micellar prodrug formulation of simvastatin (SIM/SIM-mPEG) and explore its safety in a closed femoral fracture mouse model. METHODS: The amphiphilic macromolecular prodrug of simvastatin (SIM-mPEG) was synthesized and formulated together with free simvastatin into micelles. It was also labeled with a near infrared dye for in vivo imaging purpose. A closed femoral fracture mouse model was established using a three-points bending device. The mice with established closed femoral fractures were treated with SIM/SIM-mPEG micelles, using free simvastatin and saline as controls. The therapeutic efficacy of the micelles was evaluated using a high-resolution micro-CT. Serum biochemistry and histology analyses were performed to explore the potential toxicity of the micelle formulation. RESULTS: Near Infrared Fluorescence (NIRF) imaging confirmed the passive targeting of SIM/SIM-mPEG micelles to the bone lesion of the mice with closed femoral fractures. The micelle was found to promote fracture healing with an excellent safety profile. In addition, the accelerated healing of the femoral fracture also helped to prevent disuse-associated ipsilateral tibia bone loss. CONCLUSION: SIM/SIM-mPEG micelles were found to be an effective and safe treatment for closed femoral fracture repair in mice. The evidence obtained in this study suggests that it may have the potential to be translated into a novel therapy for clinical management of skeletal fractures and non-union.
PURPOSE: To evaluate the therapeutic efficiency of a micellar prodrug formulation of simvastatin (SIM/SIM-mPEG) and explore its safety in a closed femoral fracturemouse model. METHODS:The amphiphilic macromolecular prodrug of simvastatin (SIM-mPEG) was synthesized and formulated together with free simvastatin into micelles. It was also labeled with a near infrared dye for in vivo imaging purpose. A closed femoral fracturemouse model was established using a three-points bending device. The mice with established closed femoral fractures were treated withSIM/SIM-mPEGmicelles, using free simvastatin and saline as controls. The therapeutic efficacy of the micelles was evaluated using a high-resolution micro-CT. Serum biochemistry and histology analyses were performed to explore the potential toxicity of the micelle formulation. RESULTS: Near Infrared Fluorescence (NIRF) imaging confirmed the passive targeting of SIM/SIM-mPEGmicelles to the bone lesion of the mice with closed femoral fractures. The micelle was found to promote fracture healing with an excellent safety profile. In addition, the accelerated healing of the femoral fracture also helped to prevent disuse-associated ipsilateral tibia bone loss. CONCLUSION:SIM/SIM-mPEGmicelles were found to be an effective and safe treatment for closed femoral fracture repair in mice. The evidence obtained in this study suggests that it may have the potential to be translated into a novel therapy for clinical management of skeletal fractures and non-union.
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