title: The Evaluation of Therapeutic Efficacy and Safety Profile of Simvastatin Prodrug Micelles in a Closed Fracture Mouse Model.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: The Departments of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, Nebraska, 68198-6025, USA.
authors.forename: Yijia
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Departments of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, Nebraska, 68198-6025, USA.
authors.forename: Zhenshan
authors.initials: Z
authors.lastname: Jia
authors.affiliation: The Departments of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, Nebraska, 68198-6025, USA.
authors.forename: Hongjiang
authors.initials: H
authors.lastname: Yuan
authors.affiliation: The Departments of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, Nebraska, 68198-6025, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Dusad
authors.affiliation: The Departments of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, Nebraska, 68198-6025, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Ren
authors.affiliation: The Departments of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, Nebraska, 68198-6025, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Wei
authors.affiliation: The Departments of Orthopaedic Surgery and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA.
authors.forename: Edward V
authors.initials: EV
authors.lastname: Fehringer
authors.affiliation: Hospital for Special Surgery, New York, New York, 10021, USA.
authors.forename: P Edward
authors.initials: PE
authors.lastname: Purdue
authors.affiliation: Hospital for Special Surgery, New York, New York, 10021, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Daluiski
authors.affiliation: Hospital for Special Surgery, New York, New York, 10021, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldring
authors.affiliation: The Departments of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, Nebraska, 68198-6025, USA. dwang@unmc.edu.|The Departments of Orthopaedic Surgery and Rehabilitation, University of Nebraska Medical Center, Omaha, Nebraska, 68198, USA. dwang@unmc.edu.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy*; D005596:Fractures, Closed / Q000000981:diagnostic imaging / Q000188:drug therapy*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D051379:Mice; D008823:Micelles; D011355:Prodrugs / Q000008:administration & dosage* / Q000009:adverse effects; D019821:Simvastatin / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008823:Micelles; D011355:Prodrugs; D019821:Simvastatin
keywords: ELVIS; fracture; micelle; prodrug; simvastatin