The Evaluation of Therapeutic Efficacy and Safety Profile of Simvastatin Prodrug Micelles in a Closed Fracture Mouse Model

• Published in: Pharmaceutical research 2016-08, Vol.33 (8), p.1959-1971
• Main Authors: Zhang, Yijia, Jia, Zhenshan, Yuan, Hongjiang, Dusad, Anand, Ren, Ke, Wei, Xin, Fehringer, Edward V., Purdue, P. Edward, Daluiski, Aaron, Goldring, Steven R., Wang, Dong
• Format: Article
• Language: English
• Subjects: Animals; Antilipemic agents; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; CT imaging; Disease Models, Animal; Drug Evaluation, Preclinical; Drug therapy; Femoral Fractures - diagnostic imaging; Femoral Fractures - drug therapy; Fractures; Fractures, Closed - diagnostic imaging; Fractures, Closed - drug therapy; Health aspects; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects; Male; Medical Law; Mice; Micelles; Pharmacology/Toxicology; Pharmacy; Prevention; Prodrugs - administration & dosage; Prodrugs - adverse effects; Research Paper; Rodents; Simvastatin; Simvastatin - administration & dosage; Simvastatin - adverse effects; Treatment Outcome
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-016-1932-2

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.