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.
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Abbreviations
- ALP:
-
Alkaline phosphatase
- ALT:
-
Alanine aminotransferase
- AST:
-
Aspartate aminotransferase
- BMD:
-
Bone mineral density
- BS/TV:
-
Bone surface density
- BUN:
-
Blood urea nitrogen
- BV/TV:
-
Bone volume fraction
- CON:
-
Vehicle-treated control group
- Conn.D:
-
Connectivity density
- CPK:
-
Creatine phosphokinase
- DA:
-
Degree of anisotropy
- Ecc:
-
Mean eccentricity
- ELVIS:
-
Extravasation through leaky vasculature and inflammatory cell-mediated sequestration
- FD:
-
Fractal dimension
- FX:
-
Fracture
- H&E:
-
Hematoxylin and eosin
- IACUC:
-
Institutional animal care and use committee
- micro-CT:
-
Micro-computed tomography
- MMI:
-
Mean polar moment of inertia
- NIRF:
-
Near infrared fluorescence
- PEG:
-
Polyethylene glycol
- ROI:
-
Region of interest
- SIM:
-
Simvastatin
- SIM/SIM-mPEG:
-
A micellar macromolecular prodrug formulation of simvastatin based on polyethylene glycol
- SIMA:
-
Simvastatin acid
- SMI:
-
Structure model index
- Tb.N:
-
Trabecular number
- Tb.Pf:
-
Trabecular bone pattern factor
- Tb.Sp:
-
Trabecular separation
- Tb.Th:
-
Trabecular thickness
- TLC:
-
Thin layer chromatography
- TP:
-
Total protein
- VOI:
-
Volume of interest
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Acknowledgments & Disclosures
This study was supported in part by NIH (R01 AR062680) and Nebraska Arthritis Outcome Research Center (NAORC). We thank Mr. Arun Tatiparthi of Micro Photonics for his assistance with the micro-CT analysis. Y.Z. was supported by the Bukey Fellowship from University of Nebraska Medical Center.
Y.Z., Z.J., A.D., S.R.G. and D.W. are listed as co-inventors in a PCT patent application filed for the SIM/SIM-mPEG prodrug micelle technology.
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Yijia Zhang and Zhenshan Jia contributed equally to this work.
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Zhang, Y., Jia, Z., Yuan, H. et al. The Evaluation of Therapeutic Efficacy and Safety Profile of Simvastatin Prodrug Micelles in a Closed Fracture Mouse Model. Pharm Res 33, 1959–1971 (2016). https://doi.org/10.1007/s11095-016-1932-2
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DOI: https://doi.org/10.1007/s11095-016-1932-2