Simvastatin prodrug micelles target fracture and improve healing

Zhenshan Jia, Yijia Zhang, Yen Hsun Chen, Anand Dusad, Hongjiang Yuan, Ke Ren, Fei Li, Edward V. Fehringer, P. Edward Purdue, Steven R. Goldring, Aaron Daluiski, Dong Wang

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Simvastatin (SIM), a widely used anti-lipidemic drug, has been identified as a bone anabolic agent. Its poor water solubility and the lack of distribution to the skeleton, however, have limited its application in the treatment of bone metabolic diseases. In this study, an amphiphilic macromolecular prodrug of SIM was designed and synthesized to overcome these limitations. The polyethylene glycol (PEG)-based prodrug can spontaneously self-assemble to form micelles. The use of SIM trimer as the prodrug's hydrophobic segment allows easy encapsulation of additional free SIM. The in vitro studies showed that SIM/SIM-mPEG micelles were internalized by MC3T3 cells via lysosomal trafficking and consistently induced expression of both BMP2 and DKK1 mRNA, suggesting that the prodrug micelle retains the biological functions of SIM. After systemic administration, optical imaging suggests that the micelles would passively target to bone fracture sites associated with hematoma and inflammation. Furthermore, flow cytometry study revealed that SIM/SIM-mPEG micelles had preferred cellular uptake by inflammatory and resident cells within the fracture callus tissue. The treatment study using a mouse osteotomy model validated the micelles' therapeutic efficacy in promoting bone fracture healing as demonstrated by micro-CT and histological analyses. Collectively, these data suggest that the macromolecular prodrug-based micelle formulation of SIM may have great potential for clinical management of impaired fracture healing.

Original languageEnglish (US)
Pages (from-to)23-34
Number of pages12
JournalJournal of Controlled Release
Volume200
DOIs
Publication statusPublished - Feb 28 2015

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Keywords

  • Bone fracture
  • ELVIS
  • Micelle
  • Prodrug
  • Simvastatin

ASJC Scopus subject areas

  • Pharmaceutical Science

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