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

16 Citations (Scopus)

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
StatePublished - Feb 28 2015

Fingerprint

Fracture Healing
Simvastatin
Prodrugs
Micelles
Bone Fractures
Anabolic Agents
Metabolic Bone Diseases
Optical Imaging
Bony Callus
Osteotomy
Skeleton
Hematoma
Solubility
Flow Cytometry
Therapeutics
Inflammation
Bone and Bones
Messenger RNA

Keywords

  • Bone fracture
  • ELVIS
  • Micelle
  • Prodrug
  • Simvastatin

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Simvastatin prodrug micelles target fracture and improve healing. / Jia, Zhenshan; Zhang, Yijia; Chen, Yen Hsun; Dusad, Anand; Yuan, Hongjiang; Ren, Ke; Li, Fei; Fehringer, Edward V.; Purdue, P. Edward; Goldring, Steven R.; Daluiski, Aaron; Wang, Dong.

In: Journal of Controlled Release, Vol. 200, 28.02.2015, p. 23-34.

Research output: Contribution to journalArticle

Jia, Z, Zhang, Y, Chen, YH, Dusad, A, Yuan, H, Ren, K, Li, F, Fehringer, EV, Purdue, PE, Goldring, SR, Daluiski, A & Wang, D 2015, 'Simvastatin prodrug micelles target fracture and improve healing', Journal of Controlled Release, vol. 200, pp. 23-34. https://doi.org/10.1016/j.jconrel.2014.12.028
Jia, Zhenshan ; Zhang, Yijia ; Chen, Yen Hsun ; Dusad, Anand ; Yuan, Hongjiang ; Ren, Ke ; Li, Fei ; Fehringer, Edward V. ; Purdue, P. Edward ; Goldring, Steven R. ; Daluiski, Aaron ; Wang, Dong. / Simvastatin prodrug micelles target fracture and improve healing. In: Journal of Controlled Release. 2015 ; Vol. 200. pp. 23-34.
@article{b279490516b94f38a2cffb5c4f6b59b0,
title = "Simvastatin prodrug micelles target fracture and improve healing",
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.",
keywords = "Bone fracture, ELVIS, Micelle, Prodrug, Simvastatin",
author = "Zhenshan Jia and Yijia Zhang and Chen, {Yen Hsun} and Anand Dusad and Hongjiang Yuan and Ke Ren and Fei Li and Fehringer, {Edward V.} and Purdue, {P. Edward} and Goldring, {Steven R.} and Aaron Daluiski and Dong Wang",
year = "2015",
month = "2",
day = "28",
doi = "10.1016/j.jconrel.2014.12.028",
language = "English (US)",
volume = "200",
pages = "23--34",
journal = "Journal of Controlled Release",
issn = "0168-3659",
publisher = "Elsevier",

}

TY - JOUR

T1 - Simvastatin prodrug micelles target fracture and improve healing

AU - Jia, Zhenshan

AU - Zhang, Yijia

AU - Chen, Yen Hsun

AU - Dusad, Anand

AU - Yuan, Hongjiang

AU - Ren, Ke

AU - Li, Fei

AU - Fehringer, Edward V.

AU - Purdue, P. Edward

AU - Goldring, Steven R.

AU - Daluiski, Aaron

AU - Wang, Dong

PY - 2015/2/28

Y1 - 2015/2/28

N2 - 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.

AB - 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.

KW - Bone fracture

KW - ELVIS

KW - Micelle

KW - Prodrug

KW - Simvastatin

UR - http://www.scopus.com/inward/record.url?scp=84920733555&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84920733555&partnerID=8YFLogxK

U2 - 10.1016/j.jconrel.2014.12.028

DO - 10.1016/j.jconrel.2014.12.028

M3 - Article

VL - 200

SP - 23

EP - 34

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

ER -