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.
authors.affiliation: The Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors.forename: Zhenshan
authors.initials: Z
authors.lastname: Jia
authors.affiliation: The Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors.forename: Yijia
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Yen Hsun
authors.initials: YH
authors.lastname: Chen
authors.affiliation: The Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors.forename: Anand
authors.initials: A
authors.lastname: Dusad
authors.affiliation: The Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors.forename: Hongjiang
authors.initials: H
authors.lastname: Yuan
authors.affiliation: The Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Ren
authors.affiliation: The Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: the Department of Orthopaedic Surgery and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors.forename: Edward V
authors.initials: EV
authors.lastname: Fehringer
authors.affiliation: Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: P Edward
authors.initials: PE
authors.lastname: Purdue
authors.affiliation: Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Goldring
authors.affiliation: Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Daluiski
authors.affiliation: The Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D065546:Drug Liberation; D005264:Femoral Fractures / Q000188:drug therapy* / Q000473:pathology; D005269:Femur / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008823:Micelles; D010027:Osteotomy; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D019821:Simvastatin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008823:Micelles; D011355:Prodrugs; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D019821:Simvastatin
keywords: Bone fracture; ELVIS; Micelle; Prodrug; Simvastatin