title: Macromolecular prodrug of dexamethasone prevents particle-induced peri-implant osteolysis with reduced systemic side effects.
abstract: Aseptic implant loosening related to implant wear particle-induced inflammation is the most common cause of failure after joint replacement. Modulation of the inflammatory reaction to the wear products represents a rational approach for preventing aseptic implant failure. Long-term treatment using anti-inflammatory agents, however, can be associated with significant systemic side effects due to the drugs' lack of tissue specificity. To address this issue, N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex) was developed and evaluated for prevention of wear particle-induced osteolysis and the loss of fixation in a murine prosthesis failure model. Daily administration of free dexamethasone (Dex) was able to prevent wear particle-induced osteolysis, as assessed by micro-CT and histological analysis. Remarkably, monthly P-Dex administration (dose equivalent to free Dex treatment) was equally effective as free dexamethasone, but was not associated with systemic bone loss (a major adverse side effect of glucocorticoids). The reduced systemic toxicity of P-Dex is related to preferential targeting of the sites of wear particle-induced inflammation and its subcellular sequestration and retention by local inflammatory cell populations, resulting in sustained therapeutic action. These results demonstrate the feasibility of utilizing a macromolecular prodrug with reduced systemic toxicity to prevent wear particle-induced osteolysis.
authors: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha 68198, USA.
authors: Ke
authors: K
authors: Ren
authors: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha 68198, USA.
authors: Anand
authors: A
authors: Dusad
authors: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha 68198, USA.
authors: Fang
authors: F
authors: Yuan
authors: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha 68198, USA.
authors: Hongjiang
authors: H
authors: Yuan
authors: Hospital for Special Surgery, New York 10021, USA.
authors: P Edward
authors: PE
authors: Purdue
authors: Department of Orthopaedics Surgery and Rehabilitation, University of Nebraska Medical Center, Omaha 68198, USA.
authors: Edward V
authors: EV
authors: Fehringer
authors: Department of Orthopaedics Surgery and Rehabilitation, University of Nebraska Medical Center, Omaha 68198, USA.
authors: Kevin L
authors: KL
authors: Garvin
authors: Hospital for Special Surgery, New York 10021, USA.
authors: Steven R
authors: SR
authors: Goldring
authors: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha 68198, USA. Electronic address: dwang@unmc.edu.
authors: Dong
authors: D
authors: Wang
mesh_terms: D000178:Acrylamides / Q000737:chemistry; D000818:Animals; D003692:Delayed-Action Preparations / Q000737:chemistry; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D010014:Osteolysis / Q000209:etiology / Q000517:prevention & control*; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D011475:Prosthesis Failure / Q000009:adverse effects
chemical_list: D000178:Acrylamides; D003692:Delayed-Action Preparations; D011355:Prodrugs; D003907:Dexamethasone; C045985:methacrylamide
keywords: Dexamethasone; ELVIS; HPMA copolymer; Implant loosening; Inflammation targeting; Prodrug