Macromolecular prodrug of dexamethasone prevents particle-induced peri-implant osteolysis with reduced systemic side effects

Ke Ren, Anand Dusad, Fang Yuan, Hongjiang Yuan, P. Edward Purdue, Edward V. Fehringer, Kevin L. Garvin, Steven R. Goldring, Dong Wang

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalJournal of Controlled Release
Volume175
Issue number1
DOIs
StatePublished - Feb 10 2014

Keywords

  • Dexamethasone
  • ELVIS
  • HPMA copolymer
  • Implant loosening
  • Inflammation targeting
  • Prodrug

ASJC Scopus subject areas

  • Pharmaceutical Science

Fingerprint Dive into the research topics of 'Macromolecular prodrug of dexamethasone prevents particle-induced peri-implant osteolysis with reduced systemic side effects'. Together they form a unique fingerprint.

Cite this