The Evaluation of the Therapeutic Efficacy and Side Effects of a Macromolecular Dexamethasone Prodrug in the Collagen-Induced Arthritis Mouse Model

Pharm Res. 2016 Jan;33(1):186-93. doi: 10.1007/s11095-015-1776-1. Epub 2015 Aug 19.

Abstract

Purpose: To investigate the efficacy and safety of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex) in the collagen-induced arthritis (CIA) mouse model.

Methods: HPMA copolymer labeled with a near infrared fluorescence (NIRF) dye was administered to mice with CIA to validate its passive targeting to inflamed joints and utility as a drug carrier system. The CIA mice were treated with P-Dex, dexamethasone (Dex) or saline and the therapeutic efficacy and skeletal toxicity evaluated using clinical scoring and micro-computed tomography (μ-CT).

Results: The NIRF signal of the HPMA copolymer localized to arthritic joints consistent with its passive targeting to sites of inflammation. While the CIA mice responded more rapidly to P-Dex compared to Dex, the final clinical score and endpoint μ-CT analyses of localized bone erosions indicated that both single dose P-Dex and dose equivalent daily Dex led to comparable clinical efficacy after 30 days. μ-CT analysis of the proximal tibial metaphyses showed that P-Dex treatment was associated with significantly higher BMD and BV/TV compared to Dex and the saline control, consistent with reduced glucocorticoid (GC) skeletal toxicity.

Conclusion: These results validate the therapeutic efficacy of P-Dex in the CIA mouse model. P-Dex treatment averted the adverse effects of GC's on systemic bone loss, supporting its utility in clinical development for the management of rheumatoid arthritis.

Keywords: ELVIS; HPMA copolymer; collagen-induced arthritis; glucocorticoid; prodrug.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / diagnostic imaging
  • Arthritis, Experimental / drug therapy*
  • Bone Density
  • Dexamethasone / administration & dosage
  • Dexamethasone / adverse effects
  • Dexamethasone / therapeutic use*
  • Disease Progression
  • Macromolecular Substances / administration & dosage
  • Macromolecular Substances / adverse effects
  • Macromolecular Substances / therapeutic use*
  • Methacrylates
  • Mice
  • Mice, Inbred DBA
  • Osteoporosis / drug therapy
  • Prodrugs / administration & dosage
  • Prodrugs / adverse effects
  • Prodrugs / therapeutic use*
  • Tibia / diagnostic imaging
  • Tomography, X-Ray Computed

Substances

  • Macromolecular Substances
  • Methacrylates
  • Prodrugs
  • Dexamethasone
  • hydroxypropyl methacrylate