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

Lingdong Quan, Yijia Zhang, Anand Dusad, Ke Ren, P. Edward Purdue, Steven R. Goldring, Dong Wang

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)186-193
Number of pages8
JournalPharmaceutical Research
Volume33
Issue number1
DOIs
StatePublished - Jan 1 2016

Fingerprint

Experimental Arthritis
Prodrugs
Dexamethasone
Collagen
Therapeutics
Copolymers
Toxicity
Bone
Joints
Fluorescence
Infrared radiation
Bone and Bones
Drug Carriers
Glucocorticoids
Arthritis
Tomography
Erosion
Rheumatoid Arthritis
Coloring Agents

Keywords

  • ELVIS
  • HPMA copolymer
  • collagen-induced arthritis
  • glucocorticoid
  • prodrug

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

Cite this

The Evaluation of the Therapeutic Efficacy and Side Effects of a Macromolecular Dexamethasone Prodrug in the Collagen-Induced Arthritis Mouse Model. / Quan, Lingdong; Zhang, Yijia; Dusad, Anand; Ren, Ke; Purdue, P. Edward; Goldring, Steven R.; Wang, Dong.

In: Pharmaceutical Research, Vol. 33, No. 1, 01.01.2016, p. 186-193.

Research output: Contribution to journalArticle

Quan, Lingdong ; Zhang, Yijia ; Dusad, Anand ; Ren, Ke ; Purdue, P. Edward ; Goldring, Steven R. ; Wang, Dong. / The Evaluation of the Therapeutic Efficacy and Side Effects of a Macromolecular Dexamethasone Prodrug in the Collagen-Induced Arthritis Mouse Model. In: Pharmaceutical Research. 2016 ; Vol. 33, No. 1. pp. 186-193.
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