Pharmaceutical Research

, Volume 25, Issue 12, pp 2910–2919 | Cite as

Synthesis and Evaluation of a Well-defined HPMA Copolymer–Dexamethasone Conjugate for Effective Treatment of Rheumatoid Arthritis

  • Xin-Ming Liu
  • Ling-Dong Quan
  • Jun Tian
  • Yazen Alnouti
  • Kai Fu
  • Geoffrey M. Thiele
  • Dong Wang
Research Paper

Abstract

Purpose

To develop a pH-sensitive dexamethasone (Dex)-containing N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugate with well-defined structure for the improved treatment of rheumatoid arthritis (RA).

Methods

A new pH-sensitive Dex-containing monomer (MA–Gly–Gly–NHN=Dex) was synthesized and copolymerized with HPMA using reversible addition–fragmentation transfer (RAFT) polymerization. The structure of the resulting HPMA copolymer–Dex conjugate (P-Dex) was analyzed and its therapeutic efficacy was evaluated on adjuvant-induced arthritis (AIA) rats.

Results

P-Dex was synthesized with controllable molecular weight and polydispersity index (PDI). The Dex content can be controlled by the feed-in ratio of MA–Gly–Gly–NHN=Dex. The P-Dex used for in vitro and in vivo evaluation has a average molecular weight (Mw) of 34 kDa and a PDI of 1.34. The in vitro drug-release studies showed that the Dex release from the conjugate was triggered by low pH. Clinical measurements, endpoint bone mineral density (BMD) test and histology grading from the in vivo evaluation all suggest that newly synthesized P-Dex has strong and long-lasting anti-inflammatory and joint protection effects.

Conclusions

A HPMA copolymer–dexamethasone conjugate with a well-defined structure has been synthesized and proved to be an effective anti-arthritis therapy. It may have a unique clinical application in the treatment of rheumatoid arthritis.

KEY WORDS

dexamethasone drug delivery macromolecular therapy RAFT polymerization rheumatoid arthritis 

Abbreviations

AI

articular index

AIA

adjuvant-induced arthritis

BMD

bone mineral density

DCC

N,N′-dicyclohexylcarbodiimide

DCU

dicyclohexylurea

Dex

dexamethasone

DMARDs

disease-modifying anti-rheumatic drugs

GCs

glucocorticoids

H & E

hematoxylin and eosin

HPMA

N-(2-hydroxypropyl)methacrylamide

LA

N,N-dioctadecyl-N′,N′-bis(2-hydroxyethyl)propanediamine

MA-FITC

N-methacryloylaminopropyl fluorescein thiourea

MA–Gly–Gly–OH

N-methacryloylglycylglycine

MA–Gly–Gly–NHN=Dex

pH-sensitive Dex-containing monomer or N-(2-(2-(2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-7,8,11,12,13,15,16,17-octahydro-6H-cyclopenta[a]phenanthren-3(9H,10H,14H)-ylidene)hydrazinyl)-2-oxoethylamino)-2-oxoethyl)methacrylamide as generated by ChemDraw Ultra 9.0 (CambridgeSoft, Cambridge, MA, USA)

Mn

number average molecular weight

Mw

weight average molecular weight

NSAIDs

nonsteroidal anti-inflammatory drugs

P-Dex

copolymer of MA–Gly–Gly–NHN=Dex and HPMA

pDEXA

peripheral dual energy x-ray absorptiometry

PDI

polydispersity index

SEC

size exclusion chromatography

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Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Xin-Ming Liu
    • 1
  • Ling-Dong Quan
    • 1
  • Jun Tian
    • 1
  • Yazen Alnouti
    • 1
  • Kai Fu
    • 2
  • Geoffrey M. Thiele
    • 3
  • Dong Wang
    • 1
  1. 1.Department of Pharmaceutical SciencesUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Department of Pathology and MicrobiologyUniversity of Nebraska Medical CenterOmahaUSA
  3. 3.Internal Medicine/Rheumatology DivisionUniversity of Nebraska Medical CenterOmahaUSA

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