Synthesis and evaluation of a well-defined HPMA copolymer-dexamethasone conjugate for effective treatment of rheumatoid arthritis.

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 (M (w)) 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.

• Authors: Xin-Ming Liu, Ling-Dong Quan, Jun Tian, Yazen Alnouti, Kai Fu, Geoffrey M Thiele, Dong Wang
• Journal: Pharmaceutical research (Pharm Res) Vol. 25 Issue 12 Pg. 2910-9 (Dec 2008) ISSN: 0724-8741 [Print] United States
• PMID: 18649124 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Methacrylates
• Dexamethasone
• hydroxypropyl methacrylate

Topics

• Animals
• Ankle Joint (pathology)
• Arthritis, Experimental (drug therapy, pathology)
• Arthritis, Rheumatoid (drug therapy, pathology)
• Bone Density (drug effects)
• Dexamethasone (administration & dosage, chemistry)
• Drug Delivery Systems
• Male
• Methacrylates (administration & dosage, chemistry)
• Rats
• Rats, Inbred Lew
• Solubility