72 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2910-2919
Number of pages10
JournalPharmaceutical Research
Volume25
Issue number12
DOIs
StatePublished - Dec 1 2008

Fingerprint

Dexamethasone
Rheumatoid Arthritis
Copolymers
Therapeutics
Polydispersity
N-(2-hydroxypropyl)methacrylamide
Molecular Weight
Molecular weight
Histology
Experimental Arthritis
Polymerization
Bone Density
Arthritis
Minerals
Rats
Bone
Anti-Inflammatory Agents
Joints
Monomers

Keywords

  • Dexamethasone
  • Drug delivery
  • Macromolecular therapy
  • RAFT polymerization
  • Rheumatoid arthritis

ASJC Scopus subject areas

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

Cite this

Synthesis and evaluation of a well-defined HPMA copolymer-dexamethasone conjugate for effective treatment of rheumatoid arthritis. / Liu, Xin Ming; Quan, Ling Dong; Tian, Jun; Alnouti, Yazen; Fu, Kai; Thiele, Geoffrey Milton; Wang, Dong.

In: Pharmaceutical Research, Vol. 25, No. 12, 01.12.2008, p. 2910-2919.

Research output: Contribution to journalArticle

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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.",
keywords = "Dexamethasone, Drug delivery, Macromolecular therapy, RAFT polymerization, Rheumatoid arthritis",
author = "Liu, {Xin Ming} and Quan, {Ling Dong} and Jun Tian and Yazen Alnouti and Kai Fu and Thiele, {Geoffrey Milton} and Dong Wang",
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T1 - Synthesis and evaluation of a well-defined HPMA copolymer-dexamethasone conjugate for effective treatment of rheumatoid arthritis

AU - Liu, Xin Ming

AU - Quan, Ling Dong

AU - Tian, Jun

AU - Alnouti, Yazen

AU - Fu, Kai

AU - Thiele, Geoffrey Milton

AU - Wang, Dong

PY - 2008/12/1

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N2 - 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.

AB - 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.

KW - Dexamethasone

KW - Drug delivery

KW - Macromolecular therapy

KW - RAFT polymerization

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