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. 2008 Dec;25(12):2910-9.
doi: 10.1007/s11095-008-9683-3. Epub 2008 Jul 23.

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

Xin-Ming Liu  1 , Ling-Dong Quan, Jun Tian, Yazen Alnouti, Kai Fu, Geoffrey M Thiele, Dong Wang
Affiliations

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

Xin-Ming Liu et al. Pharm Res. 2008 Dec.

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.

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Figures

Figure 1
Figure 1
In vitro Dex release from P-Dex at pH = 5.0 and 7.4. Each sample was measured 3 times. The mean values and standard deviation were calculated with Microsoft Excel. For the linear regression, R2 > 0.99.
Figure 2
Figure 2
The change of right ankle joint diameter of the four animal groups (P-Dex, Dex, saline and healthy) during the entire experiment.
Figure 3
Figure 3
The change of articular index (AI) score of the four animal groups (P-Dex, Dex, saline and healthy) during the entire experiment.
Figure 4
Figure 4
The endpoint bone mineral density (BMD) and representative pDEXA images of the right ankle joints of the four animal groups (P-Dex, Dex, saline and healthy). One-way ANOVA analysis, P < 0.01.
Figure 5
Figure 5
Histological evaluation of the ankle joints from the four animal groups (P-Dex, Dex, saline and healthy). One-way ANOVA analysis, P < 0.0001.
Figure 6
Figure 6
Representative histology pictures of the ankle joints from the four animal groups. A. P-Dex; B. Healthy; C. Free Dex; D. Saline. Synovial cell lining and villous hyperplasia (**), bone destruction (single arrow) and cartilage damage (double arrow) are clearly evident in free Dex and saline groups. Tib = Tibia, Ast = astrogalus. Bar = 0.5 mm.
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Scheme 1
Synthesis of MA-Gly-Gly-NHN=Dex.
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Scheme 2
Synthesis of HPMA copolymer-Dex conjugate (P-Dex) via RAFT copolymerization.
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Scheme 3
The structures syn (bottom)/anti (top) diastereomers of MA-Gly-Gly-NHN=Dex.
See this image and copyright information in PMC

References

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