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

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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 (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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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)

M n :

number average molecular weight

M w :

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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Acknowledgment

This work was supported in part by NIH grants AR053325 (DW) and AA10435 (GMT), the College of Pharmacy, University of Nebraska Medical Center and the UNeMed Corporation.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Xin-Ming Liu, Ling-Dong Quan, Jun Tian, Yazen Alnouti & Dong Wang

  2. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Kai Fu

  3. Internal Medicine/Rheumatology Division, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Geoffrey M. Thiele

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  1. Xin-Ming Liu
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  2. Ling-Dong Quan
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Correspondence to Dong Wang.

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Xin-Ming Liu and Ling-Dong Quan have contributed equally to this work.

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Liu, XM., Quan, LD., Tian, J. et al. Synthesis and Evaluation of a Well-defined HPMA Copolymer–Dexamethasone Conjugate for Effective Treatment of Rheumatoid Arthritis. Pharm Res 25, 2910–2919 (2008). https://doi.org/10.1007/s11095-008-9683-3

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  • DOI: https://doi.org/10.1007/s11095-008-9683-3

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