Synthesis and Evaluation of a Well-defined HPMA Copolymer–Dexamethasone Conjugate for Effective Treatment of Rheumatoid Arthritis
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- Liu, XM., Quan, LD., Tian, J. et al. Pharm Res (2008) 25: 2910. doi:10.1007/s11095-008-9683-3
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).
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.
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.
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 WORDSdexamethasonedrug deliverymacromolecular therapyRAFT polymerizationrheumatoid arthritis
bone mineral density
disease-modifying anti-rheumatic drugs
- H & E
hematoxylin and eosin
N-methacryloylaminopropyl fluorescein thiourea
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)
number average molecular weight
weight average molecular weight
nonsteroidal anti-inflammatory drugs
copolymer of MA–Gly–Gly–NHN=Dex and HPMA
peripheral dual energy x-ray absorptiometry
size exclusion chromatography