@article{7be0d6219d12442fa1419a1fc421cc1e,
title = "Structural optimization of HPMA copolymer-based dexamethasone prodrug for improved treatment of inflammatory arthritis",
abstract = "Despite their notorious adverse effects, glucocorticoids (GC, potent anti-inflammatory drugs) are used extensively in clinical management of rheumatoid arthritis (RA) and other chronic inflammatory diseases. To achieve a sustained therapeutic efficacy and reduced toxicities, macromolecular GC prodrugs have been developed with promising outcomes for the treatment of RA. Fine-tuning the activation kinetics of these prodrugs may further improve their therapeutic efficacy and minimize the off-target adverse effects. To assess the feasibility of this strategy, five different dexamethasone (Dex, a potent GC)-containing monomers with distinctively different linker chemistries were designed, synthesized, and copolymerized with N-(2-hydroxypropyl) methacrylamide (HPMA) to obtain 5 macromolecular Dex prodrugs. Their Dex releasing rates were analyzed in vitro and shown to display a wide spectrum of activation kinetics. Their therapeutic efficacy and preliminary toxicology profiles were assessed and compared in vivo in an adjuvant-induced arthritis (AA) rat model in order to identify the ideal prodrug design for the most effective and safe treatment of inflammatory arthritis. The in vivo data demonstrated that the C3 hydrazone linker-containing prodrug design was the most effective in preserving joint structural integrity. The results from this study suggest that the design and screening of different activation mechanisms may help to identify macromolecular prodrugs with the most potent therapeutic efficacy and safety for the management of inflammatory arthritis.",
keywords = "Controlled release, Dexamethasone, HPMA copolymer, Inflammation, Prodrug, Rheumatoid arthritis",
author = "Zhenshan Jia and Gang Zhao and Xin Wei and Dexuan Kong and Yuanyuan Sun and You Zhou and Lele, {Subodh M.} and Fehringer, {Edward V.} and Garvin, {Kevin L.} and Goldring, {Steven R.} and Dong Wang",
note = "Funding Information: This study was supported in part by grants from National Institute of Health (R01 AR062680, R01 AI119090), China Scholarship Council (XW, GZ, DK, YZ), and UNMC College of Pharmacy. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ZSJ and GZ contributed equally to this work. DW and ZSJ conceived the design of different Dex containing monomers. ZSJ synthesized monomers and XW performed the polymerization. XW and GZ conducted the in vivo animal experiments. XW design and performed the in vitro release experiment with the assistance of DXK. GZ conducted the micro-CT analysis. YYS and YZ assisted the animal euthanasia and tissue processing for SML to perform the pathological analysis. EVF, KLG, SRG contributed to the experiment planning, data interpretation and manuscript preparation. XW and ZSJ drafted the manuscript with support from GZ. DW developed the overall experiment plan together with XW and finalize the manuscript. All authors discussed the results and contributed to the manuscript preparation. Funding Information: This study was supported in part by grants from National Institute of Health ( R01 AR062680 , R01 AI119090 ), China Scholarship Council (XW, GZ, DK, YZ), and UNMC College of Pharmacy. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2020",
year = "2020",
month = aug,
day = "10",
doi = "10.1016/j.jconrel.2020.05.028",
language = "English (US)",
volume = "324",
pages = "560--573",
journal = "Journal of Controlled Release",
issn = "0168-3659",
publisher = "Elsevier",
}