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MTX-cIBR Conjugate for Targeting Methotrexate to Leukocytes: Conjugate Stability and in vivo Efficacy in Suppressing Rheumatoid Arthritis
dc.contributor.author | Majumdar, Sumit | |
dc.contributor.author | Anderson, Meagan E. | |
dc.contributor.author | Xu, Christine R. | |
dc.contributor.author | Yakovleva, Tatyana | |
dc.contributor.author | Gu, Leo C. | |
dc.contributor.author | Malefyt, Thomas R. | |
dc.contributor.author | Siahaan, Teruna J. | |
dc.date.accessioned | 2017-04-25T19:43:57Z | |
dc.date.available | 2017-04-25T19:43:57Z | |
dc.date.issued | 2012-09 | |
dc.identifier.citation | Majumdar, S., Anderson, M. E., Xu, C. R., Yakovleva, T. V., Gu, L. C., Malefyt, T. R., & Siahaan, T. J. (2012). MTX-cIBR Conjugate for Targeting Methotrexate to Leukocytes: Conjugate Stability and in vivo Efficacy in Suppressing Rheumatoid Arthritis. Journal of Pharmaceutical Sciences, 101(9), 3275–3291. http://doi.org/10.1002/jps.23164 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/23775 | |
dc.description.abstract | Methotrexate (MTX) has been used to treat rheumatoid arthritis at low doses and leukemia at high doses; however, this drug can produce severe side effects. Our hypothesis is that MTX side effects can be attenuated by directing the drug to the target cells (i.e., leukocytes) using cIBR peptide. To test this hypothesis, MTX was conjugated to the N-terminus of cIBR peptide to give MTX-cIBR conjugate. MTX-cIBR (5.0 mg/kg) suppressed joint arthritis in adjuvant arthritis rats and prevented periarticular inflammation and bone resorption of the limb joints. In vitro, the toxicity of MTX-cIBR peptide against Molt-3 T cells was inhibited by anti-LFA-1 antibody and cIBR peptide in a concentration-dependent manner, suggesting that the uptake of MTX-cIBR was partially mediated by LFA-1. Chemical stability studies indicated that MTX-cIBR was most stable at pH 6.0. The MTX portion of MTX-cIBR was unstable under acidic conditions whereas the cIBR portion was unstable under basic conditions. In biological media, MTX-cIBR had short half-lives in rat plasma (44 min) and homogenized rat heart tissue (38 min). This low plasma stability may contribute to the low in vivo efficacy of MTX-cIBR; therefore, there is a need to design a more stable conjugate to improve the in vivo efficacy. | en_US |
dc.publisher | Elsevier | en_US |
dc.rights | This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 4.0 (CC BY-NC-ND 4.0), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | en_US |
dc.subject | Targeted delivery | en_US |
dc.subject | ICAM-1 | en_US |
dc.subject | cIBR | en_US |
dc.subject | MTX-cIBR | en_US |
dc.subject | LFA-1 | en_US |
dc.subject | Methotrexate | en_US |
dc.subject | In vitro | en_US |
dc.subject | In vivo | en_US |
dc.subject | Chemical stability | en_US |
dc.subject | Enzymatic stability | en_US |
dc.subject | Arthritis | en_US |
dc.title | MTX-cIBR Conjugate for Targeting Methotrexate to Leukocytes: Conjugate Stability and in vivo Efficacy in Suppressing Rheumatoid Arthritis | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Majumdar, Sumit | |
kusw.kuauthor | Anderson, Meagan E. | |
kusw.kuauthor | Xu, Christine R. | |
kusw.kuauthor | Yakovleva, Tatyana V. | |
kusw.kuauthor | Gu, Leo C. | |
kusw.kuauthor | Malefyt, Thomas R. | |
kusw.kuauthor | Siahaan, Teruna J. | |
kusw.kudepartment | Pharmaceutical Chemistry | en_US |
dc.identifier.doi | 10.1002/jps.23164 | en_US |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC4474090 | en_US |
dc.rights.accessrights | openAccess |
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Except where otherwise noted, this item's license is described as: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 4.0 (CC BY-NC-ND 4.0), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.