Novel dexamethasone-HPMA copolymer conjugate and its potential application in treatment of rheumatoid arthritis.
Novel dexamethasone-HPMA copolymer conjugate and its potential application in treatment of rheumatoid arthritis.
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DOI：
10.1186/ar2106
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发表时间：
2007
影响因子：
4.9
通讯作者：
Goldring SR
中科院分区：
文献类型：
--
作者：
Wang D;Miller SC;Liu XM;Anderson B;Wang XS;Goldring SR
类风湿关节炎(RA)是一种病因不明的慢性自身免疫性疾病。由于缺乏选择性地针对受影响的关节组织的药物，这种疾病的有效治疗一直受到阻碍。我们开发了一种基于N-(2-羟丙基)甲基丙烯酰胺共聚物(P-Dex)的新型pH敏感型地塞米松(Dex)给药系统，并证明该给药系统在关节炎动物模型的炎症关节中特异积聚。我们假设给药系统的关节亲和性和局部酸中毒介导的药物释放在RA治疗中提供了更好的治疗效果和潜在的减少副作用。初步的体外释药研究证实，地塞米松的释放确实依赖于环境的pH。在pH为5，37℃时，该偶联物具有最高的药物释放水平。当在佐剂诱导的关节炎大鼠模型中全身给药时，与全身给药的游离地塞米松相比，P-Dex提供了更好和更持久的抗炎效果。此外，与游离地塞米松相比，P-地塞米松组的骨和软骨保存更好。我们的数据表明，结合物的差异性作用与其选择性积聚、潜在的巨噬细胞介导的滞留以及对pH敏感的药物(细胞外和细胞内)在关节炎关节中的释放有关。这种新开发的药物输送系统提供了一种独特的方法，可以选择性地将糖皮质激素靶向炎症的关节，这可能会潜在地减少全身副作用。
Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown etiology. Effective treatment of this disorder has been hampered by the lack of availability of agents that selectively target affected joint tissue. We developed a novel pH-sensitive drug delivery system of dexamethasone (Dex) based on an N-(2-hydroxypropyl)methacrylamide copolymer (P-Dex) and have shown that the delivery system specifically accumulates in inflamed joints in an animal model of arthritis. We hypothesize that the arthrotropism of the delivery system and the local acidosis-mediated drug release provide superior therapeutic efficacy and potentially reduced side effects in RA treatment. The initial in vitro drug-release study confirmed that the Dex release is indeed dependent upon the environmental pH. At pH 5, 37°C, the conjugate shows the highest level of drug release. When administered systemically in an adjuvant-induced arthritis rat model, P-Dex offers superior and longer-lasting anti-inflammatory effects compared with systemically administered free Dex. In addition, greater bone and cartilage preservation was observed with the P-Dex treatment compared with free Dex treatment. Our data indicate that the differential effect of the conjugate is related to its selective accumulation, potential macrophage-mediated retention, and pH-sensitive drug release (extracellular and intracellular) in arthritic joints. This newly developed drug delivery system provides a unique method for selective targeting of glucocorticoids to inflamed joints which may potentially reduce systemic side effects.
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DOI：
10.1002/macp.1977.021780803
发表时间：
1977-01-01
期刊：
MAKROMOLEKULARE CHEMIE-MACROMOLECULAR CHEMISTRY AND PHYSICS
影响因子：
--
作者：
REJMANOVA, P;LABSKY, J;KOPECEK, J
通讯作者：
KOPECEK, J
影响因子：
--
作者：
Metselaar, JM;Wauben, MHM;Storm, G
通讯作者：
Storm, G
影响因子：
5.5
作者：
Fiehn, C;Müller-Ladner, U;Wunder, A
通讯作者：
Wunder, A
影响因子：
--
作者：
GOETZL, EJ;RYNES, RI;STILLMAN, JS
通讯作者：
STILLMAN, JS
影响因子：
4.7
作者：
KANEKO, T;WILLNER, D;VYAS, DM
通讯作者：
VYAS, DM