Development of a macromolecular prodrug for the treatment of inflammatory arthritis: mechanisms involved in arthrotropism and sustained therapeutic efficacy.
Development of a macromolecular prodrug for the treatment of inflammatory arthritis: mechanisms involved in arthrotropism and sustained therapeutic efficacy.
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DOI：
10.1186/ar3130
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发表时间：
2010
影响因子：
4.9
通讯作者：
Wang D
中科院分区：
文献类型：
--
作者：
Quan LD;Purdue PE;Liu XM;Boska MD;Lele SM;Thiele GM;Mikuls TR;Dou H;Goldring SR;Wang D
本手稿的目的是测试的假设，即向关节定位和滑膜细胞内化的N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物-地塞米松共轭物（P-Dex，地塞米松的大分子前体药物）的独特能力，以诱导持续改善关节炎症和抑制组织损伤的炎性关节炎的动物模型。用P-Dex、游离地塞米松、生理盐水或HPMA均聚物治疗具有佐剂诱导的关节炎（AA）的大鼠。为了确定P-Dex的生物分布，将具有不同成像标记的缀合物给予AA大鼠并进行分析。通过荧光激活细胞分选（FACS）和免疫组化染色评价分离的关节组织。使用人单核细胞-巨噬细胞和成纤维细胞检查P-Dex的细胞摄取及其对细胞凋亡和促炎细胞因子产生的影响。单次全身施用P-Dex完全抑制AA>20天。磁共振成像表明，较高的HPMA共聚物流入发炎关节比正常关节。关节炎关节的免疫组织化学和FACS分析显示滑膜成纤维细胞和髓系细胞广泛摄取聚合物缀合物。在单核细胞-巨噬细胞培养物中证实了P-Dex抑制炎症的能力，其中P-Dex处理导致抑制脂多糖诱导的IL-6和TNFα释放。类似地，TNFα诱导的类风湿性关节炎患者滑膜成纤维细胞中基质金属蛋白酶（MMP 1和MMP 3）的表达被P-Dex抑制。P-Dex对单核细胞凋亡无明显影响。与等效剂量的游离地塞米松相比，P-Dex可提供上级和持续的AA改善。P-Dex的向关节性和局部保留归因于关节炎关节中血管通透性的增强和滑膜细胞对P-Dex的内化。巨噬细胞和成纤维细胞对P-Dex的摄取和加工，以及促炎介质的下调，为P-Dex在这种炎性关节炎模型中的持续抗炎功效提供了解释。
The purpose of the present manuscript is to test the hypothesis that arthrotropic localization and synovial cell internalization account for the unique capacity of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex, a macromolecular prodrug of dexamethasone) to induce sustained amelioration of joint inflammation and inhibition of tissue damage in an animal model of inflammatory arthritis. Rats with adjuvant-induced arthritis (AA) were treated with P-Dex, free dexamethasone, saline or HPMA homopolymer. To define the biodistribution of P-Dex, conjugates with different imaging labels were given to AA rats and analyzed. Isolated joint tissues were evaluated by fluorescence-activated cell sorting (FACS) and immunohistochemical staining. Cellular uptake of P-Dex and its effects on apoptosis and production of proinflammatory cytokines were examined using human monocyte-macrophages and fibroblasts. A single systemic administration of P-Dex completely suppressed AA for >20 days. Magnetic resonance imaging demonstrated higher HPMA copolymer influx into the inflamed joints than the normal joints. Immunohistochemistry and FACS analyses of arthritic joints revealed extensive uptake of the polymer conjugate by synovial fibroblasts and myeloid lineage cells. The capacity of P-Dex to suppress inflammation was confirmed in monocyte-macrophage cultures in which P-Dex treatment resulted in suppression of lipopolysaccharide-induced IL-6 and TNFα release. Similarly, TNFα-induced expression of matrix metalloproteinases (MMP1 and MMP3) in synovial fibroblasts from a rheumatoid arthritis patient was suppressed by P-Dex. P-Dex showed no detectable effect on monocyte apoptosis. P-Dex provides superior and sustained amelioration of AA compared with an equivalent dose of free dexamethasone. The arthrotropism and local retention of P-Dex is attributed to the enhanced vascular permeability in arthritic joints and the internalization of P-Dex by synovial cells. The uptake and processing of P-Dex by macrophages and fibroblasts, and downregulation of proinflammatory mediators, provides an explanation for the sustained anti-inflammatory efficacy of P-Dex in this model of inflammatory arthritis.
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影响因子：
4.9
作者：
Wang D;Miller SC;Liu XM;Anderson B;Wang XS;Goldring SR
通讯作者：
Goldring SR
影响因子：
16.1
作者：
Liu, Xin-Ming;Miller, Scott C.;Wang, Dong
通讯作者：
Wang, Dong
影响因子：
5.3
作者：
Rakshit, DS;Ly, K;Purdue, PE
通讯作者：
Purdue, PE
影响因子：
--
作者：
Avnir, Yuval;Ulmansky, Rina;Naparstek, Yaakov
通讯作者：
Naparstek, Yaakov
影响因子：
4.4
作者：
Wunder, A;Müller-Ladner, U;Fiehn, C
通讯作者：
Fiehn, C