The Evaluation of the Therapeutic Efficacy and Side Effects of a Macromolecular Dexamethasone Prodrug in the Collagen-Induced Arthritis Mouse Model.
The Evaluation of the Therapeutic Efficacy and Side Effects of a Macromolecular Dexamethasone Prodrug in the Collagen-Induced Arthritis Mouse Model.
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DOI：
10.1007/s11095-015-1776-1
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发表时间：
2016-01
影响因子：
3.7
通讯作者：
Wang D
中科院分区：
文献类型：
--
作者：
Quan L;Zhang Y;Dusad A;Ren K;Purdue PE;Goldring SR;Wang D
目的：观察N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚物-地塞米松偶联物(P-Dex)对胶原性关节炎(CIA)小鼠模型的疗效和安全性。将标记有近红外荧光(NIRF)染料的HPMA共聚物应用于CIA小鼠，以验证其对炎症关节的被动靶向及其作为药物载体系统的有效性。分别用P-地塞米松(P-Dex)、地塞米松(Dex)或生理盐水对CIA小鼠进行治疗，并通过临床评分和微型计算机断层扫描(µ-CT)对其疗效和骨骼毒性进行评价。HPMA共聚物的NIRF信号定位于关节炎关节，与其被动靶向炎症部位一致。虽然CIA小鼠对P-Dex的反应比Dex快，但对局部骨质侵蚀的最终临床评分和终点µ-CT分析表明，单剂P-Dex和每日剂量当量的Dex在30天后具有类似的临床疗效。对胫骨近端干骺端的微CT分析显示，与地塞米松和生理盐水对照组相比，P-地塞米松治疗组的BMD和BV/TV显著增加，与糖皮质激素(GC)的骨骼毒性降低一致。这些结果验证了P-Dex在CIA小鼠模型中的治疗效果。P-Dex治疗避免了GC对全身骨丢失的不利影响，支持了其在治疗类风湿性关节炎的临床开发中的应用。
To investigate the efficacy and safety of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex) in the collagen-induced arthritis (CIA) mouse model. HPMA copolymer labeled with a near infrared fluorescence (NIRF) dye was administered to mice with CIA to validate its passive targeting to inflamed joints and utility as a drug carrier system. The CIA mice were treated with P-Dex, dexamethasone (Dex) or saline and the therapeutic efficacy and skeletal toxicity evaluated using clinical scoring and micro-computed tomography (µ-CT). The NIRF signal of the HPMA copolymer localized to arthritic joints consistent with its passive targeting to sites of inflammation. While the CIA mice responded more rapidly to P-Dex compared to Dex, the final clinical score and endpoint µ-CT analyses of localized bone erosions indicated that both single dose P-Dex and dose equivalent daily Dex led to comparable clinical efficacy after 30 days. µ-CT analysis of the proximal tibial metaphyses showed that P-Dex treatment was associated with significantly higher BMD and BV/TV compared to Dex and the saline control, consistent with reduced glucocorticoid (GC) skeletal toxicity. These results validate the therapeutic efficacy of P-Dex in the CIA mouse model. P-Dex treatment averted the adverse effects of GC’s on systemic bone loss, supporting its utility in clinical development for the management of rheumatoid arthritis.