Cartilage-targeting dexamethasone prodrugs increase the efficacy of dexamethasone
Cartilage-targeting dexamethasone prodrugs increase the efficacy of dexamethasone
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DOI：
10.1016/j.jconrel.2018.12.025
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发表时间：
2019-02-01
影响因子：
10.8
通讯作者：
Zenobi-Wong, Marcy
中科院分区：
文献类型：
--
作者：
Formica, Florian A.;Barreto, Goncalo;Zenobi-Wong, Marcy
糖皮质激素（如地塞米松）的关节内给药是骨关节炎炎症和疼痛的常见治疗方法。尽管其具有强效抗炎特性，但多种屏障阻碍了药物在关节间隙中的有效性。特别地，滑液的高周转率和致密的软骨细胞外基质（ECM）导致药物渗透到软骨中的差。为了增加渗透和保留时间，开发了两种地塞米松前药。首先，地塞米松与聚阳离子壳聚糖缀合，由于其与软骨ECM的高负固定电荷的强静电相互作用，导致药物深入和持续地渗透到全层软骨中。其次，地塞米松与II型胶原蛋白结合肽WYRGRL结合，并且该前药显示通过与软骨特异性II型胶原蛋白束的特异性相互作用保留在软骨的深层。在这两种情况下，活性地塞米松通过酯键水解从载体中释放。与游离药物相比，地塞米松与壳聚糖或II型胶原蛋白亲和载体的复合物增加了其在软骨内的结合和治疗功效。在离体模型中，两种地塞米松缀合物均显著降低炎症标志物的水平并减缓糖胺聚糖的损失。单剂量的软骨靶向地塞米松前药代表了一种有希望的替代重复糖皮质激素注射，需要补偿其从关节腔中的快速清除。
Intra-articular administration of glucocorticoids such as dexamethasone is a common treatment for osteoarthritic inflammation and pain. Despite its potent anti-inflammatory properties, multiple barriers hinder the drug's effectiveness in the articular space. In particular, the high turnover rate of the synovial fluid and the dense cartilage extracellular matrix (ECM) lead to poor drug penetration into cartilage. In order to increase the infiltration and retention time, two dexamethasone prodrugs were developed. Firstly, dexamethasone was conjugated to polycationic chitosan, which led to deep and sustained infiltration of the drug into full thickness cartilage, due to its strong electrostatic interactions with the high negative fixed charges of the cartilage ECM. Secondly, dexamethasone was conjugated to a collagen type II-binding peptide, WYRGRL, and this prodrug was shown to be retained in the deep zones of cartilage through specific interactions with cartilage-specific collagen type II bundles. In both cases, active dexamethasone was released from the carrier by ester linkage hydrolysis. Complexing dexamethasone with either chitosan or collagen type II-affinity carriers increased its binding and therapeutic efficacy inside cartilage, compared to the free drug. Both dexamethasone conjugates significantly reduced levels of inflammatory markers and slowed the loss of glycosaminoglycans in an ex vivo model. A single dose of a cartilage-targeting dexamethasone prodrug represents a promising alternative to the repetitive glucocorticoid injections needed to compensate for its rapid clearance from the joint cavity.