Sustained intra-cartilage delivery of low dose dexamethasone using a cationic carrier for treatment of post traumatic osteoarthritis.
Sustained intra-cartilage delivery of low dose dexamethasone using a cationic carrier for treatment of post traumatic osteoarthritis.
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DOI：
10.22203/ecm.v034a21
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发表时间：
2017-12-05
影响因子：
3.1
通讯作者：
Porter RM
中科院分区：
文献类型：
--
作者：
Bajpayee AG;De la Vega RE;Scheu M;Varady NH;Yannatos IA;Brown LA;Krishnan Y;Fitzsimons TJ;Bhattacharya P;Frank EH;Grodzinsky AJ;Porter RM
缓解疾病的骨关节炎药物 (DMOAD) 应以最佳剂量到达其组织内目标部位，以实现临床疗效。致密、带负电的软骨基质对潜在治疗药物的运输构成了主要障碍。在这项工作中，利用静电相互作用来克服这一挑战，并使地塞米松 (Dex) 在兔软骨内具有更高的吸收、全层渗透和增强的保留。这是通过使用带正电荷的糖蛋白亲和素作为纳米载体，通过可释放的接头与 Dex 缀合来实现的。在前交叉韧带横断 (ACLT) 后 3 周，对兔子进行单次关节内注射低剂量亲和素-Dex (0.5 mg Dex) 的治疗效果进行评估。免疫染色证实抗生物素蛋白渗透到整个软骨厚度并保留至少 3 周。 Avidin-Dex 比游离 Dex 更能抑制损伤引起的关节肿胀和分解代谢基因表达。它还显着改善了关节周围滑膜内细胞浸润和形态发生的组织学评分。微型计算机断层扫描证实，avidin-Dex 治疗后骨赘的发生率和体积有所减少。然而，两种治疗方法均无法恢复 ACLT 后软骨硬度的丧失，这表明需要采用促合成代谢因子的联合治疗来增强基质生物合成。使用的抗生物素蛋白剂量导致显着的糖胺聚糖（GAG）损失，表明在未来的制剂中使用更高的Dex：抗生物素蛋白比率，使得递送的抗生物素蛋白剂量可能远小于显示影响GAG的剂量。这种基于电荷的输送系统将软骨转化为药物库，也可用于输送到附近的滑膜、半月板和韧带，从而实现各种 DMOAD 的临床转化。
Disease-modifying osteoarthritis drugs (DMOADs) should reach their intra-tissue target sites at optimal doses for clinical efficacy. The dense, negatively charged matrix of cartilage poses a major hindrance to the transport of potential therapeutics. In this work, electrostatic interactions were utilised to overcome this challenge and enable higher uptake, full-thickness penetration and enhanced retention of dexamethasone (Dex) inside rabbit cartilage. This was accomplished by using the positively charged glycoprotein avidin as nanocarrier, conjugated to Dex by releasable linkers. Therapeutic effects of a single intra-articular injection of low dose avidin-Dex (0.5 mg Dex) were evaluated in rabbits 3 weeks after anterior cruciate ligament transection (ACLT). Immunostaining confirmed that avidin penetrated the full cartilage thickness and was retained for at least 3 weeks. Avidin-Dex suppressed injury-induced joint swelling and catabolic gene expression to a greater extent than free Dex. It also significantly improved the histological score of cell infiltration and morphogenesis within the periarticular synovium. Micro-computed tomography confirmed the reduced incidence and volume of osteophytes following avidin-Dex treatment. However, neither treatment restored the loss of cartilage stiffness following ACLT, suggesting the need for a combinational therapy with a pro-anabolic factor for enhancing matrix biosynthesis. The avidin dose used caused significant glycosaminoglycan (GAG) loss, suggesting the use of higher Dex : avidin ratios in future formulations, such that the delivered avidin dose could be much less than that shown to affect GAGs. This charge-based delivery system converted cartilage into a drug depot that could also be employed for delivery to nearby synovium, menisci and ligaments, enabling clinical translation of a variety of DMOADs.