Drug Delivery and Translational Research ( IF 5.7 ) Pub Date : 2022-09-15 , DOI: 10.1007/s13346-022-01235-1 Huseyin Ozkan 1 , Martina Di Francesco 2 , Helen Willcockson 1 , José Valdés-Fernández 1, 3 , Valentina Di Francesco 2 , Froilán Granero-Moltó 3, 4, 5, 6 , Felipe Prósper 3, 5, 6, 7, 8 , Paolo Decuzzi 2 , Lara Longobardi 1
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Posttraumatic osteoarthritis (PTOA) is mostly treated via corticosteroid administration, and total joint arthroplasty continues to be the sole effective intervention in severe conditions. To assess the therapeutic potential of CCR2 targeting in PTOA, we used biodegradable microplates (µPLs) to achieve a slow and sustained intraarticular release of the CCR2 inhibitor RS504393 into injured knees and followed joint damage during disease progression. RS504393-loaded µPLs (RS-µPLs) were fabricated via a template-replica molding technique. A mixture of poly(lactic-co-glycolic acid) (PLGA) and RS504393 was deposited into 20 × 10 μm (length × height) wells in a polyvinyl alcohol (PVA) square-patterned template. After physicochemical and toxicological characterizations, the RS504393 release profile from µPL was assessed in PBS buffer. C57BL/6 J male mice were subjected to destabilization of the medial meniscus (DMM)/sham surgery, and RS-µPLs (1 mg/kg) were administered intraarticularly 1 week postsurgery. Administrations were repeated at 4 and 7 weeks post-DMM. Drug free-µPLs (DF-µPLs) and saline injections were performed as controls. Mice were euthanized at 4 and 10 weeks post-DMM, corresponding to the early and severe PTOA stages, respectively. Knees were evaluated for cartilage structure score (ACS, H&E), matrix loss (safranin O score), osteophyte formation and maturation from cartilage to bone (cartilage quantification), and subchondral plate thickness. The RS-µPL architecture ensured the sustained release of CCR2 inhibitors over several weeks, with ~ 20% of RS504393 still available at 21 days. This prolonged release improved cartilage structure and reduced bone damage and synovial hyperplasia at both PTOA stages. Extracellular matrix loss was also attenuated, although with less efficacy. The results indicate that local sustained delivery is needed to optimize CCR2-targeted therapies.
Graphical abstract
中文翻译：
在创伤后骨关节炎中通过聚合物微板的关节内沉积持续抑制 CC-趋化因子受体-2
创伤后骨关节炎 (PTOA) 主要通过皮质类固醇给药进行治疗，全关节置换术仍然是严重情况下唯一有效的干预措施。为了评估 PTOA 中 CCR2 靶向的治疗潜力，我们使用可生物降解的微孔板 (µPL) 实现 CCR2 抑制剂 RS504393 缓慢和持续的关节内释放到受伤的膝盖中，并在疾病进展期间跟踪关节损伤。RS504393 -加载的 µPL (RS-µPL) 是通过模板复制成型技术制造的。将聚（乳酸-乙醇酸共聚物）(PLGA) 和 RS504393 的混合物沉积到聚乙烯醇 (PVA) 方形模板中的 20 × 10 μm（长 × 高）孔中。在进行物理化学和毒理学表征后，在 PBS 缓冲液中评估了 µPL 的 RS504393 释放曲线。对 C57BL/6 J 雄性小鼠进行内侧半月板 (DMM)/假手术不稳定，并在术后 1 周关节内给予 RS-µPL (1 mg/kg)。在 DMM 后 4 周和 7 周重复给药。无药物-µPLs (DF-µPLs) 和盐水注射作为对照进行。小鼠在 DMM 后 4 周和 10 周被安乐死，分别对应于早期和严重的 PTOA 阶段。评估膝盖的软骨结构评分（ACS，H&E）、基质损失（番红 O 评分）、骨赘形成和从软骨到骨骼的成熟（软骨量化）和软骨下板厚度。RS-µPL 架构确保 CCR2 抑制剂在数周内持续释放，约 20% 的 RS504393 在 21 天时仍可用。这种延长的释放改善了软骨结构并减少了 PTOA 两个阶段的骨损伤和滑膜增生。细胞外基质损失也有所减轻，但疗效较低。结果表明需要局部持续递送来优化 CCR2 靶向治疗。约 20% 的 RS504393 在 21 天内仍然可用。这种延长的释放改善了软骨结构并减少了 PTOA 两个阶段的骨损伤和滑膜增生。细胞外基质损失也有所减轻，但疗效较低。结果表明需要局部持续递送来优化 CCR2 靶向治疗。约 20% 的 RS504393 在 21 天内仍然可用。这种延长的释放改善了软骨结构并减少了 PTOA 两个阶段的骨损伤和滑膜增生。细胞外基质损失也有所减轻，但疗效较低。结果表明需要局部持续递送来优化 CCR2 靶向治疗。
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