Targeting CD34+ cells of the inflamed synovial endothelium by guided nanoparticles for the treatment of rheumatoid arthritis
Targeting CD34+ cells of the inflamed synovial endothelium by guided nanoparticles for the treatment of rheumatoid arthritis
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DOI：
10.1016/j.jaut.2019.05.016
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发表时间：
2019-09-01
影响因子：
12.8
通讯作者：
Macor, Paolo
中科院分区：
文献类型：
--
作者：
Colombo, Federico;Durigutto, Paolo;Macor, Paolo
尽管类风湿关节炎（RA）的治疗在过去几年中取得了进展，但一些患者诊断较晚，对治疗无反应或因无效和/或毒性而不得不停止治疗，仍然留下了巨大的未满足需求。组织特异性策略有可能解决其中的一些问题。这项研究的目的是开发一种安全的纳米技术方法，用于组织特异性的药物递送和诊断探针。使用靶向可生物降解纳米颗粒（tBNPs）处理炎症滑膜中的CD34（+）内皮前体。这些纳米结构由聚乳酸、聚己内酯和聚乙二醇制成，然后涂有滑膜归巢肽。免疫荧光分析清楚地表明，它们能够选择性地处理人、小鼠和大鼠滑膜组织中的CD34（+）内皮细胞。在两种不同的类风湿关节炎动物模型（抗原诱导关节炎/AIA和胶原诱导关节炎/CIA）中的生物分布研究证实了炎症关节中的选择性积累，但也证明了tBNP检测疾病早期阶段和肝脏优先消除的能力。研究了甲氨蝶呤（MTX）负载tBNPs与常规MTX剂量的治疗效果。与MTX相比，MTX负载的tBNPs以更低的剂量和更少的给药频率预防和治疗CIA和AIA。此外，mtx负载的tBNP显示出一种新的作用机制，其中颗粒靶向并杀死CD34（+）内皮祖细胞，阻止新血管生成，从而阻止滑膜炎症。tBNPs代表了一个稳定和安全的平台，用于开发高度敏感的RA成像和治疗方法，特别是针对滑膜新生血管生成以减少局部炎症。
Despite the advances in the treatment of rheumatoid arthritis (RA) achieved in the last few years, several patients are diagnosed late, do not respond to or have to stop therapy because of inefficacy and/or toxicity, leaving still a huge unmet need. Tissue-specific strategies have the potential to address some of these issues. The aim of the study is the development of a safe nanotechnology approach for tissue-specific delivery of drugs and diagnostic probes. CD34(+) endothelial precursors were addressed in inflamed synovium using targeted biodegradable nanoparticles (tBNPs). These nanostructures were made of poly-lactic acid, poly-caprolactone, and PEG and then coated with a synovial homing peptide. Immunofluorescence analysis clearly demonstrated their capacity to selectively address CD34(+) endothelial cells in synovial tissue obtained from human, mouse, and rat. Biodistribution studies in two different animal models of rheumatoid arthritis (antigen-induced arthritis/AIA and collagen-induced arthritis/CIA) confirmed the selective accumulation in inflamed joints but also evidenced the capacity of tBNP to detect early phases of the disease and the preferential liver elimination. The therapeutic effect of methotrexate (MTX)-loaded tBNPs were studied in comparison with conventional MTX doses. MTX-loaded tBNPs prevented and treated CIA and AIA at a lower dose and reduced administration frequency than MTX. Moreover, MTX-loaded tBNP showed a novel mechanism of action, in which the particles target and kill CD34(+) endothelial progenitors, preventing neo-angiogenesis and, consequently, synovial inflammation. tBNPs represent a stable and safe platform to develop highly-sensitive imaging and therapeutic approaches in RA targeting specifically synovial neo-angiogenesis to reduce local inflammation.