超声联合微泡介导载药声敏eLiposomes对炎性关节病靶向治疗的实验研究

Inflammatory arthritis (IA) is a group of rheumatism with high disability and multi-drug treatment is needed in IA, which target is proliferated synovial membranes in inflammatory joints. Due to lack of targeted drugs, severe side effects including infection and tumor caused by long term and high level systematic use of drugs and increase of economic burden, exploring a safer and more effective targeted drug-delivery system has become the focus of treatment. Although liposomes have characteristics of high biocompatibility and drug-loading and the ability to load both hydrophilic and hydrophobic drugs, they cannot realize high drug concentration in the target region; Ultrasound can be used for targeted and site-specific delivery of drugs, but common liposomes are not ultrasound-sensitive. However, the drug-loaded ultrasound-sensitive emulsion liposomes (eLiposomes) encapsulating perfluorocarbon emulsion nanodroplets combines ultrasound and liposomes together. According to our previous studies, we have proved that ultrasound combined with microbubbles could locate inflammatory joints and promote drug’s entry into synoviocytes via cavitation effect, and we also have prepared drug-loaded liposomes. We intend to prepare multi-drug loaded targeted ultrasound-sensitive eLiposomes. We look for the treatment targets through CEUS first, then release drugs from eLiposomes by ultrasound combined with mirobubbles and cavitation effect, and realize the drug accumulation in the target field. We try to investigate the mechanism and assess the efficacy of the treatment. We aim to provide theoretical and experimental evidence for a new, efficient and fewer side effects targeted treatment for IA.

炎性关节病(IA)是致残率高的一大类疾病，需多种药物联合治疗，治疗靶点为炎性关节增生滑膜，由于药物缺乏靶向性，长期大剂量系统性使用易导致感染、肿瘤等严重副作用，并增加经济负担，探索更安全有效的靶向给药系统成为治疗热点。脂质体有高生物相容性、高载药和亲疏水药物均能负载能力，但并不能实现靶区药物高浓聚；超声能用于靶向定点释药，但普通脂质体没有声敏性；包裹氟碳乳剂的载药声敏乳化脂质体（eLiposomes）则能将超声与脂质体结合起来。基于我们前期研究证实超声联合微泡可定位炎性关节，并可通过空化效应促进药物进入滑膜组织及细胞，同时也已成功制备可载药脂质体，我们拟制备可负载多种药物的靶向声敏eLiposomes，先通过超声造影寻找治疗靶点，然后超声联合微泡介导脂质体释放药物并联合超声空化效应，实现药物在靶区浓聚，探讨治疗机理并评估疗效，旨在为IA探索新型、高效、低副作用的靶向治疗提供理论与实验依据。

炎性关节病(IA)是致残率高的一大类疾病，需多种药物联合治疗，治疗靶点为炎性关节增生滑膜，由于药物缺乏靶向性，长期大剂量系统性使用易导致感染、肿瘤等严重副作用，并增加经济负担，探索更安全有效的靶向给药系统成为治疗热点。脂质体有高生物相容性、高载药和亲疏水药物均能负载能力，但并不能实现靶区药物高浓聚；超声能用于靶向定点释药，但普通脂质体没有声敏性；包裹氟碳乳剂的载药声敏乳化脂质体（eLiposomes）则能将超声与脂质体结合起来。由于直接合成稳定的载药靶向声敏脂质体难度较大，本项目分别研究了超声联合微泡介导载药靶向脂质体以及超声介导载药靶向相变纳米液粒治疗关节炎的作用。在本研究中，我们通过薄膜水化法和声震法成功制备了纳米级的载地塞米松脂质体和包裹全氟戊烷的声敏相变纳米液粒，体外释放实验结果证实，超声能够促进二者的释药，且在体外超声造影成像中可以观察到纳米液粒的相变行为。体外细胞实验证实脂质体和纳米液粒对内皮细胞均没有明显的细胞毒性作用，对巨噬细胞具有明显的靶向性和活性抑制作用，且在超声作用下活性抑制作用更显著。我们也成功建立了大鼠关节炎模型，结果证实，载药脂质体和载药相变纳米液粒能够减少血液中炎性细胞因子的浓度，抑制关节腔内滑膜增生和炎性细胞浸润，防止关节骨和软骨损伤，从而实现对大鼠关节炎进行治疗的目的。本研究为今后开发更高效的超声响应IA诊疗一体化的纳米材料奠定了实践基础。