仿生化皮肤黏附性纳米结构脂质载体离子液凝胶的皮内递药作用及机制研究

Inspired by the essential components of the mussel adhesive proteins, development of novel biomimetic adhesive materials has exhibited great prospect in the field of biology and medicine. In our previous investigation, it was found that the surface modified lipid nanoparticles with polydopamine, a structural analogue of mussel adhesive proteins, significantly promoted the intra-dermal drug delivery and exhibited excellent skin compatibility, while the underlying mechanisms, the drug distribution in different skin layers, as well as the relationship between their properties and the delivering effect have not been illustrated. Based on this research, terbinafine and amphotericin B would be selected as the model drug in the present study, and biomimetic nano-structure lipid carriers with different coatings and particle structures would be prepared by altering the conditions of self-polymerization-composite of dopamine. The influence of their structures and properties on the drug penetration into different skin layers would be studied in detail. For explaining their mechanisms of action, the interaction of nanoparticles with the skin, and the delivering effect via the intercellular route and follicle route would be also investigated. In addition, to enhance the dispersion of the bio-inspired nanoparticles and protect the system from self-aggregating, a temperature sensitive ionic liquid gel would be developed as the matrix of the above nano-carriers, which would also be helpful for its efficacy of the in vivo drug delivery. Above all, the study will provide some new ideas for the design, evaluation and mechanistic investigations on nanocarriers for skin drug delivery.

受贻贝黏附蛋白主要成分的启发，开发其仿生黏附性材料在生物与医药领域具有重要的研究与应用价值。申请者前期研究发现，表面经该蛋白结构类似物聚多巴胺修饰的脂质纳米粒具有良好的皮内递药性能与皮肤相容性，但是其性质与递药作用间的关系、药物在皮肤各层组织中的分布特征及机制尚不明确。本项目拟在此基础上，选择特比萘芬与两性霉素B作为模型药物，通过改变多巴胺自聚-复合改性条件，构建具有不同涂层及粒子结构特征的仿生化纳米结构脂质载体；利用皮肤组织分布学研究，深入考察载体性质对不同层次皮内递药作用的影响；并结合对纳米粒与皮肤相互作用的研究，从角质细胞间脂质与皮肤附属器两种递药途径探索其作用机制与规律；此外，为提高其分散性以避免发生自聚现象，本项目构建一种温敏型离子液凝胶作为其基质，可在增强其稳定性的同时，进一步提高其体内递药能力。综上，本项目将为纳米粒系皮肤递药系统的设计、评价与机制研究提供有价值的借鉴与参考。

纳米结构脂质载体是一种发展潜力巨大的新型纳米递药系统，广泛应用于各种给药途径，特别是在皮肤递药及皮肤相关疾病治疗领域具有重要的开发与临床应用价值。但是受皮肤屏障功能限制，通过NLC将药物递送至皮肤深层组织仍是一个很大挑战。聚多巴胺是一种贻贝黏附蛋白仿生改性材料，由于其具有良好的生物相容性、较强的吸附性以及光热转换等优势，目前在生物传感、药物递送、生物成像、组织工程和抗菌等领域受到极大的关注。本项目基于聚多巴胺仿生修饰技术创新性地开发了聚多巴胺修饰纳米结构脂质载体作为一种新型经皮递药纳米载体；引入多种理化表征手段对其结构进行深入研究，明确了聚多巴胺的修饰条件、方法与相关的结构特征；通过对纳米载体粒径与包封率稳定性研究，表明聚多巴胺修饰对纳米结构脂质载体稳定性的保护作用；同时搭建了皮肤组织药物分布全方位评价平台，包括角质层、活性表皮层、真皮层以及毛囊与非毛囊转运途径的药物分布研究方法，以对聚多巴胺修饰纳米结构脂质载体的皮肤递药行为进行全面系统研究，并且发现了其皮内特异性递药作用与毛囊递药机制；通过细胞摄取及抑制定性与定量研究，明确了聚多巴胺修饰纳米结构脂质载体改善皮肤细胞摄取的能力以及以小窝蛋白/脂阀介导为主的内吞摄取机制；通过CCK-8实验研究揭示了其皮肤细胞相容性与皮肤应用安全性；结合壳聚糖凝胶基质，通过在体皮肤递药实验研究阐明了其改善在体皮肤递药的能力。本项目研究成果可应用于皮肤靶向、免疫制剂的设计与研发，还可结合其他治疗手段应用于临床治疗皮肤疾病，提高制剂研发的技术含量与创新性，具有很好的研发与临床应用前景，同时相关成果也将为纳米粒系皮肤递药制剂的设计与机制研究提供新材料与新思路。在本项目执行期间，项目负责人以第一/通讯作者发表标注本项目SCI论文3篇、会议论文1篇，申请发明专利1项，培养在读硕士研究生4名，已完成计划书的各项考核指标。