载冬凌草甲素快速穿越粘液层及上皮细胞靶向黏附新型脂质聚合物纳米粒的研究

Low bioavailability, large dose and side effects have been the bottlenecks for clinical application of poorly water-soluble active components of TCM. Nanocarriers may increase drug solubility and enhance intestinal absorption. However, the mucus, a viscoelastic gel and continuously being cleared, is a barrer for nanocarriers to deliver drugs. In addition, the short residence time at the absorption site of epithelia leads to fail in efficient drug delivery. In this study, oridonin loaded novel lectin modified PEGylated lipid-polymer hybrid nanoparticles were developed based on rapid mucus penetration and specific enterocyte bioadhesion. This project will be carried out mainly on estabilishing a novel preparation method for lectin modification to lipid-polymer nanoparticles, in vitro and in vivo rational evaluation, in vivo pharmacokinetics as well as mechanism investigation. Studies on rapid mucus penetration, bioadhesion drug delivery systems have been previously reported, respectively. To the best of our knowledge, no nanocarrier combined with rapid mucus penetration and specific enterocyte bioadhesion has been reported so far. This project will promote the research on nanocarriers for TCM oral delivery, and may provide new strategy to solve the limitation of poorly water-soluble components and even effective parts from TCM in clinical application.

难溶性中药活性成分口服生物利用度低、用药剂量大、易产生毒副作用等问题已成为临床用药的瓶颈。纳米载体可以改善药物溶解性和促进药物吸收，但高粘弹性且动态更新的粘液层是纳米载体递药的屏障，易捕获并清除纳米载体，降低载体利用率，加之在粘膜细胞表面滞留时间较短，致使载体难以充分发挥递药作用。基于快速穿越粘液层及特异性上皮细胞靶向黏附原理，本项目提出利用PEG化及凝集素修饰构建冬凌草甲素脂质聚合物纳米粒高效递药系统。建立凝集素修饰脂质聚合物纳米粒的新型制备方法，合理评价制剂体内外性质，研究体内药动学并探究作用机制。在快速穿越粘液层的载体研究，以及生物黏附给药系统研究方面，国内外已有部分研究报道，但在基于高效穿越粘液层和肠上皮细胞特异性靶向黏附两者联合应用构建的该给药系统模式国内外尚无报道。本项目将促进中药纳米口服载体的研究，为解决难溶性中药活性成分乃至有效部位临床应用受限制的问题提供新思路。

难溶性中药活性成分口服生物利用度低、用药剂量大、易产生毒副作用等问题已成为临床用药的瓶颈。纳米载体可以改善药物溶解性和促进药物吸收，但高粘弹性且动态更新的粘液层是纳米载体递药的屏障，易捕获并清除纳米载体，降低载体利用率，加之在粘膜细胞表面滞留时间较短，致使载体难以充分发挥递药作用。基于快速穿越粘液层及特异性上皮细胞靶向黏附原理，本项目提出利用PEG化及凝集素修饰构建冬凌草甲素脂质聚合物纳米粒高效递药系统。建立凝集素修饰脂质聚合物纳米粒的新型制备方法，合理评价制剂体内外性质，研究体内药动学并探究作用机制。采用纳米沉淀法结合后插入法成功制备WGA修饰脂质聚合物纳米粒（WGA-LPNs），电镜下可见纳米粒具有典型的壳核结构，形态圆整，且免疫电镜下可见胶体金粒子分布在WGA-LPNs外层，揭示WGA修饰成功。采用多粒子追踪技术考察WGA-LPNs体外粘液层穿越性能，结果表明PEG化修饰WGA-LPNs提高了纳米粒在粘液层中单位时间内的运动均方位移，揭示PEG化可增强纳米粒在粘液层中的穿越能力。与LPNs相比，WGA-LPNs促进了体外Caco-2细胞对纳米粒的摄取，作用机制涉及网格蛋白介导的内吞和受体介导的内吞。体外特异性细胞摄取以及离体大鼠肠黏附性研究结果表明WGA-LPNs可被Caco-2细胞特异性摄取，具有特异性细胞生物黏附作用。在体肠吸收研究发现与未修饰制剂相比，WGA修饰脂质聚合物纳米粒促进药物口服吸收。利用激光共聚焦断层扫描技术研究在体肠扩散性，证实了WGA-LPNs可穿越粘液层抵达肠细胞表面，且被细胞内吞。以LPNs为参比制剂，WGA-LPNs大鼠口服生物利用度提高了1.96倍，且较高的MRT值提示可实现单次给药后较长的药物体内滞留时间，有利于更好地发挥药效。本项目将促进中药纳米口服载体的研究，为解决难溶性中药活性成分乃至有效部位临床应用受限制的问题提供新思路。

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