Ac-SDKP肺纤维化靶向仿生LDH@外泌体模拟囊泡核壳纳米制剂的制备及其抗矽肺纤维化机制的研究

Silicosis is one of the most severe occupational diseases in China. Many studies indicate that Ac-SDKP is an effective anti-fibrosis peptide. However, many factors limit its clinical application, such as short life-time in vivo, low bioavailability, inconvenient drug delivery and so on. Our team previous works designed an Ac-SDKP nano delivery system bases on layered double hydroxides (LDH) with properties of pH-sensitive controlled release. Although the designed drug delivery system enhanced the stability of Ac-SDKP, and increased the anti-fibrosis effect of Ac-SDKP, it played not well in active target and long circulation in vivo. Considering that mononuclear macrophage can target inflammatory site via the interaction of LFA-1and ICAM-1, and LDH as the carrier of Ac-SDKP can obviously enhance the anti-fibrosis effect of Ac-SDKP, in this project, Ac-SDKP-intercalated LDH nanoparticles are firstly prepared, followed by being encapsulated with a layer of mononuclear macrophage-derived exosome-mimetic nanovesicles. And then cell and animal studies are designed to evaluate the anti-fibrosis effect of the new-designed Ac-SDKP delivery nano system. Through the repeated optimization of preparation conditions according to the feedback from the results of cell and animal studies, this project aims to obtain a LDH@exosome-mimetic nanovesicles delivery system with long circulation in the body and pH-sensitive controlled release, which can deliver Ac-SDKP to pulmonary fibrosis microenvironment.

尘（矽）肺病是我国最严重的职业病。研究表明N-乙酰-丝氨酰-天门冬氨酰-赖氨酰-脯氨酸（Ac-SDKP）是一种有效的抗器官纤维化多肽，但由于其体内半衰期短、生物利用度低、给药方式不便等因素限制其临床应用。课题组前期开发的基于层状双氢氧化物（LDH）的pH敏感Ac-SDKP控释纳米递送体系虽然能够提高Ac-SDKP稳定性，增加抗矽肺纤维化效果，但该体系主动靶向和体内长循环性能不足。鉴于单核巨噬细胞可通过LFA-1与ICAM-1相互作用实现炎症部位靶向，且LDH作为Ac-SDKP的载体能够显著提高Ac-SDKP抗矽肺纤维化效果，本项目拟制备Ac-SDKP插层的LDH纳米复合体系，然后包裹一层单核巨噬细胞来源的外泌体模拟囊泡，通过细胞和动物水平的效果评价，并反复优化制备条件，最终旨在得到一种体内长循环、靶向肺纤维化微环境的Ac-SDKP pH敏感控释纳米仿生囊泡递送载体。

尘(矽)肺病是我国最严重的职业病。研究表明N-乙酰-丝氨酰-天门冬氨酰-赖氨酰-脯氨 酸(Ac-SDKP)是一种有效的抗器官纤维化多肽，但由于其体内半衰期短、生物利用度低、给药方式不便等因素限制其临床应用。课题组开发了基于层状双氢氧化物(LDH)的pH敏感Ac-SDKP控释纳米递送体系虽然能够提高Ac-SDKP稳定性，增加抗矽肺纤维化效果，并利用蛋白组学阐释其抗纤维化作用机制。同时，通过生物素修饰构建新型具有抗纤维化能力的可视化Ac-B短肽。为了提高LDH搭载Ac-SDKP复合物主动靶向和体内长循环性能力。鉴于单核巨噬细胞可通过LFA-1与ICAM-1相互作用实现炎症部位靶向，且LDH作为Ac-SDKP的载体能够显著提高Ac-SDKP抗矽肺纤维化效果，本项目在Ac-SDKP的LDH纳米复合体系外包裹一层单核巨噬细胞来源的外泌体模拟囊泡，得到一种体内长循环、靶向肺纤维化微环境的Ac-SDKP pH敏感控释纳米仿生囊泡递送载体。与单纯Ac-SDKP相比，新制剂Ac-LDH和AL@NV均具有更加明显的抗矽肺纤维化能力，其中Ac-LDH在矽肺纤维化早期预防效果显著，而Ac-LDH的靶向性优势更为明显，可显著提高药物利用度。本项研究的仿生囊泡递送载体不仅有效保护了Ac-SDKP不被降解，提高了其生物利用度，同时为研发其他抗器官纤维化药物提供了新颖且有效的改造思路和潜在临床价值。