基于花形乳糖装载PEG修饰姜黄素SLN肺部吸入缓释递药系统的构建及其调控Wnt/β-catenin治疗COPD气道重塑的作用

COPD due to lung tissue hyperplasia, poor blood supply, chronic inflammation and high mucus secretion, greatly affect the distribution of drugs into the lesion, the treatment effect is poor. In the early stage, we constructed a flower-shaped lactose-loaded curcumin SLN inhalation delivery system to improve the distribution of drugs at the target site and to treat COPD. This project intends to modify the surface of biodegradable SLN by PEG, and construct flower-shaped lactose-loaded PEGylated SLN particles for pulmonary inhalation. The aim is to combine the rapid release of SLN and PEGylated SLN from flower-shaped lactose to avoid macrophage phagocytosis and enhance mucoadhesion. The attached characteristics enable rapid dissolution of drug-loaded DPI and release of PEG-Cur-SLN, which greatly increases lung deposition, drug dissolution rate and mucosal adhesion, prolongs the retention time in the lung and releases the drug slowly in the lesion. It is intended to demonstrate the effects of PEG chain length and modification ratio on macrophage phagocytosis and adhesion of lung epithelial cell surface mucosa through cell and in vivo experiments, and to explore its lung safety; fluorescence labeling, isotope tracing and other techniques to verify inhalation The cellular uptake and clearance mechanism of DPI; elucidation of its mechanism of treatment of COPD by regulating Wnt/β-catenin, providing new ideas for designing a safe and efficient COPD targeted delivery system.

COPD因肺组织增生重构、血运差、慢性炎症和黏液高分泌，极大影响药物分布进入病变部位，治疗效果差。前期我们构建了花形乳糖装载姜黄素SLN吸入递药系统提高了药物在靶部位的分布及治疗COPD疗效。本项目拟利用PEG对可生物降解的SLN表面进行修饰，构建花形乳糖装载PEG化SLN微粒用于肺部吸入，旨在联合花形乳糖快速释放SLN及PEG化SLN逃避巨噬细胞吞噬、增强黏膜粘附的特性，实现载药DPI吸入后迅速溶解释放出PEG-Cur-SLN，大幅提高肺内沉积、药物溶解速度和黏膜粘附性，延长肺内滞留时间并在病变部位缓慢释药。拟通过细胞和在体实验，阐明PEG链长及修饰比例对巨噬细胞吞噬、肺上皮细胞表面黏膜粘附性的影响，深入探讨其肺部安全性；荧光标记、同位素示踪等技术求证吸入DPI的细胞摄取、清除机制；阐明其通过调控Wnt/β-catenin治疗COPD的机制，为设计安全高效的COPD靶向递药系统提供新思路

COPD因肺组织增生重构、血运差、慢性炎症和黏液高分泌，极大地影响药物分布进入病变部位，治疗效果差。肺吸入给药是实现COPD等呼吸系统疾病肺靶向或全身给药的理想给药途径。为改善姜黄素等难溶性中药成分溶解差、生物利用度极低、靶部位药物浓度低和治疗效果差等问题，本研究利用PEG对可生物降解的SLN表面进行修饰，而后采用自主研发的花形乳糖装载PEG化SLN微粒用于肺部吸入给药，构建了一种以PEG化SLN为载药形式的肺吸入超细复合颗粒，旨在联合花形乳糖快速释放SLN和PEG化SLN逃避巨噬细胞吞噬的特性、增强SLN稳定性和延长药物在肺内循环时间的特性，实现载药吸入制剂给药后迅速溶解释放出PEG-Cur-SLN，显著提高肺内沉积、药物溶解速度，延长肺内滞留时间和肺局部药物浓度，减少吸收入血。PEG-Cur-SLN-FL吸入给药后释放出的一级微粒为装载PEG化SLN的纳米多孔花形乳糖微粒，顺利转弯到达细支气管提高小气道沉积，而后迅速水化释放出二级微粒，为PEG修饰的SLN粒子，可快速穿透肺黏液层屏障，改善难溶性药物溶出与吸收。通过LPS诱导经PEG-Cur-SLN-FL处理24 h的BEAS-2B细胞凋亡情况，阐明其可通过调节线粒体膜电位减轻LPS引起的BEAS-2B细胞凋亡。荧光标记PEG修饰SLN探讨该递药系统穿透黏液层进入BEAS-2B和A549细胞靶向转运的可行性，而后对PEG修饰SLN吸入微粉的体外细胞毒性、小鼠吸入急性性毒性和肺内刺激性进行评估，为姜黄素提供了一种安全高效的肺内缓释递药方案。最后在验证肺吸入花形乳糖装载PEG修饰姜黄素SLN治疗COPD小鼠疗效的基础上，阐明姜黄素通过调控Wnt/β-catenin信号通路发挥对COPD气道重塑的治疗作用。本项目部分研究结果发表论文7篇，其中SCI论文2篇，申请专利3项，其中授权发明专利1项，培养研究生2名。本项目的完成为姜黄素等难溶性药物治疗COPD等呼吸系统疾病治疗提供一种新型更加精准靶向小气道的肺内高效递药方案。