Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai, 200237, China.
Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai, 200237, China; Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
Biomaterials. 2021 Apr;271:120761. doi: 10.1016/j.biomaterials.2021.120761. Epub 2021 Mar 17.
Pulmonary fibrosis is a rapidly progressive and fatal fibrotic lung disease with high mortality and morbidity. However, pulmonary fibrosis therapy in the clinic has been limited by poor selectivity and inefficiency of drug delivery to fibroblasts. Herein, a clodronate (CLD)-loaded liposome and fibroblast-derived exosome (EL-CLD) hybrid drug delivery system with non-specific phagocytosis inhibition and fibroblast homing properties, was designed for the treatment of pulmonary fibrosis. EL-CLD effectively depleted Kupffer cells via apoptosis by passive targeting after intravenous injection, and thus significantly reduced accumulation in the liver. Notably, the EL-CLD hybrid system preferentially accumulated in the fibrotic lung, and significantly increased penetration inside pulmonary fibrotic tissue by targeted delivery due to the specific affinity for fibroblasts of the homologous exosome. Nintedanib (NIN), an anti-fibrotic agent used to treat pulmonary fibrosis, was loaded in the EL-CLD system, and achieved a remarkable improvement in curative effects. The enhanced therapeutic efficacy of NIN was a result of enhanced pulmonary fibrotic tissue accumulation and delivery, combined with a diminished macrophage-induced inflammatory response. Hence, the EL-CLD hybrid system acts as an efficient carrier for pulmonary anti-fibrotic drug delivery and should be developed as an efficient fibroblast specific therapy.
肺纤维化是一种快速进展且致命的肺纤维化疾病，死亡率和发病率都很高。然而，临床上的肺纤维化治疗受到药物向成纤维细胞传递的选择性和效率差的限制。本文设计了一种载有氯膦酸酯（CLD）的脂质体和来源于成纤维细胞的细胞外囊泡（EL-CLD）的杂化药物传递系统，具有非特异性吞噬抑制和成纤维细胞归巢特性，用于治疗肺纤维化。EL-CLD 经静脉注射后通过被动靶向作用有效地诱导库普弗细胞凋亡，从而显著减少在肝脏中的积累。值得注意的是，由于同源细胞外囊泡对成纤维细胞的特异性亲和力，EL-CLD 杂化系统优先在纤维化肺中积累，并通过靶向递送显著增加了对肺纤维化组织的穿透。尼达尼布（NIN）是一种用于治疗肺纤维化的抗纤维化药物，被装载在 EL-CLD 系统中，显著提高了疗效。NIN 的治疗效果增强是由于增强了肺纤维化组织的积累和传递，同时减少了巨噬细胞诱导的炎症反应。因此，EL-CLD 杂化系统可作为一种有效的肺抗纤维化药物传递载体，并应开发为一种有效的成纤维细胞特异性治疗方法。
