Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Cantabria (UC), Santander, Spain.
Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo de Miramón 194, Donostia-San Sebastián 20014, Spain.
Theranostics. 2024 Jan 1;14(1):176-202. doi: 10.7150/thno.85409. eCollection 2024.
The discovery of extracellular vesicles (EVs) as efficient exogenous biotransporters of therapeutic agents into cells across biological membranes is an exciting emerging field. Especially the potential of EVs as targeted delivery systems for diseases with selective treatments, such as fibrosis, whose treatment causes side effects in other organs not involved in the disease. Methods: In this study, we collected embryonic fibroblast-derived EVs from two different centrifugation fractions, 10 K g and 100 K g fractions from a NIH-3T3 cell line loaded with an experimental drug. Mice with fibrotic hearts and lungs were obtained by administration of angiotensin II. We generated fluorescent EVs and bioluminescent drug to observe their accumulation by colocalization of their signals in fibrotic heart and lung. The biodistribution of the drug in various organs was obtained by detecting the Au present in the drug nanostructure. Results: The drug-loaded EVs successfully reduced fibrosis in pathological fibroblasts , and modified the biodistribution of the experimental drug, enabling it to reach the target organs . We described the pre-analytical characteristics of EVs related to physical variables, culture and harvesting conditions, crucial for their application as nanotransporters using a previously validated protein-based antifibrotic drug. The results showed the colocalization of EVs and the experimental drug and and the efficient reduction of fibrosis . This work demonstrates that 10K-EVs and 100K-EVs derived from fibroblasts can act as effective biotransporters for targeted drug delivery to profibrotic fibroblasts, lungs, or heart. We observed that fibroblast-derived 10K-EVs and 100K-EVs are useful biotransporters encapsulating a new generation drug leading to a reduction of fibrosis in profibrotic fibroblasts . In addition, drug containing EVs were shown to reach fibrotic heart and lungs , enhancing free drug biodistribution.
细胞外囊泡 (EVs) 作为治疗剂穿过生物膜进入细胞的高效外源性生物转运体的发现是一个令人兴奋的新兴领域。特别是 EVs 作为具有选择性治疗的疾病的靶向递药系统的潜力，例如纤维化，其治疗会导致未涉及疾病的其他器官产生副作用。
在这项研究中，我们从 NIH-3T3 细胞系中收集了两种不同离心分数（10 K g 和 100 K g 分数）的胚胎成纤维细胞衍生的 EVs，这些细胞系负载有实验药物。通过给予血管紧张素 II 获得纤维化心脏和肺部的小鼠。我们生成了荧光 EVs 和生物发光药物，通过观察其信号在纤维化心脏和肺部中的共定位来观察它们的积累。通过检测药物纳米结构中存在的 Au 获得了药物在各种器官中的生物分布。
负载药物的 EVs 成功地减少了病理成纤维细胞中的纤维化，并改变了实验药物的生物分布，使其能够到达靶器官。我们描述了与物理变量、培养和收获条件相关的 EVs 的预分析特性，这些特性对于使用以前验证的基于蛋白质的抗纤维化药物作为纳米转运体至关重要。结果表明 EVs 与实验药物的共定位以及纤维化的有效减少。这项工作表明，来自成纤维细胞的 10K-EVs 和 100K-EVs 可以作为靶向递药到促纤维化成纤维细胞、肺或心脏的有效生物转运体。我们观察到，源自成纤维细胞的 10K-EVs 和 100K-EVs 是有用的生物转运体，可封装新一代药物，从而减少促纤维化成纤维细胞中的纤维化。此外，含有药物的 EVs 被证明可以到达纤维化的心脏和肺部，增强游离药物的生物分布。
