Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a high mortality rate due to limited treatment options. Current therapies cannot effectively reverse the damage caused by IPF. Research suggests that promoting programmed cell death (apoptosis) in myofibroblasts, the key cells driving fibrosis, could be a promising strategy. However, inducing apoptosis in healthy cells like epithelial and endothelial cells can cause unwanted side effects. This project addresses this challenge by developing a targeted approach to induce apoptosis specifically in myofibroblasts. We designed liposomes (LPS) decorated with peptides that recognize VCAM-1, a protein highly expressed on myofibroblasts in fibrotic lungs. These VCAM1-targeted LPS encapsulate Venetoclax (VNT), a small molecule drug that inhibits BCL-2, an anti-apoptotic protein. By delivering VNT directly to myofibroblasts, we hypothesize that VCAM1-VNT-LPS can selectively induce apoptosis in these cells, leading to reduced fibrosis and improved lung function. We successfully characterized VCAM1-VNT-LPS for size, surface charge, and drug loading efficiency. Additionally, we evaluated their stability over three months at different temperatures. In vitro and in vivo studies using a bleomycin-induced mouse model of lung fibrosis demonstrated the therapeutic potential of VCAM1-VNT-LPS. These studies showed a reduction in fibrosis-associated proteins (collagen, α-SMA, VCAM1) and BCL-2, while simultaneously increasing apoptosis in myofibroblasts. These findings suggest that VCAM1-targeted delivery of BCL-2 inhibitors using liposomes presents a promising and potentially selective therapeutic approach for IPF.

中文翻译：

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脂质纳米颗粒实现细胞选择性 BCL-2 抑制可减轻肺纤维化

特发性肺纤维化（IPF）是一种毁灭性的肺部疾病，由于治疗选择有限，死亡率很高。目前的治疗方法无法有效逆转 IPF 造成的损害。研究表明，促进肌成纤维细胞（驱动纤维化的关键细胞）的程序性细胞死亡（细胞凋亡）可能是一种有前途的策略。然而，诱导健康细胞（如上皮细胞和内皮细胞）凋亡可能会导致不必要的副作用。该项目通过开发一种专门诱导肌成纤维细胞凋亡的靶向方法来应对这一挑战。我们设计了用识别 VCAM-1 的肽装饰的脂质体 (LPS)，VCAM-1 是一种在纤维化肺部的肌成纤维细胞上高度表达的蛋白质。这些靶向 VCAM1 的 LPS 封装了 Venetoclax (VNT)，这是一种抑制 BCL-2（一种抗凋亡蛋白）的小分子药物。通过将 VNT 直接递送至肌成纤维细胞，我们假设 VCAM1-VNT-LPS 可以选择性诱导这些细胞凋亡，从而减少纤维化并改善肺功能。我们成功地表征了 VCAM1-VNT-LPS 的尺寸、表面电荷和载药效率。此外，我们还评估了它们在不同温度下三个月的稳定性。使用博莱霉素诱导的肺纤维化小鼠模型进行的体外和体内研究证明了 VCAM1-VNT-LPS 的治疗潜力。这些研究表明，纤维化相关蛋白（胶原蛋白、α-SMA、VCAM1）和 BCL-2 减少，同时肌成纤维细胞凋亡增加。这些发现表明，使用脂质体靶向 VCAM1 递送 BCL-2 抑制剂为 IPF 提供了一种有前途且具有潜在选择性的治疗方法。