Abstract：
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.
摘要：
特发性肺纤维化（IPF）是一种破坏性的肺部疾病，由于治疗选择有限，死亡率很高。目前的疗法不能有效地逆转由IPF引起的损害。研究表明，促进肌成纤维细胞的程序性细胞死亡（凋亡），驱动纤维化的关键细胞，可能是一个有前途的策略。然而,诱导上皮细胞和内皮细胞等健康细胞的凋亡会引起不必要的副作用。该项目通过开发一种靶向方法来特异性地在肌成纤维细胞中诱导细胞凋亡来解决这一挑战。我们设计了用识别VCAM-1的肽修饰的脂质体（LPS），VCAM-1是一种在纤维化肺成肌纤维细胞上高度表达的蛋白质。这些VCAM1靶向LPS封装维奈托克（VNT），一种抑制抗凋亡蛋白BCL-2的小分子药物。通过将VNT直接递送到肌成纤维细胞，我们假设VCAM1-VNT-LPS可以选择性诱导这些细胞的凋亡，导致纤维化减少和肺功能改善。我们成功地表征了VCAM1-VNT-LPS的大小，表面电荷,和药物装载效率。此外,我们评估了它们在不同温度下三个月的稳定性。使用博来霉素诱导的肺纤维化小鼠模型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，同时增加肌成纤维细胞的凋亡。这些发现表明使用脂质体的BCL-2抑制剂的VCAM1靶向递送为IPF提供了有希望的和潜在的选择性治疗方法。
