Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, No.17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, No.17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
Acta Biomater. 2023 Sep 1;167:574-582. doi: 10.1016/j.actbio.2023.06.024. Epub 2023 Jun 24.
The progressive formation of fibroblastic foci characterizes idiopathic pulmonary fibrosis (IPF), and excessive oral doses of approved pirfenidone (PFD) always cause gastrointestinal side effects. The fibrotic response driven by activated fibroblasts could perpetuate epithelial damage and promote abnormal extracellular matrix (ECM) deposition. When modified nanoparticles reach their target, it is important to ensure a responsive release of PFD. Hypoxia is a determining factor in IPF, leading to alveolar dysfunction and deeper cellular fibrosis. Herein, a fibroblastic foci-targeting and hypoxia-cleavable drug delivery system (Fn-Azo-BSA@PEG) was established to reprogram the fibrosis in IPF. We have modified the FnBAP5 peptide to enable comprehensive fibroblastic foci targeting, which helps BSA nanoparticles recognize and accumulate at fibrotic sites. Meantime, the hypoxia-responsive azobenzene group allowed for efficient and rapid drug diffusion, while the PEGylated BSA reduced system toxicity and increased circulation in vivo. As expected, the strategy of the fibronectin-targeting-modification and hypoxia-responsive drug release synergistically inhibited activated fibroblasts and reduced the secretion of the fibrosis-related protein. Fn-Azo-BSA@PEG could accumulate in pulmonary tissue and prolong the survival time in bleomycin-induced pulmonary fibrosis mice. Together, the multivalent BSA nanoparticles offered an efficient approach for improving lung architecture and function by regulating the fibroblastic foci and hypoxia. STATEMENT OF SIGNIFICANCE: We established fibroblastic foci-targeting and hypoxia-cleavable bovine serum albumin (BSA) nanoparticles (Fn-Azo-BSA@PEG) to reprogramme the fibroblastic foci in idiopathic pulmonary fibrosis (IPF). Fn-Azo-BSA@PEG was designed to actively target fibroblasts and abnormal ECM with the FnBPA5 peptide, delivering more FDA-approved pirfenidone (PFD) to the cross-talk within the foci. Once the drug reached fibroblastic foci, the azobenzene group acted as a hypoxia-responsive linker to trigger effective and rapid drug release. Hypoxic responsiveness and FnBAP5-modification of Fn-Azo-BSA@PEG synergistically inhibited the secretion of proteins closely related to fibrogenesis. BSA's inherent transport and metabolic pathways in the pulmonary reduced the side effects of the main organs. The multivalent BSA nanoparticles efficiently inhibited IPF-fibrosis progress and preserved the lung architecture by regulating the fibroblastic foci and hypoxia.
特发性肺纤维化（IPF）的特征是成纤维细胞灶的渐进形成，而过量口服批准的吡非尼酮（PFD）总会引起胃肠道副作用。激活的成纤维细胞驱动的纤维化反应可使上皮损伤持久，并促进异常细胞外基质（ECM）沉积。当修饰后的纳米颗粒到达目标时，确保 PFD 响应性释放非常重要。缺氧是 IPF 的决定因素，导致肺泡功能障碍和更深的细胞纤维化。在此，建立了一种成纤维细胞灶靶向和缺氧可裂解的药物传递系统（Fn-Azo-BSA@PEG），以重新编程 IPF 中的纤维化。我们已经修饰了 FnBAP5 肽，使其能够全面靶向成纤维细胞灶，帮助 BSA 纳米颗粒识别并在纤维化部位积累。同时，缺氧响应性偶氮苯基团允许高效快速的药物扩散，而 PEG 化 BSA 降低了系统毒性并增加了体内循环。正如预期的那样，纤维连接蛋白靶向修饰和缺氧响应性药物释放的协同策略抑制了激活的成纤维细胞，并减少了纤维化相关蛋白的分泌。Fn-Azo-BSA@PEG 可以在博来霉素诱导的肺纤维化小鼠的肺组织中积累，并延长其存活时间。总之，多价 BSA 纳米颗粒通过调节成纤维细胞灶和缺氧提供了一种有效改善肺结构和功能的方法。
