Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
Acta Biomater. 2023 Sep 15;168:484-496. doi: 10.1016/j.actbio.2023.06.032. Epub 2023 Jun 29.
Activated hepatic stellate cells (HSCs) are considered the key driver of excessive extracellular matrix and abnormal angiogenesis, which are the main pathological manifestations of hepatic fibrosis. However, the absence of specific targeting moieties has rendered the development of HSC-targeted drug delivery systems a significant obstacle in the treatment of liver fibrosis. Here we have identified a notable increase in fibronectin expression on HSCs, which positively correlates with the progression of hepatic fibrosis. Thus, we decorated PEGylated liposomes with CREKA, a peptide with high affinity for fibronectin, to facilitate the targeted delivery of sorafenib to activated HSCs. The CREKA-coupled liposomes exhibited enhanced cellular uptake in the human hepatic stellate cell line LX2 and selective accumulation in CCl-induced fibrotic liver through the recognition of fibronectin. When loaded with sorafenib, the CREKA-modified liposomes effectively suppressed HSC activation and collagen accumulation in vitro. Furthermore. in vivo results demonstrated that the administration of sorafenib-loaded CREKA-liposomes at a low dose significantly mitigated CCl-induced hepatic fibrosis, prevented inflammatory infiltration and reduced angiogenesis in mice. These findings suggest that CREKA-coupled liposomes have promising potential as a targeted delivery system for therapeutic agents to activated HSCs, thereby providing an efficient treatment option for hepatic fibrosis. STATEMENT OF SIGNIFICANCE: In liver fibrosis, activated hepatic stellate cells (aHSCs) are the key driver of extracellular matrix and abnormal angiogenesis. Our investigation has revealed a significant elevation in fibronectin expression on aHSCs, which is positively associated with the progression of hepatic fibrosis. Thus, we developed PEGylated liposomes decorated with CREKA, a molecule with a high affinity for fibronectin, to facilitate the targeted delivery of sorafenib to aHSCs. The CREKA-coupled liposomes can specifically target aHSCs both in vitro and in vivo. Loading sorafenib into CREKA-Lip significantly alleviated CCl-induced liver fibrosis, angiogenesis and inflammation at low doses. These findings suggest that our drug delivery system holds promise as a viable therapeutic option for liver fibrosis with minimal risk of adverse effects.
活化的肝星状细胞 (HSCs) 被认为是细胞外基质过度产生和异常血管生成的关键驱动因素，而这正是肝纤维化的主要病理表现。然而，由于缺乏特异性靶向分子，使得开发针对 HSCs 的药物传递系统成为治疗肝纤维化的一个重大障碍。在这里，我们发现 HSCs 上的纤维连接蛋白表达显著增加，并且与肝纤维化的进展呈正相关。因此，我们用 CREKA（一种对纤维连接蛋白具有高亲和力的肽）对聚乙二醇化脂质体进行修饰，以促进索拉非尼靶向递送至活化的 HSCs。载有 CREKA 的脂质体在人肝星状细胞系 LX2 中表现出增强的细胞摄取能力，并通过识别纤维连接蛋白选择性地在 CCl4 诱导的纤维化肝脏中积累。当负载索拉非尼时，CREKA 修饰的脂质体可有效抑制体外 HSC 活化和胶原积累。此外，体内结果表明，低剂量给予载有索拉非尼的 CREKA-脂质体可显著减轻 CCl4 诱导的肝纤维化，防止炎症浸润并减少小鼠的血管生成。这些发现表明，CREKA 偶联的脂质体具有作为针对活化的 HSCs 的治疗药物的靶向传递系统的潜力，从而为肝纤维化提供了一种有效的治疗选择。
