Hengyang Medical School, University of South China, Hengyang, Hunan, 410001, China.
School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, Sichuan 610031, China.
Acta Biomater. 2023 Sep 15;168:497-514. doi: 10.1016/j.actbio.2023.07.035. Epub 2023 Jul 26.
The persistent transformation of quiescent hepatic stellate cells (HSCs) into myofibroblasts (MFs) and the excessive proliferation of MF-HSCs in the liver contribute to the pathogenesis of liver fibrosis, cirrhosis, and liver cancer. Glycolysis inhibition of MF-HSCs can reverse their MF phenotype and suppress their abnormal expansion. Here, we have developed vitamin A-derivative (VA) decorated PEG-PCL polymeric micelles to encapsulate the labile and hydrophobic camptothecin (CPT) and direct its active attack on HSCs, selectively inhibiting of HIF-1α and cellular glycolysis, ultimately repressing hepatic fibrogenesis. The obtained micelles exhibited a good stability, biocompatibility, pH sensitivity, and exceptional HSC-targetability, allowing an efficient accumulation of their carried CPT in acutely and chronically injured livers. On their intracellular release of CPT specifically in MF-HSCs, these CPT micelles nicely inhibited the HIF-1α and a series of glycolytic players in MF-HSCs and prominently suppressed their proliferation and MF phenotypic characteristics. Accordingly, on in vitro administration to the mice challenged by CCl or subjected to bile duct ligation, these VA-decorated CPT micelles ameliorated the pathological symptoms of the livers, as evidenced by the significant reduction in serum levels of ALT and AST, infiltration of inflammatory cells, and collagen accumulation, the drastic down-regulation of multiple fibrotic genes, and the good recovery of attenuated hepatocyte CYP2E1 and lipogenesis regulator PPARγ. Overall, the CPT carried by VA-decorated PEG-PCL polymeric micelles can selectively inhibit the glycolysis and expansion of HSCs and thus suppress fibrogenesis, providing an original and effective approach for anti-fibrotic therapy. STATEMENT OF SIGNIFICANCE: Our work introduces an innovative antifibrotic drug system that is developed upon the active targeting of CPT and aims for the fate reversal of HSCs. Through HSC-targeted delivery achieved by PEG-PCL polymeric micelles decorated with vitamin A-derivatives, CPT significantly suppressed the expressions of HIF-1α and glycolytic enzymes in MF-HSCs, as well as their pathologic expansion in mouse livers. It effectively ameliorated chronic liver fibrosis in mice induced by CCl injection or BDL and restored the damaged liver structure and function. These compelling findings demonstrate the therapeutic potential of glycolytic HSC-targeting in combating fibrosis and related disorders and thus provide new promise for future clinical management of such prevalent and life-threatening conditions.
静止的肝星状细胞（HSCs）向肌成纤维细胞（MFs）的持续转化以及肝内 MF-HSCs 的过度增殖导致肝纤维化、肝硬化和肝癌的发病机制。MF-HSCs 的糖酵解抑制可以逆转其 MF 表型并抑制其异常扩张。在这里，我们开发了维生素 A 衍生物（VA）修饰的 PEG-PCL 聚合物胶束来包封不稳定和疏水性喜树碱（CPT），并直接靶向 HSCs，选择性抑制 HIF-1α 和细胞糖酵解，最终抑制肝纤维化。所得胶束表现出良好的稳定性、生物相容性、pH 敏感性和出色的 HSC 靶向性，允许其携带的 CPT 在急性和慢性损伤的肝脏中有效积累。在它们的细胞内，CPT 特异性地在 MF-HSCs 中释放，这些 CPT 胶束很好地抑制了 HIF-1α 和 MF-HSCs 中的一系列糖酵解因子，并显著抑制了它们的增殖和 MF 表型特征。因此，在体外给予 CCl 或胆管结扎的小鼠，这些 VA 修饰的 CPT 胶束改善了肝脏的病理症状，血清 ALT 和 AST 水平显著降低，炎症细胞浸润和胶原积累减少，多个纤维化基因明显下调，减弱的肝细胞 CYP2E1 和脂生成调节剂 PPARγ 得到良好恢复。总的来说，VA 修饰的 PEG-PCL 聚合物胶束携带的 CPT 可以选择性地抑制 HSCs 的糖酵解和扩张，从而抑制纤维化，为抗纤维化治疗提供了一种新颖有效的方法。
我们的工作介绍了一种创新的抗纤维化药物系统，该系统是基于 CPT 的主动靶向开发的，旨在逆转 HSCs 的命运。通过维生素 A 衍生物修饰的 PEG-PCL 聚合物胶束实现的 HSC 靶向递送，CPT 显著抑制了 MF-HSCs 中 HIF-1α 和糖酵解酶的表达，以及它们在小鼠肝脏中的病理性扩张。它有效地改善了 CCl 注射或 BDL 诱导的慢性肝纤维化，并恢复了受损的肝结构和功能。这些令人信服的发现表明，在对抗纤维化和相关疾病方面，靶向糖酵解的 HSC 具有治疗潜力，为这种普遍且危及生命的疾病的未来临床管理提供了新的希望。
