Wu Pengkai, Luo Xinping, Wu Hui, Zhang Qingyan, Dai Yuanxin, Sun Minjie
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China.
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China.
Biomaterials. 2020 Dec;261:120311. doi: 10.1016/j.biomaterials.2020.120311. Epub 2020 Aug 8.
The treatment options of liver fibrosis remain limited except for liver transplantation due to the complexity and slow development in its progression. Besides, liver fibrosis recurrence and intervention time have not been reported as significant indicators to affect the anti-fibrotic efficacy of tested drugs/strategies. Herein, a novel fluoropolymer is developed to achieve high drug loading of sorafenib and efficient delivery of miR155 inhibitor (anti-miR155) for dual-targeting of hepatic stellate cells (HSCs) and kupffer cells (KCs), and we report a detailed plan on the design of treatment regimen to reveal the relationship between chemogene therapy, intervention time and fibrosis recurrence. Such a combined chemo-gene therapy of sorafenib and anti-miR155 can achieve superior therapeutic efficiency by polarizing the pro-inflammatory M1 to anti-inflammatory M2 of KCs and inhibiting the proliferation of HSCs. Importantly, efficacy and recurrence prevention of chemogene therapy earlier in the liver fibrosis will be more effective than the treatment at later stage. In conclusion, this work proposes a novel strategy to improve the efficacy and prevent recurrence of liver fibrosis by dual-regulating of KCs and HSCs, and emphasizes the importance of therapy earlier in the treatment of liver fibrosis.
由于肝纤维化进展的复杂性和缓慢，除肝移植外，其治疗选择仍然有限。此外，肝纤维化复发和干预时间尚未被报道为影响受试药物/策略抗纤维化疗效的重要指标。在此，开发了一种新型含氟聚合物，以实现索拉非尼的高载药量和miR155抑制剂（抗miR155）的高效递送，用于对肝星状细胞（HSCs）和库普弗细胞（KCs）进行双靶点治疗，并且我们报告了一项关于治疗方案设计的详细计划，以揭示化学基因治疗、干预时间与纤维化复发之间的关系。索拉非尼和抗miR155的这种联合化学基因治疗可通过将KCs的促炎性M1极化为抗炎性M2并抑制HSCs的增殖来实现卓越的治疗效果。重要的是，在肝纤维化早期进行化学基因治疗的疗效和预防复发将比后期治疗更有效。总之，这项工作提出了一种通过对KCs和HSCs进行双重调节来提高肝纤维化疗效和预防复发的新策略，并强调了在肝纤维化治疗中早期治疗的重要性。
