Abstract:
Nanoparticle-based drug delivery systems (DDS) have shown promising results in reversing hepatic fibrosis, a common pathological basis of chronic liver diseases (CLDs), in preclinical animal models. However, none of these nanoparticle formulations has transitioned to clinical usage and there are currently no FDA-approved drugs available for liver fibrosis. This highlights the need for a better understanding of the challenges faced by nanoparticles in this complex disease setting. Here, we have systematically studied the impact of targeting strategy, the degree of macrophage infiltration during fibrosis, and the severity of fibrosis, on the liver uptake and intrahepatic distribution of nanocarriers. When tested in mice with advanced liver fibrosis, we demonstrated that the targeting ligand density plays a significant role in determining the uptake and retention of the nanoparticles in the fibrotic liver whilst the type of targeting ligand modulates the trafficking of these nanoparticles into the cell population of interest - activated hepatic stellate cells (aHSCs). Engineering the targeting strategy indeed reduced the uptake of nanoparticles in typical mononuclear phagocyte (MPS) cell populations, but not the infiltrated macrophages. Meanwhile, additional functionalization may be required to enhance the efficacy of DDS in end-stage fibrosis/cirrhosis compared to early stages.
摘要:
基于纳米颗粒的药物递送系统(DDS)已显示出逆转肝纤维化的有希望的结果,慢性肝病(CLDs)的共同病理基础,在临床前动物模型中。然而,这些纳米颗粒制剂没有过渡到临床使用,目前没有FDA批准的药物可用于肝纤维化。这凸显了需要更好地了解纳米粒子在这种复杂疾病环境中面临的挑战。这里,我们系统地研究了目标战略的影响,纤维化过程中巨噬细胞浸润的程度,以及纤维化的严重程度,纳米载体的肝脏摄取和肝内分布。当在患有晚期肝纤维化的小鼠中进行测试时,我们证明,靶向配体密度在决定纳米颗粒在纤维化肝脏中的摄取和保留中起着重要作用,而靶向配体的类型调节了这些纳米颗粒向感兴趣的细胞群-激活的肝星状细胞(aHSC)的运输。工程化靶向策略确实减少了典型的单核吞噬细胞(MPS)细胞群体中纳米颗粒的摄取,但不是浸润的巨噬细胞.同时,与早期相比,可能需要额外的功能化以增强DDS在终末期纤维化/肝硬化中的功效。