Liu Xinlin, Mu Xiaoyang, Wang Ying, Liu Zhu, Li Yian, Lan Jiaru, Feng Shuaipeng, Wang Siling, Zhao Qinfu
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning Province 110016, PR China.
School of Libra Arts of Shenyang Pharmaceutical University, Shenyang, Liaoning Province 110016, PR China.
J Colloid Interface Sci. 2025 Apr 15;684(Pt 1):586-599. doi: 10.1016/j.jcis.2025.01.081. Epub 2025 Jan 10.
Liver fibrosis is a common pathological stage in the development of several chronic liver diseases, and early intervention can effectively reverse the developing process. Excessive reactive oxygen species (ROS) can promote the activation of hepatic stellate cells (HSCs), but existing treatments have not addressed this problem. In this study, different metal-based mesoporous polydopamine (MPDA) was prepared by the soft template method, and their free radical scavenging abilities, as well as the efficacy and safety of the carriers were investigated, so as to select Cu-coordinated MPDA (CMP) as the optimal nanocarrier. CMP exhibited superior SOD- and CAT-like activities compared to MPDA. Subsequently, a novel liver-targeted nanodrug delivery system (Cur/CMPH) with biosafety was constructed. Moreover, Cur/CMPH consisted of CMP loaded with the antifibrotic drug curcumin (Cur/CMP) and coated hyaluronic acid (HA) with liver-targeting properties on the surface of Cur/CMP, thus effectively intervening in the progression of liver fibrosis. Cur/CMPH possessed uniform particle size, negative Zeta potential, excellent antioxidant capacity, and pH-responsive drug release. Furthermore, Cur/CMPH in vitro studies demonstrated efficient cellular uptake, inhibition of the proliferation of HSCs, and excellent intracellular ROS scavenging without cytotoxicity. Besides, Cur/CMPH had specific targeting effect on fibrotic liver as well as good accumulation ability. In vivo studies, Cur/CMPH showcased the combined therapeutic effect of Cur and CMP, which significantly decreased the deposition of collagen fibers and alleviated the degree of liver fibrosis with good biosafety. In summary, the construction of Cur/CMPH opens up a novel idea in the field of nanodrug delivery systems for the treatment of liver fibrosis.
肝纤维化是几种慢性肝病发展过程中常见的病理阶段，早期干预可有效逆转其发展进程。过量的活性氧（ROS）可促进肝星状细胞（HSCs）的活化，但现有治疗方法尚未解决这一问题。本研究通过软模板法制备了不同的金属基介孔聚多巴胺（MPDA），并研究了它们的自由基清除能力以及载体的有效性和安全性，从而选择铜配位的MPDA（CMP）作为最佳纳米载体。与MPDA相比，CMP表现出优异的超氧化物歧化酶（SOD）样和过氧化氢酶（CAT）样活性。随后，构建了一种具有生物安全性的新型肝靶向纳米药物递送系统（Cur/CMPH）。此外，Cur/CMPH由负载抗纤维化药物姜黄素（Cur/CMP）的CMP和在Cur/CMP表面包覆具有肝靶向特性的透明质酸（HA）组成，从而有效干预肝纤维化的进程。Cur/CMPH具有均匀的粒径、负的zeta电位、优异的抗氧化能力和pH响应性药物释放特性。此外，Cur/CMPH的体外研究表明其具有高效的细胞摄取能力、抑制肝星状细胞增殖的能力以及优异的细胞内ROS清除能力且无细胞毒性。此外，Cur/CMPH对纤维化肝脏具有特异性靶向作用以及良好的蓄积能力。在体内研究中，Cur/CMPH展现出Cur和CMP的联合治疗效果，显著减少胶原纤维沉积并减轻肝纤维化程度，且具有良好的生物安全性。综上所述，Cur/CMPH的构建为肝纤维化治疗的纳米药物递送系统领域开辟了新思路。
