State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, P. R. China.
Nanjing University Medical School, Nanjing, 210093, China.
Nanoscale. 2022 Jun 23;14(24):8709-8726. doi: 10.1039/d1nr06514a.
Atherosclerosis, the leading cause of death in the elderly worldwide, is typically characterized by elevated reactive oxygen species (ROS) levels and a chronic inflammatory state at the arterial plaques. Herein, pH-sensitive nanoparticles (HR NPs) co-delivering all-trans retinal (ATR), an antioxidant linked to hyaluronic acid (HA) through a pH-sensitive hydrazone bond, and rapamycin (RAP), an anti-atherosclerotic drug loaded into the nanoparticle core, are developed for targeted combination therapy of atherosclerosis. In this way, HR NPs might simultaneously reduce ROS levels ATR antioxidant activity and reduce inflammation the anti-inflammatory effect of RAP. In response to mildly acidic conditions mimicking the lesional inflammation , HR NPs dissociated and both ATR and RAP were effectively released. The developed HR NPs effectively inhibited pro-inflammatory macrophage proliferation, and displayed dose- and time-dependent specific internalization by different cellular models of atherosclerosis. Also, HR NP combination therapy showed an efficient synergetic anti-atherosclerotic effect by effectively inhibiting the inflammatory response and oxidative stress in inflammatory cells. More importantly, HR NPs specifically accumulated in the atherosclerotic plaques of apolipoprotein E-deficient (ApoE) mice, by active interaction with HA receptors overexpressed by different cells of the plaque. The treatment with HR NPs remarkably inhibited the progression of atherosclerosis in ApoE mice which resulted in stable plaques with considerably smaller necrotic cores, lower matrix metalloproteinase-9, and decreased proliferation of macrophages and smooth muscle cells (SMCs). Furthermore, HR NPs attenuated RAP adverse effects and exhibited a good safety profile after long-term treatment in mice. Consequently, the developed pH-sensitive HR NP represent a promising nanoplatform for atherosclerosis combination therapy.
动脉粥样硬化是全球老年人死亡的主要原因，其特征通常是动脉斑块处活性氧（ROS）水平升高和慢性炎症状态。在此，开发了 pH 敏感纳米粒子（HR NPs），用于同时递送全反式视黄醛（ATR）和雷帕霉素（RAP）的靶向联合治疗。ATR 是一种通过 pH 敏感腙键与透明质酸（HA）连接的抗氧化剂，而 RAP 是一种载药纳米粒子核心的抗动脉粥样硬化药物。通过这种方式，HR NPs 可能同时降低 ROS 水平（ATR 的抗氧化活性）和减轻炎症（RAP 的抗炎作用）。针对模拟病变炎症的微酸性条件，HR NPs 解离，ATR 和 RAP 均得到有效释放。所开发的 HR NPs 可有效抑制促炎巨噬细胞增殖，并显示出剂量和时间依赖性的通过不同的动脉粥样硬化细胞模型的特异性内化。此外，HR NP 联合治疗通过有效抑制炎症细胞中的炎症反应和氧化应激，表现出有效的协同抗动脉粥样硬化作用。更重要的是，HR NPs 通过与斑块中过度表达的不同细胞的 HA 受体的主动相互作用，特异性地积聚在载脂蛋白 E 缺陷（ApoE）小鼠的动脉粥样硬化斑块中。用 HR NPs 治疗可显著抑制 ApoE 小鼠动脉粥样硬化的进展，导致斑块稳定，坏死核心明显变小，基质金属蛋白酶-9 降低，巨噬细胞和平滑肌细胞（SMCs）增殖减少。此外，HR NPs 减轻了 RAP 的不良反应，并在小鼠长期治疗后表现出良好的安全性。因此，所开发的 pH 敏感 HR NP 代表了动脉粥样硬化联合治疗的一种有前途的纳米平台。
