Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China; Institute of Materia Medica, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
Biomaterials. 2017 Oct;143:93-108. doi: 10.1016/j.biomaterials.2017.07.035. Epub 2017 Jul 29.
Atherosclerosis is the leading cause of many fatal cardiovascular and cerebrovascular diseases. Whereas nanomedicines are promising for targeted therapy of atherosclerosis, great challenges remain in development of effective, safe, and translational nanotherapies for its treatment. Herein we hypothesize that non-proinflammatory nanomaterials sensitive to low pH or high reactive oxygen species (ROS) may serve as effective platforms for triggerable delivery of anti-atherosclerotic therapeutics in cellular and tissue microenvironments of inflammation. To demonstrate this hypothesis, an acid-labile material of acetalated β-cyclodextrin (β-CD) (Ac-bCD) and a ROS-sensitive β-CD material (Ox-bCD) were separately synthesized by chemical modification of β-CD, which were formed into responsive nanoparticles (NPs). Ac-bCD NP was rapidly hydrolyzed in mildly acidic buffers, while hydrolysis of Ox-bCD NP was selectively accelerated by HO. Using an anti-atherosclerotic drug rapamycin (RAP), we found stimuli-responsive release of therapeutic molecules from Ac-bCD and Ox-bCD nanotherapies. Compared with non-responsive poly(lactide-co-glycolide) (PLGA)-based NP, Ac-bCD and Ox-bCD NPs showed negligible inflammatory responses in vitro and in vivo. By endocytosis in cells and intracellularly releasing cargo molecules in macrophages, responsive nanotherapies effectively inhibited macrophage proliferation and suppressed foam cell formation. After intraperitoneal (i.p.) delivery in apolipoprotein E-deficient (ApoE) mice, fluorescence imaging showed accumulation of NPs in atherosclerotic plaques. Flow cytometry analysis indicated that the lymphatic translocation mediated by neutrophils and monocytes/macrophages may contribute to atherosclerosis targeting of i.p. administered NPs, in addition to targeting via the leaky blood vessels. Correspondingly, i.p. treatment with different nanotherapies afforded desirable efficacies. Particularly, both pH and ROS-responsive nanomedicines more remarkably delayed progression of atherosclerosis and significantly enhanced stability of atheromatous lesions, in comparison to non-responsive PLGA nanotherapy. Furthermore, responsive nanovehicles displayed good safety performance after long-term administration in mice. Consequently, for the first time our findings demonstrated the therapeutic advantages of nanomedicines responsive to mildly acidic or abnormally high ROS microenvironments for the treatment of atherosclerosis.
动脉粥样硬化是许多致命心血管和脑血管疾病的主要原因。尽管纳米医学在动脉粥样硬化的靶向治疗方面具有广阔的前景，但在开发有效、安全且可转化的纳米疗法方面仍存在巨大挑战。在此，我们假设对低 pH 值或高活性氧（ROS）敏感的非促炎纳米材料可作为在炎症细胞和组织微环境中触发递呈抗动脉粥样硬化治疗药物的有效平台。为了验证这一假设，我们通过β-环糊精（β-CD）的化学修饰分别合成了一种酸敏感的缩醛化β-环糊精（Ac-bCD）和一种 ROS 敏感的β-CD 材料（Ox-bCD），并将其制成响应性纳米颗粒（NPs）。Ac-bCD NP 在温和的酸性缓冲液中迅速水解，而 Ox-bCD NP 的水解则被 HO 选择性加速。使用一种抗动脉粥样硬化药物雷帕霉素（RAP），我们发现 Ac-bCD 和 Ox-bCD 纳米疗法中的治疗分子具有刺激响应性释放。与非响应性聚乳酸-羟基乙酸共聚物（PLGA）基 NP 相比，Ac-bCD 和 Ox-bCD NPs 在体外和体内均表现出可忽略的炎症反应。通过细胞内吞作用和在巨噬细胞中细胞内释放货物分子，响应性纳米疗法有效抑制了巨噬细胞的增殖并抑制了泡沫细胞的形成。在载脂蛋白 E 缺陷（ApoE）小鼠经腹腔（i.p.）给药后，荧光成像显示 NPs 在动脉粥样硬化斑块中积累。流式细胞术分析表明，除了通过渗漏血管靶向外，中性粒细胞和单核细胞/巨噬细胞介导的淋巴转移可能有助于 i.p. 给予的 NPs 对动脉粥样硬化的靶向。相应地，不同纳米疗法的 i.p. 治疗均显示出良好的疗效。特别地，与非响应性 PLGA 纳米疗法相比，pH 和 ROS 双重响应纳米药物更显著地延缓了动脉粥样硬化的进展，并显著增强了粥样硬化病变的稳定性。此外，在小鼠体内长期给药后，响应性纳米载体表现出良好的安全性。因此，我们的研究结果首次证明了对微酸性或异常高 ROS 微环境有响应的纳米药物在治疗动脉粥样硬化方面的治疗优势。
