Wang Anqi, Yue Kai, Zhong Weishen, Zhang Genpei, Zhang Xinxin, Wang Lei
School of Energy and Environmental Engineering, University of Science and Technology Beijing, Beijing 100083, China.
School of Energy and Environmental Engineering, University of Science and Technology Beijing, Beijing 100083, China.
J Control Release. 2024 Dec;376:753-765. doi: 10.1016/j.jconrel.2024.10.051. Epub 2024 Oct 31.
There is increasing evidence supporting the unique benefits of targeted therapy in treating atherosclerotic disease. Given the complex nature of atherosclerosis development, we proposed a novel strategy for the efficient delivery of rapamycin (RAPA) by targeting both the exposed subendothelial collagen and oxidized low-density lipoprotein (oxLDL) present in plaques. In response, we developed multifunctional peptide (MP) nanoparticles for targeted drug delivery. The ability of MP nanoparticles to load RAPA and target collagen/oxLDL was investigated through molecular dynamics simulations and in vitro experiments. The efficacy of MP nanoparticles in atherosclerosis treatment was assessed via in vivo experiments on ApoE mice. Results indicate that MP nanoparticles have encapsulation and drug loading efficiencies for RAPA of 78.3 % and 43.9 %, respectively. By targeting collagen, MP nanoparticles create steric hindrance that inhibits 77.2 % of platelet adhesion. These nanoparticles can also target oxLDL, delivering RAPA into plaques and significantly reducing macrophage uptake of oxLDL. In vivo experiments showed that MP nanoparticles effectively targeted and accumulated in plaques. Treating mice with MP@RAPA nanoparticles for 10 weeks led to an 81.3 % reduction in the aortic vascular plaque area and decreased concentrations of MCP-1, hs-CRP, MMP-1, P-selectin, IL-1β, and IL-8 inflammatory factors, as well as the optical density of platelet-associated proteins (CD42, CD61, and PECAM-1). These results highlight the promising potential of MP nanoparticles for atherosclerotic disease treatment.
越来越多的证据支持靶向治疗在治疗动脉粥样硬化疾病方面的独特益处。鉴于动脉粥样硬化发展的复杂性，我们提出了一种新策略，即通过靶向斑块中暴露的内皮下胶原蛋白和氧化型低密度脂蛋白（oxLDL）来高效递送雷帕霉素（RAPA）。为此，我们开发了用于靶向药物递送的多功能肽（MP）纳米颗粒。通过分子动力学模拟和体外实验研究了MP纳米颗粒负载RAPA以及靶向胶原蛋白/oxLDL的能力。通过对载脂蛋白E（ApoE）小鼠进行体内实验评估了MP纳米颗粒在动脉粥样硬化治疗中的疗效。结果表明，MP纳米颗粒对RAPA的包封率和载药率分别为78.3%和43.9%。通过靶向胶原蛋白，MP纳米颗粒产生空间位阻，抑制77.2%的血小板黏附。这些纳米颗粒还可以靶向oxLDL，将RAPA递送至斑块中，并显著减少巨噬细胞对oxLDL的摄取。体内实验表明，MP纳米颗粒有效地靶向并积聚在斑块中。用MP@RAPA纳米颗粒治疗小鼠10周后，主动脉血管斑块面积减少了81.3%，单核细胞趋化蛋白-1（MCP-1）、超敏C反应蛋白（hs-CRP）、基质金属蛋白酶-1（MMP-1）、P选择素、白细胞介素-1β（IL-1β）和白细胞介素-8（IL-8）等炎症因子的浓度以及血小板相关蛋白（CD42、CD61和血小板内皮细胞黏附分子-1（PECAM-1））的光密度均降低。这些结果突出了MP纳米颗粒在动脉粥样硬化疾病治疗方面的潜在应用前景。
