Department of Cardiology, The First Affiliated Hospital, Cardiovascular Institute, Harbin Medical University, Harbin 150001, P. R. China.
Department of Ultrasound, Chongqing Key Laboratory of Ultrasound Molecular Imaging, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P. R. China.
Biomater Sci. 2021 Aug 21;9(16):5652-5664. doi: 10.1039/d1bm00343g. Epub 2021 Jul 13.
Pathological angiogenesis is a critical contributor to atherosclerotic plaque rupture. However, there are few effective theranostic strategies to stabilize plaques by suppressing neovascularization. In this study, we fabricated a polymeric nanosystem using 3 nm manganese ferrite (MnFeO) and perfluorohexane (PFH) stabilized by polylactic acid-glycolic acid (PLGA) shells and conjugated to the surface of an anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody [ramucirumab (Ram)]. The PFH@PLGA/MnFeO-Ram nanoparticles (NPs) were used as atherosclerotic plaque angiogenesis theranostics for multimodal imaging-guided photothermal therapy (PTT). Three-nanometer MnFeO is an excellent magnetic resonance imaging T1 and photoacoustic imaging contrast agent. Upon exposure to near-infrared (NIR) light, MnFeO in the NPs could transform NIR light into thermal energy for the photothermal elimination of plaque angiogenesis. Additionally, optical droplet vaporization of PFH in the NPs triggered by the thermal effect to form gas bubbles enhanced ultrasound imaging. Our in vitro experiments revealed that PFH@PLGA/MnFeO-Ram NPs actively accumulated in rabbit aortic endothelial cells, and NP-mediated PTT promoted endothelial cell apoptosis while inhibiting their proliferation, migration, and tubulogenesis. Notably, the PFH@PLGA/MnFeO-Ram NPs possessed excellent photostability and biocompatibility. In the rabbit advanced atherosclerotic plaque model, PFH@PLGA/MnFeO-Ram NP-guided PTT significantly induced apoptosis of neovascular endothelial cells and improved the hypoxia status in the plaque 3 days after treatment. On day 28, PTT significantly reduced the density of neovessels and subsequently stabilized rabbit plaques by inhibiting plaque hemorrhage and macrophage infiltration. Collectively, these results suggest that PFH@PLGA/MnFeO-Ram NP-guided PTT is a safe and effective theranostic strategy for inhibiting atherosclerotic plaque angiogenesis.
病理性血管生成是动脉粥样硬化斑块破裂的关键因素。然而，目前很少有有效的治疗策略可以通过抑制新生血管化来稳定斑块。在这项研究中，我们使用 3nm 锰铁氧体（MnFeO）和全氟己烷（PFH）制备了一种聚合物纳米系统，该系统由聚乳酸-羟基乙酸（PLGA）壳稳定，并与血管内皮生长因子受体 2（VEGFR2）抗体[雷莫芦单抗（Ram）]表面连接。PFH@PLGA/MnFeO-Ram 纳米颗粒（NPs）被用作动脉粥样硬化斑块血管生成治疗学的多模式成像引导光热治疗（PTT）。3nm 的 MnFeO 是一种极好的磁共振成像 T1 和光声成像造影剂。在近红外（NIR）光照射下，纳米颗粒中的 MnFeO 可以将 NIR 光转化为热能，用于光热消除斑块血管生成。此外，纳米颗粒中 PFH 的热效应引发的液滴蒸发形成气泡增强了超声成像。我们的体外实验表明，PFH@PLGA/MnFeO-Ram NPs 可以主动积聚在兔主动脉内皮细胞中，并且 NP 介导的 PTT 促进内皮细胞凋亡，同时抑制其增殖、迁移和管状形成。值得注意的是，PFH@PLGA/MnFeO-Ram NPs 具有优异的光稳定性和生物相容性。在兔晚期动脉粥样硬化斑块模型中，PFH@PLGA/MnFeO-Ram NP 引导的 PTT 显著诱导新生血管内皮细胞凋亡，并在治疗后 3 天改善斑块的缺氧状态。在第 28 天，PTT 显著减少了新生血管的密度，并通过抑制斑块出血和巨噬细胞浸润来稳定兔斑块。综上所述，这些结果表明，PFH@PLGA/MnFeO-Ram NP 引导的 PTT 是一种安全有效的抑制动脉粥样硬化斑块血管生成的治疗学策略。
