Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States.
Institute for Bioscience and Biotechnology Research, University of Maryland, College Park, MD, United States.
Biomaterials. 2017 Dec;147:14-25. doi: 10.1016/j.biomaterials.2017.08.045. Epub 2017 Sep 6.
Nanocarriers (NCs) help improve the performance of therapeutics, but their removal by phagocytes in the liver, spleen, tissues, etc. diminishes this potential. Although NC functionalization with polyethylene glycol (PEG) lowers interaction with phagocytes, it also reduces interactions with tissue cells. Coating NCs with CD47, a protein expressed by body cells to avoid phagocytic removal, offers an alternative. Previous studies showed that coating CD47 on non-targeted NCs reduces phagocytosis, but whether this alters binding and endocytosis of actively-targeted NCs remains unknown. To evaluate this, we used polymer NCs targeted to ICAM-1, a receptor overexpressed in many diseases. Co-coating of CD47 on anti-ICAM NCs reduced macrophage phagocytosis by ∼50% for up to 24 h, while increasing endothelial-cell targeting by ∼87% over control anti-ICAM/IgG NCs. Anti-ICAM/CD47 NCs were endocytosed via the CAM-mediated pathway with efficiency similar (0.99-fold) to anti-ICAM/IgG NCs. Comparable outcomes were observed for NCs targeted to PECAM-1 or transferrin receptor, suggesting broad applicability. When injected in mice, anti-ICAM/CD47 NCs reduced liver and spleen uptake by ∼30-50% and increased lung targeting by ∼2-fold (∼10-fold over IgG NCs). Therefore, co-coating NCs with CD47 and targeting moieties reduces macrophage phagocytosis and improves targeted uptake. This strategy may significantly improve the efficacy of targeted drug NCs.
纳米载体 (NCs) 有助于提高治疗效果，但它们被肝脏、脾脏、组织等中的吞噬细胞清除，从而降低了这种潜力。尽管用聚乙二醇 (PEG) 对 NC 进行功能化可以降低与吞噬细胞的相互作用，但它也会降低与组织细胞的相互作用。用 CD47 对 NC 进行涂层处理，CD47 是一种由身体细胞表达以避免吞噬清除的蛋白质，这提供了一种替代方法。先前的研究表明，在非靶向 NC 上涂层 CD47 可减少吞噬作用，但这是否会改变主动靶向 NC 的结合和内吞作用尚不清楚。为了评估这一点，我们使用了针对细胞间黏附分子-1 (ICAM-1) 的聚合物 NC，ICAM-1 是许多疾病中过度表达的受体。CD47 与抗-ICAM NC 的共涂层将巨噬细胞吞噬作用降低了约 50%，持续 24 小时，同时使内皮细胞靶向性增加了约 87%，与对照的抗-ICAM/IgG NC 相比。抗-ICAM/CD47 NC 通过 CAM 介导的途径进行内吞，效率与抗-ICAM/IgG NC 相似（0.99 倍）。针对 PECAM-1 或转铁蛋白受体的 NC 也观察到类似的结果，表明具有广泛的适用性。当在小鼠中注射时，抗-ICAM/CD47 NC 使肝脏和脾脏摄取减少了约 30-50%，并使肺部靶向增加了约 2 倍（与 IgG NC 相比增加了约 10 倍）。因此，用 CD47 和靶向配体共涂层 NC 可降低巨噬细胞吞噬作用并提高靶向摄取。这种策略可能会显著提高靶向药物 NC 的疗效。
