Vascular targeting of nanocarriers: perplexing aspects of the seemingly straightforward paradigm.
Vascular targeting of nanocarriers: perplexing aspects of the seemingly straightforward paradigm.
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DOI：
10.1021/nn500136z
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发表时间：
2014-05-27
期刊：
影响因子：
17.1
通讯作者：
Muzykantov, Vladimir
中科院分区：
文献类型：
--
作者：
Howard, Melissa;Zern, Blaine J.;Anselmo, Aaron C.;Shuvaev, Vladimir V.;Mitragotri, Samir;Muzykantov, Vladimir
关键词：
靶向纳米药物有望在许多医疗领域找到临床用途。排列在血管管腔表面的内皮细胞是治疗炎症、缺血、血栓形成、中风和其他神经、心血管、肺和肿瘤疾病的关键靶点。在其他情况下，内皮细胞是组织渗透的障碍或不良影响的受害者。一些内皮细胞表面标志物，包括多肽酶(如ACE、APP和APN)和黏附分子(如ICAM-1和PECAM)已被确定为关键靶点。纳米载体与这些分子的结合使药物能够靶向并随后穿透血管内皮细胞，提供非靶向载体无法达到的治疗效果。我们分析了内皮纳米药物的不同方面，包括(I)具有不同几何结构的载体的循环和靶向，(Ii)载体与内皮的多价相互作用，(Iii)锚定在多个决定因素上，(Iv)结合部位的可及性和细胞对其参与的反应，(V)细胞表型和微环境在靶向中的作用，(Vi)通过降低载体亲和力来优化靶向，(Vii)通过与其配体内化无关的分子来调节多价载体的内吞作用，以及(Viii)通过选择靶决定簇上的特定表位、载体几何形状和流体动力学因素来调节细胞的摄取和运输。这些方面的改进和对血管生物学和病理学的理解的提高可能使血管内皮细胞靶向纳米载体的临床翻译成为可能。
Targeted nanomedicine holds promise to find clinical use in many medical areas. Endothelial cells that line the luminal surface of blood vessels represent a key target for treatment of inflammation, ischemia, thrombosis, stroke, and other neurological, cardiovascular, pulmonary, and oncological conditions. In other cases, the endothelium is a barrier for tissue penetration or a victim of adverse effects. Several endothelial surface markers including peptidases (e.g., ACE, APP, and APN) and adhesion molecules (e.g., ICAM-1 and PECAM) have been identified as key targets. Binding of nanocarriers to these molecules enables drug targeting and subsequent penetration into or across the endothelium, offering therapeutic effects that are unattainable by their nontargeted counterparts. We analyze diverse aspects of endothelial nanomedicine including (i) circulation and targeting of carriers with diverse geometries, (ii) multivalent interactions of carrier with endothelium, (iii) anchoring to multiple determinants, (iv) accessibility of binding sites and cellular response to their engagement, (v) role of cell phenotype and microenvironment in targeting, (vi) optimization of targeting by lowering carrier avidity, (vii) endocytosis of multivalent carriers via molecules not implicated in internalization of their ligands, and (viii) modulation of cellular uptake and trafficking by selection of specific epitopes on the target determinant, carrier geometry, and hydrodynamic factors. Refinement of these aspects and improving our understanding of vascular biology and pathology is likely to enable the clinical translation of vascular endothelial targeting of nanocarriers.
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影响因子：
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