Muro Silvia, Garnacho Carmen, Champion Julie A, Leferovich John, Gajewski Christine, Schuchman Edward H, Mitragotri Samir, Muzykantov Vladimir R
Department of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Mol Ther. 2008 Aug;16(8):1450-8. doi: 10.1038/mt.2008.127. Epub 2008 Jun 17.
Endocytosis in endothelial cells (ECs) is important for many biomedical applications, including drug delivery by nano- and microscale carriers. However, little is known about how carrier geometry influences endothelial drug targeting, intracellular trafficking, and effects. We studied this using prototype polymer carriers of various sizes (0.1-10 mum) and shapes (spheres versus elliptical disks). Carriers were targeted to intercellular adhesion molecule 1 (ICAM-1), a transmembrane glycoprotein that is upregulated in many pathologies and used as a target for intraendothelial drug delivery. ECs internalized anti-ICAM-coated carriers of up to several microns in size via cell adhesion molecule-mediated endocytosis. This pathway is distinct from caveolar and clathrin endocytosis that operate for submicron-size objects. Carrier geometry was found to influence endothelial targeting in the vasculature, and the rate of endocytosis and lysosomal transport within ECs. Disks had longer half-lives in circulation and higher targeting specificity in mice, whereas spheres were endocytosed more rapidly. Micron-size carriers had prolonged residency in prelysosomal compartments, beneficial for endothelial antioxidant protection by delivered catalase. Submicron carriers trafficked to lysosomes more readily, optimizing effects of acid sphingomyelinase (ASM) enzyme replacement in a model of lysosomal storage disease. Therefore, rational design of carrier geometry will help optimize endothelium-targeted therapeutics.
内皮细胞（ECs）中的内吞作用对许多生物医学应用都很重要，包括通过纳米和微米级载体进行药物递送。然而，关于载体几何形状如何影响内皮细胞药物靶向、细胞内运输及效果，我们知之甚少。我们使用了各种尺寸（0.1 - 10微米）和形状（球形与椭圆形盘状）的原型聚合物载体来研究这一问题。载体靶向细胞间黏附分子1（ICAM - 1），这是一种跨膜糖蛋白，在许多病理状态下上调，用作内皮内药物递送的靶点。内皮细胞通过细胞黏附分子介导的内吞作用内化尺寸达数微米的抗ICAM包被载体。该途径不同于作用于亚微米尺寸物体的小窝蛋白介导的内吞作用和网格蛋白介导的内吞作用。发现载体几何形状会影响脉管系统中的内皮靶向性，以及内皮细胞内的内吞速率和溶酶体运输。盘状载体在循环中的半衰期更长，在小鼠中的靶向特异性更高，而球形载体的内吞速度更快。微米尺寸的载体在前溶酶体区室中的停留时间延长，这有利于通过递送过氧化氢酶进行内皮抗氧化保护。亚微米载体更容易运输到溶酶体，在溶酶体贮积病模型中优化酸性鞘磷脂酶（ASM）酶替代的效果。因此，合理设计载体几何形状将有助于优化内皮靶向治疗。
