Biological functionalization of drug delivery carriers to bypass size restrictions of receptor-mediated endocytosis independently from receptor targeting.
Biological functionalization of drug delivery carriers to bypass size restrictions of receptor-mediated endocytosis independently from receptor targeting.
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DOI：
10.1021/nn404719c
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发表时间：
2013-12-23
期刊：
影响因子：
17.1
通讯作者：
Muro, Silvia
中科院分区：
文献类型：
--
作者：
Ansar, Maria;Serrano, Daniel;Papademetriou, Iason;Bhowmick, Tridib Kumar;Muro, Silvia
关键词：
药物载体靶向参与内吞作用的细胞表面受体是细胞内药物传递的常用方法。然而，大多数内吞受体通过与≤200 nm囊泡相关的网状蛋白或空泡途径来介导摄取，这限制了载体的设计。我们最近发现，细胞间黏附分子-1(ICAM-1)介导的内吞作用不同于笼蛋白和空泡介导的途径，它允许纳米和微载体在细胞培养和体内摄取，这是因为细胞鞘磷脂酶被募集到质膜上。这导致在载体结合部位产生神经酰胺并形成肌动蛋白应力纤维，从而能够吞噬和吸收各种大小的载体。在这里，我们采用了这一范例，以增强药物载体对与大小受限的通路相关的受体的摄取。我们将鞘磷脂酶包被到针对笼蛋白相关甘露糖-6-磷酸受体的模型(聚苯乙烯)亚微米和微载体上。在内皮细胞中，这提供了神经酰胺在细胞表面的浓缩和肌动蛋白应激纤维的形成，改变了摄取途径，增强了载体的内吞作用，而不影响靶向、内体运输、细胞相关降解或细胞活力。这种改善依赖于载体大小和酶剂量，其他受体(转铁蛋白受体)和细胞类型(上皮细胞)也观察到类似的结果。这一现象也增加了载体静脉注射后在小鼠体内的组织蓄积。因此，通过用模仿ICAM-1途径的生物元件对药物载体进行功能化，可以在绕过其相关内吞途径的自然大小限制的同时，保持对选定受体的靶向。这一战略在提高靶向给药系统设计的灵活性方面具有相当大的前景。
Targeting of drug carriers to cell-surface receptors involved in endocytosis is commonly used for intracellular drug delivery. However, most endocytic receptors mediate uptake via clathrin or caveolar pathways associated with ≤200-nm vesicles, restricting carrier design. We recently showed that endocytosis mediated by intercellular adhesion molecule 1 (ICAM-1), which differs from clathrin- and caveolar-mediated pathways, allows uptake of nano- and micro-carriers in cell culture and in vivo due to recruitment of cellular sphingomyelinases to the plasmalemma. This leads to ceramide generation at carrier binding sites and formation of actin stress-fibers, enabling engulfment and uptake of a wide size-range of carriers. Here we adapted this paradigm to enhance uptake of drug carriers targeted to receptors associated with size-restricted pathways. We coated sphingomyelinase onto model (polystyrene) submicro- and micro-carriers targeted to clathrin-associated mannose-6-phosphate receptor. In endothelial cells, this provided ceramide enrichment at the cell surface and actin stress-fiber formation, modifying the uptake pathway and enhancing carrier endocytosis without affecting targeting, endosomal transport, cell-associated degradation, or cell viability. This improvement depended on the carrier size and enzyme dose, and similar results were observed for other receptors (transferrin receptor) and cell types (epithelial cells). This phenomenon also enhanced tissue accumulation of carriers after intravenous injection in mice. Hence, it is possible to maintain targeting toward a selected receptor while bypassing natural size-restrictions of its associated endocytic route by functionalization of drug carriers with biological elements mimicking the ICAM-1 pathway. This strategy holds considerable promise to enhance flexibility of design of targeted drug delivery systems.
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DOI：
10.1083/jcb.200112126
发表时间：
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期刊：
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影响因子：
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作者：
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