Avidity and Cell Uptake of Integrin-Targeting Polypeptide Micelles is Strongly Shape-Dependent
Avidity and Cell Uptake of Integrin-Targeting Polypeptide Micelles is Strongly Shape-Dependent
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DOI：
10.1021/acs.nanolett.9b02095
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发表时间：
2019-09-01
期刊：
影响因子：
10.8
通讯作者：
Chilkoti, Ashutosh
中科院分区：
文献类型：
--
作者：
Dzuricky, Michael;Xiong, Sinan;Chilkoti, Ashutosh
我们描述了一种用于靶向传递的基因编码胶束，它包括一个双嵌段多肽，其片段来自受果蝇黑腹果蝇Rec-1 Resilin启发的重复蛋白基序和人原弹性蛋白，以及C端融合的整合素靶向纤维连接蛋白III型结构域。通过系统地改变亲水性弹性蛋白样多肽(ELP)嵌段的质量分数和二嵌段多肽的相对分子质量，我们设计了不同形态的胶束，作为形状的函数来调节人野生型第10纤维连接蛋白结构域(Fn3)的结合亲和力。我们发现，呈现Fn3结构域的蠕虫状胶束对α(vβ3)受体的亲和力是单体配体的1000倍，并且亲和力大于由其多价性驱动的临床相关抗体。这些胶束被放大的亲和力导致细胞内化显著增加，这一特征可能对装载到这些胶束核心的药物在细胞内输送具有实用价值。
We describe a genetically encoded micelle for targeted delivery consisting of a diblock polypeptide with segments derived from repetitive protein motifs inspired by Drosophila melanogaster Rec-1 resilin and human tropoelastin with a C-terminal fusion of an integrin-targeting fibronectin type III domain. By systematically varying the weight fraction of the hydrophilic elastin-like polypeptide (ELP) block and molecular weight of the diblock polypeptide, we designed micelles of different morphologies that modulate the binding avidity of the human wild-type 10th fibronectin domain (Fn3) as a function of shape. We show that wormlike micelles that present the Fn3 domain have a 1000-fold greater avidity for the alpha(v beta 3) receptor compared to the monomer ligand and an avidity that is greater than a clinically relevant antibody that is driven by their multivalency. The amplified avidity of these micelles leads to significantly increased cellular internalization, a feature that may have utility for the intracellular delivery of drugs that are loaded into the core of these micelles.