温度触发多肽自组装成多价球形胶束。

Temperature triggered self-assembly of polypeptides into multivalent spherical micelles.

作者信息

Dreher Matthew R, Simnick Andrew J, Fischer Karl, Smith Richard J, Patel Anand, Schmidt Manfred, Chilkoti Ashutosh

机构信息

Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA.

出版信息

J Am Chem Soc. 2008 Jan 16;130(2):687-94. doi: 10.1021/ja0764862. Epub 2007 Dec 18.

Abstract

We report herein thermally responsive elastin-like polypeptides (ELPs) in a linear AB diblock architecture with an N-terminal peptide ligand that self-assemble into spherical micelles when heated slightly above body temperature. A series of 10 ELP block copolymers (ELP(BC)'s ) with different molecular weights and hydrophilic-to-hydrophobic block ratios were genetically synthesized by recursive directional ligation. The self-assembly of these polymers from unimers into micelles was investigated by light scattering, fluorescence spectroscopy, and cryo-TEM. These ELP(BC)'s undergo two phase transitions as a function of solution temperature: a unimer-to-spherical micelle transition at an intermediate temperature and a micelle-to-bulk aggregate transition at a higher temperature when the hydrophilic-to-hydrophobic block ratio is between 1:2 and 2:1. The critical micelle temperature is controlled by the length of the hydrophobic block, and the size of the micelle is controlled by both the total ELP(BC) length and hydrophilic-to-hydrophobic block ratio. These polypeptide micelles display a critical micelle concentration in the range 4-8 microM demonstrating the high stability of these structures. These studies have also identified a subset of ELP(BC)'s bearing terminal peptide ligands that are capable of forming multivalent spherical micelles that present multiple copies of the ligand on their corona in the clinically relevant temperature range 37-42 degrees C and target cancer cells. These ELP(BC)'s may be useful for drug targeting by thermally triggered multivalency. More broadly, the design rules uncovered by this study should be applicable to the design of other thermally reversible nanoparticles for diverse applications in medicine and biology.

摘要

我们在此报告一种具有线性AB二嵌段结构的热响应性类弹性蛋白多肽(ELP),其N端带有肽配体,当加热至略高于体温时会自组装成球形胶束。通过递归定向连接法基因合成了一系列10种不同分子量和亲水 - 疏水嵌段比的ELP嵌段共聚物(ELP(BC))。利用光散射、荧光光谱和冷冻透射电子显微镜研究了这些聚合物从单体自组装成胶束的过程。当亲水 - 疏水嵌段比在1:2至2:1之间时,这些ELP(BC)随溶液温度经历两个相变:在中间温度下从单体转变为球形胶束,在较高温度下从胶束转变为块状聚集体。临界胶束温度由疏水嵌段的长度控制,胶束大小由ELP(BC)的总长度和亲水 - 疏水嵌段比共同控制。这些多肽胶束的临界胶束浓度在4 - 8 microM范围内,表明这些结构具有高稳定性。这些研究还鉴定出了一部分带有末端肽配体的ELP(BC),它们能够形成多价球形胶束,在37 - 42摄氏度这一临床相关温度范围内,其表面呈现多个配体拷贝,可靶向癌细胞。这些ELP(BC)可能有助于通过热触发的多价性进行药物靶向。更广泛地说,本研究揭示的设计规则应适用于设计其他用于医学和生物学中各种应用的热可逆纳米颗粒。

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