通过类肽-肽水凝胶中肽的长度来控制纳米片的宽度外文翻译资料

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Cite this: RSC Adv., 2016, 6, 67025

Received 13th June 2016 Accepted 9th July 2016

DOI: 10.1039/c6ra15291k

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Controlling the width of nanosheets by peptide length in peptoid–peptide biohybrid hydrogelsdagger;

Xinrui Ren, Chengbiao Yang, Can Li, Jie Gao, Yang Shi* and Zhimou Yang*

Through changing the peptide length, the width of self-assembled nanosheets can be controlled in peptoid–peptide biohybrid hydrogels.

In the late 1980s, peptoids were exploited as synthetically convenient, peptidomimetic molecules for combinatorial drug discovery and therapeutics.1 The side chains of peptoids connect to the nitrogen of amides while those of peptides link the a-carbons.2 Such structural change in peptoids renders their resistance to degradation by proteases. Due to the chemical similarity to peptides, better stability in biological systems, and bioactivity, peptoids have gained extensive research interests.3 Recent research interest about peptoids has moved to the development of self-assembling peptoids and the study of their functions.4 For example, Zuckermann and co-workers found that peptoids with a special secondary structure of Sigma-stand could self-assemble into nanosheets, which could serve as 2D templates for mineral growth.5 Furthermore, they discovered that peptoids with more than 12 residues could form more stable nanosheets than shorter peptoids.6 Meanwhile, the longer peptoids formed nanosheets with flatter structure and higher thickness. Compared with the strategy to control the thickness of self-assembled nanosheets, one to control the width of nanosheets of peptoids remains a challenge.

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Molecular hydrogels of peptides are promising biomaterials7 for drug delivery,8 cancer cells inhibition,9 regenerative medi- cine,10 and detection of important analytes.11 However, the stability of peptide-based hydrogels in biological system is needed to be improved because peptides are easily degraded by digestion enzymes. We recently reported several molecular hydrogelators of peptoid–peptide conjugates with superior stability against enzyme digestion of proteinase K and good biocompatibility to different cells.12 In the study, we also found that a peptoid–peptide biohybrid of F0F0F0F0GRGD could self- assemble into nanosheets. We opted to test whether we could change the self-assembling behavior and gelation property of F0F0F0F0GRGD by variation of the number of glycine (G) between

State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China. E-mail: yangzm@nankai.edu.cn

dagger; Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra15291k

the peptoid F0F0F0F0 and the peptide RGD. We finally found in this study that the mechanical property of resulting gels and more importantly, the width of self-assembled nanosheets formed by these peptoid–peptide biohybrids (F04GnRGD, n frac14; 0–

3) could be controlled by the variation of the number of G.

Similar to our previous strategy to prepare peptoid–peptide biohybrids and peptides,12,13 we prepared the designed compounds using standard solid phase peptide synthesis and then used reverse phase high performance liquid chromatog- raphy (HPLC) to purify the compounds. After the successful synthesis of our designed compounds, we tested their gelation ability by the invert-tube method. As shown in Fig. 1, through a heating–cooling process, the four compounds we designed could form gels at a concentration of 1.0 wt% in phosphate buffer saline (PBS) buffer solutions (pH frac14; 7.4, G0gel, G1gel,

Fig. 1 Chemical structures of molecular hydrogelators of peptoid– peptide conjugates and optical images of their corresponding gels containing 1.0 wt% of compounds in PBS buffer solutions (pH frac14; 7.4).

G2gel, and G3gel for F04RGD, F04GRGD, F04GGRGD, and F04- GGGRGD, respectively). The minimum gelation concentration of four compounds was similar (around 0.4–0.5 wt%), and the resulting four gels showed similar appearance with slightly opaque property.

Published on 11 July 2016. Downloaded by test 3 on 04/03/2017 12:03:16.

We characterized the self-assembled nanostructures in four gels using transmission electron microscopy (TEM). Fig. 2 showed the results, and the four peptoid–peptide biohybrids self-assembled into nanosheets in hydrogels (1.0 wt%). However, it could be clearly seen that the width of nanosheets was signiftcantly different. We randomly chose 50 fibres in each sample to determine the width of the nanosheets. The average width of nanosheets in G0gel was the largest, which was about 277 T 51 nm. The width of nanosheets in G1gel, G2gel, and G3gel was 251 T 32, 195 T 20, and 162 T 16 nm, respectively. These observations suggested that the width of nanosheets decreased along with the increase of number of G. This is the ftrst example of control over the width of self-assembled nanosheets in peptoid–peptide hydrogels, and it provided a versatile strategy to manipulate the property and probably the function of such nanomaterials.

We then characterized the mechanical properties of the hydrogels by a rheometer. The hot solutions of compounds were transferred to parallel plates in the rheometer, and gels would form after cooling back to room temperature. We per

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通过类肽-肽水凝胶中肽的长度来控制纳米片的宽度

通过改变肽的长度，自组装纳米片的宽度可在类肽–肽混合物水凝胶中受到管理和控制

在20世纪80年代末，肽类化合物被开发成综合方便的肽模拟分子，用于组合药物的发现和治疗。肽类化合物的侧链与和alpha;-碳相连的酰胺的氮相连，这种结构的变化使他们对蛋白酶的降解具有抗性。由于肽的化学相似性、生物系统的稳定性和生物活性，肽类化合物获得了广泛的研究兴趣。近年来，关于肽类化合物的研究已转向自组装类肽的发展及其功能的研究。例如，Zucmann和他的同事发现，具有特殊二级结构的肽类物质可以自组装成纳米片，作为矿物生长的2D模板。此外，他们还发现，含有12种以上残基的肽类化合物比短肽类化合物能形成更稳定的纳米片。同时，较长的肽类物质形成了结构更平整、厚度更厚的纳米片，与控制自组装纳米片厚度的策略相比，控制肽类纳米片的宽度仍然是一个挑战。

多肽分子水凝胶是一种很有前途的生物材料，可用于药物释放、种肿瘤细胞抑制、种再生介质-电影、种重要分析物质的检测。然而，肽基水凝胶在生物系统中的稳定性还有待提高，因为多肽容易被消化酶降解。我们最近报道了几种肽-肽结合物的分子凝胶，它们对蛋白酶K的酶解具有良好的稳定性，并且对双ff传入神经细胞具有良好的生物相容性。在本研究中，我们还发现F0F0F0F0GRGD的肽肽生物杂化物可以自组装成纳米片。我们选择通过肽F0F0F0F0和肽RGD之间甘氨酸(G)数量的变化来改变F0F0F0F0GRGD的自组装行为和凝胶特性。 在本研究中，我们最终发现了所得凝胶的力学性能，更重要的是，由这些肽类肽生物杂化物(f04gnrgd，n0-1/4-)形成的自组装纳米片的宽度可以通过G数的变化来控制。

类似于我们以前制备肽肽生物杂种和肽的策略，我们采用标准固相肽合成法制备了所设计的化合物，并用反相高效液相色谱(Hplc)对其进行了纯化。在成功合成了我们设计的化合物后，我们用倒置管法测试了它们的凝胶化能力。如图1所示，通过加热-冷却过程，我们设计的四种化合物可以在磷酸盐缓冲盐水( PBS )缓冲溶液中形成浓度为1.0 wt %的凝胶(分别用于F04RGD、F04GRGD、F04GGRGDd和F04 - GGGRGD的pH 7.4、G0gel、G1gel、G2gel和gggel )。四种化合物的最小凝胶浓度相似(约0.4 - 0.5 wt % )，得到的四种凝胶表现出相似的外观，具有略微不透明的性质。

图1类肽-肽缀合物分子水凝胶的化学结构及其相应凝胶的光学图像，所述凝胶在PBS水溶液( pH 7.4 )中含有1.0 wt %的化合物。

利用透射电子显微镜( TEM )对四种凝胶中的自组装纳米结构进行了表征。图2显示了结果，四种类肽-肽生物杂化物在水凝胶( 1.0 wt % )中自组装成纳米片。然而，可以清楚地看出，纳米片的宽度显著不同。我们在每个样品中随机选择50根纤维来确定纳米片的宽度。G0gel中纳米片的平均宽度最大，约为277～51 nm。G1gel、G2gel和G3gel纳米片的宽度分别为251 T 32nm、195 T 20nm和162 T 16 nm。这些观察结果表明，纳米片的宽度随着g的增加而减小。这是控制类肽水凝胶中自组装纳米片宽度的第一个例子，它提供了一种操纵这种纳米材料的性质和可能的功能的通用策略。

图2是( A ) G0gel、( B ) G1gel、( C ) G2gel和( D ) G3gel的透射电子显微镜( TEM )图像。

然后用流变仪对水凝胶的力学性能进行了表征。化合物的热溶液在流变仪中被转移到平行板，冷却至室温后形成凝胶。当凝胶在室温( 20～25℃)稳定时，我们成功地进行了动态应变扫描和动态频率扫描。如图3所示，在0.1–100 rad s - 1的频率范围内，凝胶表现出弱的频率依赖性，表明水凝胶具有高弹性。凝胶的损耗模量( G00 )至少比储能模量( G0 )低一个数量级，表明凝胶形成了真正的凝胶。例如，G0值在1g凝胶、G1gel、G2gel和G3gel的1 rad s - 1频率下分别为约1000、300、100和20pa。结合TEM观察结果表明，较大宽度的纳米片可以形成机械强度较高的水凝胶。

图3在1.0 wt % (三角形: G0gel，正方形: G1gel，菱形: G2gel，左三角形: G3gel，填充符号: G0和开放符号: G00 )的4种水凝胶的1 %应变下的动态频率扫描。

由于凝胶中的纳米结构和凝胶的机械性能是不同的，因此我们随后测试药物的释放深度是否与这些凝胶不同。以阿霉素为药物，在37℃温度下观察其从凝胶中的释放行为。在PBS溶液中，通过加热-冷却工艺形成含有相同量阿霉素( 0.05 wt % )的类肽-肽生物杂化水凝胶。在凝胶顶部加入250 mL PBS (含0.5 % ( v / v )吐温20 )，在每个设计时间点取出200 mL上溶液进行测定。同时，将200 mL新鲜PBS加回凝胶中。我们测定了阿霉素在490 nm波长处的吸光度，以确定阿霉素从凝胶中释放的累积量。如图4所示，阿霉素在12小时时间内逐渐从四种凝胶中释放。然而，释放速度与这些凝胶略有不同。结果表明，机械强度较大的凝胶对阿霉素的释放较慢，12h内G0gel、G1gel、G2gel和G3gel对阿霉素的释放率分别为35.0 %、38.0 %、42.5 %和47.5 %。我们以前的研究表明，类肽生物杂化物比肽具有更好的酶消化稳定性。我们在本研究中获得了类似的观察结果，当用蛋白酶K处理时，f0f0f f0rgd比fffrgd稳定得多。凝胶的可控释药行为和类肽-肽生物杂化物的较好稳定性预示着该凝胶有望实现药物的缓释。总之，本研究表明，通过简单地改变肽段长度，可以控制自组装纳米片的宽度和水凝胶的力学性能。本研究报道的水凝胶具有良好的稳定性和可控的力学性能，有望用于药物的控释。本研究为控制类肽-多肽自组装生物杂化材料的性能提供了一种通用的方法，有助于构建基于类肽的功能生物材料。

图4分别从G0gel、G1gel、G2gel和G3gel释放阿霉素。

声明

本研究得到了天津市微软技术俱乐部( 15JCZDJC38100 )和长江学者与高校创新研究团队项目( irt130 30 )的支持。

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