基于非对映脱氢三肽混合物的新型超分子水凝胶的潜在药物输送应用。

IF 5 3区 化学 Q1 POLYMER SCIENCE
Gels Pub Date : 2024-09-30 DOI:10.3390/gels10100629
Carlos B P Oliveira, André Carvalho, Renato B Pereira, David M Pereira, Loic Hilliou, Peter J Jervis, José A Martins, Paula M T Ferreira
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引用次数: 0

摘要

肽构件的自组装为自下而上制备精致的纳米结构、纳米架构和纳米结构块体材料(即水凝胶)提供了独特的机会。在这项研究中,我们介绍了新型脱氢三肽 Cbz-L-Lys(Cbz)-L,D-Asp-∆Phe-OH 和 (2-Naph)-L-Lys(2-Naph)-L,D-Asp-∆Phe-OH 的合成、表征、凝胶化和流变特性、这些脱氢三肽含有一个 N 端赖氨酸残基(Nα,ε-双帽羧基苄基(Cbz)和 2-萘基乙酰基(2-Naph)芳香分子)、一个天冬氨酸残基(Asp)和一个 C 端脱水苯丙氨酸残基(∆Phe)。脱氢三肽是以非对映混合物(L,L,Z 和 L,D,Z)的形式获得的,可能是通过天冬酰亚胺化学反应获得的。脱氢三肽在浓度极低(0.1 和 0.04 wt%)时就能形成水凝胶。这些水凝胶具有优异的弹性(G' = 5.44 × 104 Pa 和 3.43 × 106 Pa)和自愈特性。STEM 研究表明,Cbz-封端肽的非对映异构体发生了共组装,生成了纤维状三维网络,而 2-Naph 封端脱水肽的非对映异构体似乎发生了自分选,生成了具有嵌入式球形纳米结构的纤维网络。2-Naph封端的水凝胶在受到机械刺激破裂后可完全快速恢复。通过 STEM 可以看到,恢复后的水凝胶中没有球状纳米结构,这表明机械刺激引发了球状纳米结构重新排列成纤维。总之,本研究证明了非对映异构肽混合物可以成为有效的凝胶剂。重要的是,这些结果表明,封端基团的结构(大小、芳香度)对非对映异构体的自组装(共组装与自排序)具有指导作用。利用人体角质细胞(HaCaT 细胞系)评估了新合成凝胶剂的细胞毒性。结果表明,这两种凝胶剂具有一定的细胞毒性,对细胞活力的影响较小。在持续释放实验中,评估了电荷对模型药物化合物从水凝胶基质中释放速率的影响。水凝胶显示了甲基橙(阴离子)的持续释放,而亚甲基蓝(阳离子)则保留在网络中。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
New Supramolecular Hydrogels Based on Diastereomeric Dehydrotripeptide Mixtures for Potential Drug Delivery Applications.

Self-assembly of peptide building blocks offers unique opportunities for bottom-up preparation of exquisite nanostructures, nanoarchitectures, and nanostructured bulk materials, namely hydrogels. In this work we describe the synthesis, characterization, gelation, and rheological properties of new dehydrotripeptides, Cbz-L-Lys(Cbz)-L,D-Asp-∆Phe-OH and (2-Naph)-L-Lys(2-Naph)-L,D-Asp-∆Phe-OH, containing a N-terminal lysine residue Nα,ε-bis-capped with carboxybenzyl (Cbz) and 2-Naphthylacetyl (2-Naph) aromatic moieties, an aspartic acid residue (Asp), and a C-terminal dehydrophenylalanine (∆Phe) residue. The dehydrotripeptides were obtained as diastereomeric mixtures (L,L,Z and L,D,Z), presumably via aspartimide chemistry. The dehydrotripeptides afforded hydrogels at exceedingly low concentrations (0.1 and 0.04 wt%). The hydrogels revealed exceptional elasticity (G' = 5.44 × 104 and 3.43 × 106 Pa) and self-healing properties. STEM studies showed that the diastereomers of the Cbz-capped peptide undergo co-assembly, generating a fibrillar 3D network, while the diastereomers of the 2-Naph-capped dehydropeptide seem to undergo self-sorting, originating a fibril network with embedded spheroidal nanostructures. The 2-Naph-capped hydrogel displayed full fast recovery following breakup by a mechanical stimulus. Spheroidal nanostructures are absent in the recovered hydrogel, as seen by STEM, suggesting that the mechanical stimulus triggers rearrangement of the spheroidal nanostructures into fibers. Overall, this study demonstrates that diastereomeric mixtures of peptides can be efficacious gelators. Importantly, these results suggest that the structure (size, aromaticity) of the capping group can have a directing effect on the self-assembly (co-assembly vs. self-sorting) of diastereomers. The cytotoxicity of the newly synthesized gelators was evaluated using human keratinocytes (HaCaT cell line). The results indicated that the two gelators exhibited some cytotoxicity, having a small impact on cell viability. In sustained release experiments, the influence of the charge on model drug compounds was assessed in relation to their release rate from the hydrogel matrix. The hydrogels demonstrated sustained release for methyl orange (anionic), while methylene blue (cationic) was retained within the network.

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来源期刊
Gels
Gels POLYMER SCIENCE-
CiteScore
4.70
自引率
19.60%
发文量
707
审稿时长
11 weeks
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