Peptide-based low molecular weight supramolecular hydrogels hold promising aspects in various fields of application especially in biomaterial and biomedical sciences such as drug delivery, wound healing, tissue engineering, cell proliferation, and so on due to their extreme biocompatibility. Unlike linear peptides, cyclic peptides have more structural rigidity and tolerance to enzymatic degradation and high environmental stability which make them even better candidates for the above-said applications. Herein, a new small cyclic dipeptide (CDP) cyclo-(Leu-S-Bzl-Cys) (P1) consisting of L-leucine and S-benzyl protected L-cysteine was reported which formed a hydrogel at physiological conditions (at 37°C and pH = 7.46). The hydrogel formed from the cyclic dipeptide P1 showed very good tolerance towards environmental parameters such as pH and temperature and was seen to be stable for more than a year without any deformation. The hydrogel was thermoreversible and stable in the pH range 6–12. Mechanical strength of P1 hydrogel was measured by rheology experiments. Atomic force microscopy (AFM) and field emission scanning electron microscopy (FE-SEM) images revealed that, in aqueous solvents, P1 self-assembled into a highly cross-linked nanofibrillar network which immobilized water molecules inside the cages and formed the hydrogel. The self-assembled cyclic dipeptide acquired the antiparallel β-sheet secondary structure, which was evident from CD and Fourier transform infrared (FT-IR) studies. The β-sheet arrangement and formation of amyloid fibrils were further established by ThT binding assay. Furthermore, P1 was able to form a hydrogel in the presence of the anticancer drug 5-fluorouracil (5FU), and sustainable release of the drug from the hydrogel was measured in vitro. The hydrogelator P1 showed almost no cytotoxicity towards the human colorectal cancer cell line HCT116 up to a considerably high concentration and showed potential application in sustainable drug delivery. The co-assembly of 5FU and P1 hydrogel exhibited much better anticancer activity towards the HCT116 cancer cell line than 5FU alone and decreased the IC₅₀ dose of 5FU to a much lower value.

中文翻译：

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基于 S-苄基半胱氨酸的环状二肽超级水凝胶剂：通过可持续释放提高抗癌药物的功效

基于肽的低分子量超分子水凝胶由于其极高的生物相容性，在各个应用领域尤其是在生物材料和生物医学科学如药物递送、伤口愈合、组织工程、细胞增殖等方面具有广阔的应用前景。与线性肽不同，环状肽具有更高的结构刚性和对酶降解的耐受性和高环境稳定性，这使其成为上述应用的更好候选者。在此，一种由 L-亮氨酸和S据报道，-苄基保护的 L-半胱氨酸在生理条件下（37°C 和 pH = 7.46）形成水凝胶。由环状二肽 P1 形成的水凝胶对环境参数（如 pH 值和温度）表现出非常好的耐受性，并且可以稳定超过一年而没有任何变形。水凝胶在 6-12 的 pH 值范围内具有热可逆性和稳定性。P1水凝胶的机械强度通过流变实验测量。原子力显微镜 (AFM) 和场发射扫描电子显微镜 (FE-SEM) 图像显示，在水性溶剂中，P1 自组装成高度交联的纳米纤维网络，将水分子固定在笼内并形成水凝胶。自组装的环状二肽获得了反平行的β-折叠二级结构，从 CD 和傅里叶变换红外 (FT-IR) 研究中可以明显看出这一点。通过ThT结合测定进一步确定了β-折叠排列和淀粉样蛋白原纤维的形成。此外，P1 能够在抗癌药物 5-氟尿嘧啶 (5FU) 的存在下形成水凝胶，并在体外测量了药物从水凝胶中的可持续释放。水凝胶 P1 对人类结直肠癌细胞系 HCT116 几乎没有细胞毒性，直至相当高的浓度，并显示出在可持续药物输送中的潜在应用。5FU 和 P1 水凝胶的共组装对 HCT116 癌细胞系表现出比单独使用 5FU 更好的抗癌活性并降低 IC 通过ThT结合测定进一步确定了β-折叠排列和淀粉样蛋白原纤维的形成。此外，P1 能够在抗癌药物 5-氟尿嘧啶 (5FU) 的存在下形成水凝胶，并在体外测量了药物从水凝胶中的可持续释放。水凝胶 P1 对人类结直肠癌细胞系 HCT116 几乎没有细胞毒性，直至相当高的浓度，并显示出在可持续药物输送中的潜在应用。5FU 和 P1 水凝胶的共组装对 HCT116 癌细胞系表现出比单独使用 5FU 更好的抗癌活性并降低 IC 通过ThT结合测定进一步确定了β-折叠排列和淀粉样蛋白原纤维的形成。此外，P1 能够在抗癌药物 5-氟尿嘧啶 (5FU) 的存在下形成水凝胶，并在体外测量了药物从水凝胶中的可持续释放。水凝胶 P1 对人类结直肠癌细胞系 HCT116 几乎没有细胞毒性，直至相当高的浓度，并显示出在可持续药物输送中的潜在应用。5FU 和 P1 水凝胶的共组装对 HCT116 癌细胞系表现出比单独使用 5FU 更好的抗癌活性并降低 IC 水凝胶 P1 对人类结直肠癌细胞系 HCT116 几乎没有细胞毒性，直至相当高的浓度，并显示出在可持续药物输送中的潜在应用。5FU 和 P1 水凝胶的共组装对 HCT116 癌细胞系表现出比单独使用 5FU 更好的抗癌活性并降低 IC 水凝胶 P1 对人类结直肠癌细胞系 HCT116 几乎没有细胞毒性，直至相当高的浓度，并显示出在可持续药物输送中的潜在应用。5FU 和 P1 水凝胶的共组装对 HCT116 癌细胞系表现出比单独使用 5FU 更好的抗癌活性并降低 IC₅₀剂量的 5FU 值要低得多。