The clinical applications of nitrogen mustard antitumor drugs are limited by their poor aqueous solubility, poor cellular uptake, lack of targeting, and severe side effects. Cyclen could be protonated under physiological conditions, which may be beneficial for increasing cell membrane affinity and cellular uptake. Herein, a novel self-assembling peptide–drug conjugate was developed by conjugating chlorambucil (CRB) and cyclen to a self-assembling peptide. The resultant supramolecular hydrogel was prepared via a heating–cooling process and displayed improved aqueous solubility. Rheology, CD spectra, and transmission electron microscopy measurements indicated that the hydrogel with a β-sheet configuration and a nanofiber structure had favorable rheological properties. A cellular uptake experiment demonstrated that cyclen effectively increases the uptake of the resulting hydrogel by tumor cells. MTT results indicated that the hydrogel exhibited favorable inhibitory activities against A549, HeLa, and MCF-7 cancer cell lines and was less toxic towards 3T3 (normal cells). The results of γ-H2AX experiments showed that the obtained nanomedicine could induce significantly more DNA damage compared with free chlorambucil. Hematology analysis experiments revealed that the obtained nanomedicine has good biocompatibility. Our findings indicate that the self-delivery nanodrug system has clinical potential for cancer treatment.

中文翻译：

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一种肽药物水凝胶，可增强苯丁酸氮芥的抗癌活性。

氮芥类抗肿瘤药的临床应用受到水溶性差，细胞摄取差，缺乏靶向性和严重副作用的限制。周期蛋白可以在生理条件下被质子化，这对于增加细胞膜亲和力和细胞摄取可能是有益的。在本文中，通过将苯丁酸氮芥（CRB）偶联并循环成一个自组装肽，开发了一种新型的自组装肽-药物偶联物。所得的超分子水凝胶是通过加热-冷却过程并显示出改善的水溶性。流变学，CD光谱和透射电子显微镜测量表明，具有β-折叠构型和纳米纤维结构的水凝胶具有良好的流变性质。细胞吸收实验表明，cyclon有效地增加了肿瘤细胞对所得水凝胶的吸收。MTT结果表明，水凝胶对A549，HeLa和MCF-7癌细胞具有良好的抑制活性，对3T3（正常细胞）的毒性较小。γ-H2AX实验的结果表明，与游离苯丁酸氮芥相比，所获得的纳米药物可诱导更多的DNA损伤。血液学分析实验表明，所获得的纳米药物具有良好的生物相容性。