Bendamustine (BEN) is a FDA-approved bifunctional DNA-alkylating chemotherapy drug, but it suffers from short half-life, instability, and poor biocompatibility in the clinical application. Due to unique biostability of d-amino acid-containing peptides (D-peptides), constructing D-peptide-small molecule drug conjugates is emerging as a promising strategy for cancer therapy. Here, a high-affinity MDM2-targeted D-peptide (peptide 5) is discovered by applying structure-based drug design (SBDD). Taking the advantages of d-amino acids, a novel self-assembling D-peptide-small molecule drug conjugate (BEN-FF-peptide 5) is developed by simultaneously conjugating small molecule drug BEN and peptide 5 to the self-assembling peptide. In vitro results demonstrate that BEN-FF-peptide 5 exhibits superior cellular uptake ability, good biostability in human serum and strong inhibitory effect on the growth of human breast cancer (MCF-7) cells. In vivo study reveals that BEN-FF-peptide 5 significantly inhibits the growth of MCF-7 cells-derived xenograft in nude mice with no obvious side effects. This work provides a useful strategy to construct D-peptide-small molecule drug conjugates for high-efficacy and low-toxicity cancer therapy.

中文翻译：

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一种基于苯达莫司汀和 MDM2 靶向 D 肽抑制剂的超分子纳米药物用于乳腺癌治疗

苯达莫司汀（BEN）是FDA批准的双功能DNA烷基化化疗药物，但在临床应用中存在半衰期短、不稳定、生物相容性差等问题。由于含d-氨基酸的肽 (D-肽) 的独特生物稳定性，构建 D-肽-小分子药物偶联物正在成为一种有前途的癌症治疗策略。在这里，通过应用基于结构的药物设计（SBDD）发现了一种高亲和力的 MDM2 靶向 D 肽（肽 5）。发挥d的优势-氨基酸，一种新型的自组装D-肽-小分子药物偶联物（BEN-FF-肽5）是通过将小分子药物BEN和肽5同时偶联到自组装肽上而开发的。体外实验结果表明，BEN-FF-peptide 5 具有优异的细胞摄取能力，在人血清中具有良好的生物稳定性，对人乳腺癌 (MCF-7) 细胞的生长有很强的抑制作用。体内研究表明，BEN-FF-peptide 5 可显着抑制 MCF-7 细胞来源的异种移植物在裸鼠体内的生长，且无明显副作用。这项工作为构建用于高效低毒癌症治疗的 D-肽-小分子药物偶联物提供了一种有用的策略。