Purpose: Histone citrullination by peptidylarginine deiminases 4 (PAD4) regulates the gene expression of tumor suppressor. In our previously study, YW3-56 (356) was developed as a potent PAD4 inhibitor for cancer therapy with novel function in the autophagy pathway. To enhance the antitumor activity, the PAD4 inhibitor 356 was modified by the well-established cationic penetrating peptide RKKRRQRRR (peptide TAT) and gold nanoparticles to obtain 356-TAT-AuNPs which could enhance the permeability of chemical drug in solid tumor.
Methods: 356-TAT-AuNPs were prepared, and their morphology were characterized. The antitumor activity of 356-TAT-AuNPs was evaluated in vitro and in vivo.
Results: 356-TAT-AuNPs exhibited higher anticancer activity against HCT-116, MCF-7 and A549 cells than 356 and 356-AuNPs. Compared with 356 and 356-AuNPs, 356-TAT-AuNPs entered the cytoplasm and nuclear, exhibited stronger anticancer activity by increasing apoptosis, inducing autophagy and inhibiting of histone H3 citrullination, and in HCT-116 xenograft mouse model, 356-TAT-AuNPs could improve the antitumor activity.
Conclusion: The modified AuNPs with peptide TAT as drug delivery system are potent in delaying tumor growth and could be a powerful vehicle for profitable anticancer drug development. We believe that peptide TAT modification strategy may provide a simple and valuable method for improving antitumor activity of PAD4 inhibitors for clinical use.

Keywords: Au nanoparticle, transmembrane peptide, PAD4 inhibitor, antitumor


中文翻译：

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TAT 修饰的金纳米颗粒增强 PAD4 抑制剂的抗肿瘤活性

目的：肽精氨酸脱亚胺酶 4 (PAD4) 的组蛋白瓜氨酸化调节肿瘤抑制基因的表达。在我们之前的研究中，YW3-56 (356) 被开发为一种有效的 PAD4 抑制剂，用于在自噬途径中具有新功能的癌症治疗。为了增强抗肿瘤活性，PAD4抑制剂356通过成熟的阳离子穿透肽RKKRRQRRR（肽TAT）和金纳米粒子进行修饰，得到356-TAT-AuNPs，可以增强化学药物在实体瘤中的渗透性。
方法：制备356-TAT-AuNPs，对其形貌进行表征。在体外和体内评估了 356-TAT-AuNPs 的抗肿瘤活性。
结果：356-TAT-AuNPs 对 HCT-116、MCF-7 和 A549 细胞的抗癌活性高于 356 和 356-AuNPs。与 356 和 356-AuNPs 相比，356-TAT-AuNPs 进入细胞质和细胞核，通过增加细胞凋亡、诱导自噬和抑制组蛋白 H3 瓜氨酸化表现出更强的抗癌活性，在 HCT-116 异种移植小鼠模型中，356-TAT-AuNPs可以提高抗肿瘤活性。
结论：以肽 TAT 作为药物递送系统的修饰 AuNPs 可有效延缓肿瘤生长，并且可能成为有利可图的抗癌药物开发的有力载体。我们相信肽 TAT 修饰策略可以为提高 PAD4 抑制剂的抗肿瘤活性提供一种简单而有价值的方法用于临床。

关键词：金纳米粒子、跨膜肽、PAD4抑制剂、抗肿瘤