Abstract Pro-oxidant therapy utilizing pro-oxidant drugs that can induce cytotoxic oxidative stress in cancer cells has attracted widespread attention for cancer-specific therapy. Piperlongumine (PL) has gained great interest as a novel pro-oxidant agent because it can exhibit cancer-specific cytotoxicity via elevation of intracellular reactive oxygen species (ROS) in cancer cells. However, its therapeutic efficacy has been limited by its poor water-solubility, which necessitates developing suitable drug carriers for PL delivery. In this study, low-toxic poly(ethylene glycol)-poly(histidine) [PEG-poly(His)] copolymer was developed for effective intracellular delivery of PL. Stable micelles composed of a PEG shell and a poly(His) core encapsulating PL were prepared. In vitro study revealed that plain PEG-poly(His) micelles without PL were low-toxic. Importantly, PL-PEG-poly(His) micelles showed superior cytotoxicity in cancer cells over normal cells due to the PL-induced, dramatic increase of intracellular ROS in cancer cells in comparison with normal cells. PL-PEG-poly(His) micelles were further modified with folic acid (FA) to enhance their cancer-specific pro-oxidant therapy. As compared to FA-free micelles, FA-PL-PEG-poly(His) micelles revealed more facilitated cellular uptake and anticancer efficacy in folate receptor-positive cancer cells. This study demonstrates that PL-PEG-poly(His) micelles are efficient and low-toxic carriers for PL delivery, thus leading to effective and cancer-targeted pro-oxidant therapy.

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使用封装胡椒龙胺的低毒多肽胶束的癌症特异性促氧化疗法

摘要 利用促氧化药物在癌细胞中诱导细胞毒性氧化应激的促氧化治疗引起了癌症特异性治疗的广泛关注。胡椒长明 (PL) 作为一种新型促氧化剂引起了极大的兴趣，因为它可以通过提高癌细胞中的细胞内活性氧 (ROS) 来表现出癌症特异性的细胞毒性。然而，其治疗功效受到其水溶性差的限制，这需要开发合适的药物载体用于 PL 递送。在这项研究中，开发了低毒的聚（乙二醇）-聚（组氨酸）[PEG-聚（His）] 共聚物，用于有效细胞内递送 PL。制备了由 PEG 壳和包裹 PL 的聚 (His) 核组成的稳定胶束。体外研究表明，不含 PL 的普通 PEG-poly(His) 胶束是低毒的。重要的是，PL-PEG-poly(His) 胶束在癌细胞中显示出优于正常细胞的细胞毒性，因为与正常细胞相比，PL 诱导癌细胞中细胞内 ROS 显着增加。PL-PEG-poly(His) 胶束用叶酸 (FA) 进一步修饰，以增强其癌症特异性促氧化疗法。与不含 FA 的胶束相比，FA-PL-PEG-poly(His) 胶束在叶酸受体阳性癌细胞中显示出更促进的细胞摄取和抗癌功​​效。这项研究表明 PL-PEG-poly(His) 胶束是有效且低毒的 PL​​ 载体，从而导致有效的癌症靶向促氧化疗法。与正常细胞相比，癌细胞中的细胞内 ROS 显着增加。PL-PEG-poly(His) 胶束用叶酸 (FA) 进一步修饰，以增强其癌症特异性促氧化疗法。与不含 FA 的胶束相比，FA-PL-PEG-poly(His) 胶束在叶酸受体阳性癌细胞中显示出更促进的细胞摄取和抗癌功​​效。这项研究表明 PL-PEG-poly(His) 胶束是有效且低毒的 PL​​ 载体，从而导致有效的癌症靶向促氧化疗法。与正常细胞相比，癌细胞中的细胞内 ROS 显着增加。PL-PEG-poly(His) 胶束用叶酸 (FA) 进一步修饰，以增强其癌症特异性促氧化疗法。与不含 FA 的胶束相比，FA-PL-PEG-poly(His) 胶束在叶酸受体阳性癌细胞中显示出更促进的细胞摄取和抗癌功​​效。这项研究表明 PL-PEG-poly(His) 胶束是有效且低毒的 PL​​ 载体，从而导致有效的癌症靶向促氧化疗法。FA-PL-PEG-poly(His) 胶束在叶酸受体阳性癌细胞中显示出更促进的细胞摄取和抗癌功​​效。该研究表明，PL-PEG-poly(His) 胶束是有效且低毒的 PL​​ 载体，可实现有效的癌症靶向促氧化疗法。FA-PL-PEG-poly(His) 胶束在叶酸受体阳性癌细胞中显示出更促进的细胞摄取和抗癌功​​效。这项研究表明 PL-PEG-poly(His) 胶束是有效且低毒的 PL​​ 载体，从而导致有效的癌症靶向促氧化疗法。