The nonviral delivery systems that combine genes with photosensitizers for multimodal tumor gene/photodynamic therapy (PDT) have attracted much attention. In this study, a series of ROS-sensitive cationic bola-lipids were applied for the gene/photosensitizer codelivery. Zn-DPA was introduced as a cationic headgroup to enhance DNA binding, while the hydrophobic linking chains may facilitate the formation of lipid nanoparticles (LNP) and the encapsulation of photosensitizer Ce6. The length of the hydrophobic chain played an important role in the gene transfection process, and 14-TDZn containing the longest chains showed better DNA condensation, gene transfection, and cellular uptake. 14-TDZn LNPs could well load photosensitizer Ce6 to form 14-TDC without a loss of gene delivery efficiency. 14-TDC was used for codelivery of p53 and Ce6 to achieve enhanced therapeutic effects on the tumor cell proliferation inhibition and apoptosis. Results showed that the codelivery system was more effective in the inhibition of tumor cell proliferation than individual p53 or Ce6 monotherapy. Mechanism studies showed that the production of ROS after Ce6 irradiation could increase the accumulation of p53 protein in tumor cells, thereby promoting caspase-3 activation and inducing apoptosis, indicating some synergistic effect. These results demonstrated that 14-TDC may serve as a promising nanocarrier for gene/PDT combination therapy.

中文翻译：

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ROS 响应性 Bola-Lipid 纳米颗粒作为基因/光动力联合治疗的共传递系统

将基因与光敏剂结合用于多模式肿瘤基因/光动力治疗（PDT）的非病毒递送系统引起了广泛关注。在本研究中，一系列ROS敏感的阳离子波拉脂质被应用于基因/光敏剂共传递。 Zn-DPA 被引入作为阳离子头基以增强 DNA 结合，而疏水性连接链可能促进脂质纳米颗粒 (LNP) 的形成和光敏剂 Ce6 的封装。疏水链的长度在基因转染过程中起着重要作用，含有最长链的14-TDZn表现出更好的DNA缩合、基因转染和细胞摄取。 14-TDZn LNPs 可以很好地负载光敏剂 Ce6 形成14-TDC，而不会损失基因传递效率。14-TDC用于共递送p53和Ce6以增强对肿瘤细胞增殖抑制和凋亡的治疗效果。结果表明，联合递送系统比单独的 p53 或 Ce6 单一疗法更有效地抑制肿瘤细胞增殖。机制研究表明，Ce6照射后产生的ROS可以增加肿瘤细胞内p53蛋白的积累，从而促进caspase-3激活并诱导细胞凋亡，具有一定的协同作用。这些结果表明14-TDC可以作为基因/PDT联合治疗的有前途的纳米载体。