Key Laboratory of Green Chemistry and Technology (Ministry of Education), College of Chemistry, Sichuan University, Chengdu 610064, PR China.
Department of Chemistry, University of Virginia, McCormick Rd, Charlottesville, VA 22904, USA.
Eur J Pharm Biopharm. 2024 Aug;201:114348. doi: 10.1016/j.ejpb.2024.114348. Epub 2024 Jun 4.
Nitric oxide (NO) / β-Lapachone (Lap) combined therapy by causing oxidative stress is an effective tumor therapy strategy. Herein, a dual-responsive lipid nanoparticles (LNPs) LSNO for NO / Lap co-delivery were constructed from the zinc-coordinated lipid (DSNO(Zn)) and the hydrophobic drug Lap in the presence of helper lipids (DOPE and DSPE-PEG). The zinc-coordinated structure in LSNO might elevate the Zn content in tumor cells, contributing to antioxidant imbalance. The fluorescent assays proved the light-triggered NO release and fluorescent self-reporting abilities of LSNO. In addition, the LNPs had good drug release behavior under high concentration of GSH, indicating the NO / drug co-delivery capacity. In vitro antitumor assays showed that the NO / Lap combination treatment group could induce more significant tumor cell growth inhibition and cell apoptosis than individual NO or Lap treatment. The following mechanism studies revealed that NO / Lap combination treatment led to distinct oxidative stress by producing reactive oxygen species (ROS) and peroxynitrite anion (ONOO). On the other hand, the intracellular redox balance could be further disrupted by Lap-induced NADPH consumption and Zn / NO-induced reductase activities downregulation, thus promoting the degree of cell damage. Besides, it was also found that NO and Lap could directly damage nuclear DNA and induce mitochondrial dysfunction, thereby leading to caspase-3 activation and tumor cell death. These results proved that LSNO could serve as a promising multifunctional tumor therapy platform.
一氧化氮（NO）/β-拉帕醌（Lap）联合治疗通过引起氧化应激是一种有效的肿瘤治疗策略。本文构建了一种由锌配位脂质（DSNO(Zn)）和疏水性药物拉帕醌（Lap）在辅助脂质（DOPE 和 DSPE-PEG）存在下组成的双重响应脂质纳米粒（LNPs）LSNO，用于NO/Lap 共递送。LSNO 中的锌配位结构可能会提高肿瘤细胞中的锌含量，导致抗氧化失衡。荧光测定证明了 LSNO 的光触发 NO 释放和荧光自报告能力。此外，LNPs 在高浓度 GSH 下具有良好的药物释放行为，表明具有 NO/药物共递送能力。体外抗肿瘤实验表明，与单独的 NO 或 Lap 处理相比，NO/Lap 联合治疗组能诱导更显著的肿瘤细胞生长抑制和细胞凋亡。进一步的机制研究表明，NO/Lap 联合治疗通过产生活性氧（ROS）和过氧亚硝酸盐阴离子（ONOO）引起明显的氧化应激。另一方面，拉帕醌诱导的 NADPH 消耗和 Zn/NO 诱导的还原酶活性下调会进一步破坏细胞内氧化还原平衡，从而促进细胞损伤程度。此外，还发现 NO 和 Lap 可以直接损伤核 DNA 并诱导线粒体功能障碍，从而导致 caspase-3 激活和肿瘤细胞死亡。这些结果证明 LSNO 可以作为一种有前途的多功能肿瘤治疗平台。
