Key Laboratory of Green Chemistry and Technology (Ministry of Education), College of Chemistry, Sichuan University, Chengdu 610064, P. R. China.
Department of Chemistry, University of Virginia, McCormick Rd, Charlottesville, Virginia 22904, United States.
Mol Pharm. 2023 Feb 6;20(2):1404-1414. doi: 10.1021/acs.molpharmaceut.2c00973. Epub 2023 Jan 3.
The combination cancer therapy of nitric oxide (NO) with gene therapy is a promising method for tumor treatment. However, efficient co-delivery of gas and therapeutic genes to tumor cells remains a challenge. Herein, we designed a nano-sized ultraviolet (UV) light-responsive cationic lipid vector . Fluorescence spectroscopy and confocal imaging experiments revealed that lipid nanoparticles (LNPs) could rapidly release NO under low-power UV light irradiation. Moreover, the fluorescence turn-on might take place along with the release of NO, indicating the self-reporting ability. Gene delivery experiments showed that LNPs had good gene transfection ability, making such materials a good candidate for gas/gene combination therapy. In vitro antitumor assay demonstrated that the co-delivery system was more effective in inhibiting tumor cell proliferation than individual NO or pTrail treatment. Studies on the mechanism of tumor cell apoptosis induced by NO/pTrail co-delivery showed that NO could not only effectively increase the accumulation of p53 protein in tumor cells, thereby promoting the activation of caspase-3, but also induce mitochondrial damage. On the other hand, the Trail protein expressed by pTrail gene could enhance the degree of NO-induced caspase-3 activation, indicating the synergistic effect. These results proved that LNP may serve as a multifunctional nanocarrier for potential tumor therapy.
一氧化氮（NO）与基因治疗联合的癌症治疗是一种很有前途的肿瘤治疗方法。然而，将气体和治疗基因高效递送到肿瘤细胞仍然是一个挑战。在此，我们设计了一种纳米级的紫外（UV）光响应阳离子脂质载体。荧光光谱和共聚焦成像实验表明，脂质纳米粒（LNPs）可以在低功率 UV 光照射下迅速释放 NO。此外，荧光的开启可能伴随着 NO 的释放，表明其具有自我报告能力。基因传递实验表明，LNPs 具有良好的基因转染能力，使这类材料成为气体/基因联合治疗的良好候选物。体外抗肿瘤实验表明，与单独的 NO 或 pTrail 处理相比，共递药系统在抑制肿瘤细胞增殖方面更有效。对 NO/pTrail 共递药诱导肿瘤细胞凋亡的机制研究表明，NO 不仅能有效增加肿瘤细胞中 p53 蛋白的积累，从而促进 caspase-3 的激活，还能诱导线粒体损伤。另一方面，pTrail 基因表达的 Trail 蛋白能增强 NO 诱导的 caspase-3 激活程度，表明存在协同作用。这些结果证明 LNP 可能作为一种多功能纳米载体用于潜在的肿瘤治疗。
