Huang Zixian, Fang Junyue, Lin Li, Cai Nvlue, Chen Siyu, He Gui, Cao Yuan, Wu Guo, Wang Yuepeng, Li Wende, Huang Zhiquan, Saw Phei Er
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, P. R. China.
Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, P. R. China.
J Nanobiotechnology. 2025 Jul 18;23(1):524. doi: 10.1186/s12951-025-03577-7.
Extracellular regulated protein kinases (ERK) signaling is aberrantly activated in oral squamous cell carcinoma (OSCC), and targeting ERK signaling with ERK1/2 inhibitors is a potential strategy for OSCC treatment. However, methods for the more efficient delivery of ERK inhibitors to improve drug utilization remains a pressing challenge. Notably, the application of antiangiogenic therapies to treat OSCC has received increasing attention, yet single therapies often have very limited efficacy. The combination of antiangiogenic therapies with strategies targeting ERK1/2 signaling for the treatment of OSCC is very promising. In this study, we utilized bioactive phospholipids (dipalmitoyl phosphatidic acid, DPPA) with antiangiogenic functions to encapsulate a small-molecule ERK inhibitor (called NP-AE) and constructed an intrinsically biotherapeutically active nanomedicine delivery platform with dual therapeutic efficacy. NP-AE effectively inhibited the proliferation and promoted the apoptosis of OSCC cell lines. A tongue orthotopic xenograft model and a patient-derived xenograft (PDX) model of OSCC were subsequently used to investigate its therapeutic effect. The nanoplatform was able to accumulate in tumor tissues and was internalized by tumor cells after intravenous administration. NP-AE effectively inhibited ERK1/2 phosphorylation and Angptl2 and VEGFA expression in OSCC in vitro and in vivo and significantly inhibited the growth of xenografts. Taken together, these findings suggest that targeting ERK1/2 signaling in combination with antiangiogenic therapy by NP-AE may be a promising strategy for the treatment of OSCC.
细胞外调节蛋白激酶（ERK）信号通路在口腔鳞状细胞癌（OSCC）中异常激活，使用ERK1/2抑制剂靶向ERK信号通路是OSCC治疗的一种潜在策略。然而，更有效地递送ERK抑制剂以提高药物利用率的方法仍然是一个紧迫的挑战。值得注意的是，抗血管生成疗法在治疗OSCC方面受到越来越多的关注，但单一疗法的疗效往往非常有限。抗血管生成疗法与靶向ERK1/2信号通路的策略联合用于治疗OSCC非常有前景。在本研究中，我们利用具有抗血管生成功能的生物活性磷脂（二棕榈酰磷脂酸，DPPA）包裹一种小分子ERK抑制剂（称为NP-AE），构建了一个具有双重治疗功效的内在生物治疗活性纳米药物递送平台。NP-AE有效抑制了OSCC细胞系的增殖并促进了其凋亡。随后使用OSCC的舌原位异种移植模型和患者来源的异种移植（PDX）模型来研究其治疗效果。纳米平台能够在肿瘤组织中积累，并在静脉注射后被肿瘤细胞内化。NP-AE在体外和体内均有效抑制OSCC中ERK1/2的磷酸化以及血管生成素样蛋白2（Angptl2）和血管内皮生长因子A（VEGFA）的表达，并显著抑制异种移植瘤的生长。综上所述，这些发现表明，通过NP-AE联合抗血管生成疗法靶向ERK1/2信号通路可能是治疗OSCC的一种有前景的策略。
