Rajabi Ali, Ataee MohammadHossein, Hosseini Hamideh Mahmodzadeh, Amani Jafar
Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran.
Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jun 2. doi: 10.1007/s00210-025-04321-6.
SCLC (small-cell lung cancer) is hardly treated with chemotherapy alone, even though it was initially sensitive to the drug. A novel therapeutic combination for treating diseases that have resisted typical first-line treatments is available with immunotoxin-based anticancer medicines. The use of delta-like ligand 3 (DLL3) in target treatment has potential because of the high expression of DLL3 in patients with SCLC. Nanoparticles are gaining popularity in developing new therapeutics, with gold nanoparticles (AuNPs) being investigated as potential cancer treatments. Emerging evidence indicates that AuNPs stabilized with chitosan (CS) have interesting biological functions. Therefore, in this study, we aimed to synthesize chitosan nanogel to deliver Rova-Typhoid immunotoxins to target cancer cells. In this research, we synthesized CS-AuNPs and CS-Rova-Typh-AuNPs and analyzed their cytotoxicity in small-cell lung (A549) cancer cells and HUVEC cell lines. Then, we evaluated the inhibitory concentration (IC50), cell cycle, and mRNA expression. Free AuNPs did not show cytotoxic effects on our cell lines; however, the inhibitory concentration of Rova-Typh immunotoxin is reduced when loaded into CS-AuNPs. Besides, immunotoxin-loaded nanogel induces late apoptosis in A549 cells and effectively induces sub-G1 cell arrest. Moreover, immunotoxin-loaded nanogel causes downregulation in DLL3, HES1, and NOTCH1 genes, which are involved in the Notch signaling pathway. Our results indicate that CS-AuNPs were an effective Rova-Typh delivery means, and Rova-Typhoid immunotoxin induces apoptosis in cancer cells through inhibiting DLL3, which is a Notch signaling ligand.
小细胞肺癌（SCLC）即使最初对化疗药物敏感，但单独使用化疗很难对其进行治疗。基于免疫毒素的抗癌药物为治疗抵抗典型一线治疗的疾病提供了一种新型治疗组合。由于DLL3在小细胞肺癌患者中高表达，因此其在靶向治疗中具有潜力。纳米颗粒在开发新疗法中越来越受欢迎，金纳米颗粒（AuNPs）正在作为潜在的癌症治疗方法进行研究。新出现的证据表明，用壳聚糖（CS）稳定的金纳米颗粒具有有趣的生物学功能。因此，在本研究中，我们旨在合成壳聚糖纳米凝胶，以将Rova-Typhoid免疫毒素递送至靶癌细胞。在本研究中，我们合成了CS-AuNPs和CS-Rova-Typh-AuNPs，并分析了它们在小细胞肺癌（A549）癌细胞和人脐静脉内皮细胞系中的细胞毒性。然后，我们评估了抑制浓度（IC50）、细胞周期和mRNA表达。游离金纳米颗粒对我们的细胞系未显示出细胞毒性作用；然而，当Rova-Typh免疫毒素负载到CS-AuNPs中时，其抑制浓度降低。此外，负载免疫毒素的纳米凝胶诱导A549细胞晚期凋亡，并有效诱导亚G1期细胞停滞。此外，负载免疫毒素的纳米凝胶导致参与Notch信号通路的DLL3、HES1和NOTCH1基因下调。我们的结果表明，CS-AuNPs是一种有效的Rova-Typh递送手段，Rova-Typhoid免疫毒素通过抑制作为Notch信号配体的DLL3诱导癌细胞凋亡。
