Therapeutic agents used for non-small cell lung cancer (NSCLC) have limited curative efficacy and may trigger serious adverse effects. Cannabinoid ligands exert antiproliferative effect and induce apoptosis on numerous epithelial cancers. We confirmed that CB1 receptor (CB1R) is expressed in NSCLC cells in this study. Arachidonoylcyclopropylamide (ACPA) as a synthetic, CB1R-specific ligand decreased proliferation rate in NSCLC cells by WST-1 analysis and real-time proliferation assay (RTCA). The half-maximal inhibitory concentration (IC50) dose of ACPA was calculated as 1.39 × 10⁻¹² M. CB1 antagonist AM281 inhibited the antiproliferative effect of ACPA. Flow cytometry and ultrastructural analyzes revealed significant early and late apoptosis with diminished cell viability. Nano-immunoassay and metabolomics data on activation status of CB1R-mediated pro-apoptotic pathways found that ACPA inhibited Akt/PI3K pathway, glycolysis, TCA cycle, amino acid biosynthesis, and urea cycle and activated JNK pathway. ACPA lost its chemical stability after 24 hours tested by liquid chromatography-mass spectrometry (LC–MS/MS) assay. A novel ACPA-PCL nanoparticle system was developed by nanoprecipitation method and characterized. Sustained release of ACPA-PCL nanoparticles also reduced proliferation of NSCLC cells. Our results demonstrated that low dose ACPA and ACPA-PCL nanoparticle system harbor opportunities to be developed as a novel therapy in NSCLC patients that require further in vivo studies beforehand to validate its anticancer effect.

用于非小细胞肺癌（NSCLC）的治疗药物疗效有限，并可能引发严重的不良反应。大麻素配体对多种上皮癌发挥抗增殖作用并诱导细胞凋亡。本研究证实 CB1 受体（CB1R）在 NSCLC 细胞中表达。通过 WST-1 分析和实时增殖测定 (RTCA)，花生四烯酰环丙酰胺 (ACPA) 作为一种合成的 CB1R 特异性配体可降低 NSCLC 细胞的增殖率。 ACPA的半最大抑制浓度(IC50)剂量计算为1.39×10 ^-12 M。CB1拮抗剂AM281抑制ACPA的抗增殖作用。流式细胞术和超微结构分析揭示了显着的早期和晚期细胞凋亡以及细胞活力降低。关于 CB1R 介导的促凋亡途径激活状态的纳米免疫测定和代谢组学数据发现，ACPA 抑制 Akt/PI3K 途径、糖酵解、TCA 循环、氨基酸生物合成和尿素循环并激活 JNK 途径。通过液相色谱-质谱 (LC-MS/MS) 检测 24 小时后，ACPA 失去了化学稳定性。通过纳米沉淀法开发了一种新型 ACPA-PCL 纳米粒子系统并进行了表征。 ACPA-PCL 纳米颗粒的持续释放也减少了 NSCLC 细胞的增殖。我们的结果表明，低剂量 ACPA 和 ACPA-PCL 纳米颗粒系统有机会开发为 NSCLC 患者的新型疗法，需要事先进行进一步的体内研究以验证其抗癌效果。