Institute of Nano Science and Technology (INST), Knowledge City, Sector-81, SAS Nagar, Punjab 140306, India; University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
Institute of Nano Science and Technology (INST), Knowledge City, Sector-81, SAS Nagar, Punjab 140306, India.
Int J Biol Macromol. 2024 Nov;279(Pt 4):135411. doi: 10.1016/j.ijbiomac.2024.135411. Epub 2024 Sep 7.
Lung carcinoma, particularly non-small-cell lung cancer (NSCLC), accounts for a significant portion of cancer-related deaths, with a fatality rate of approximately 19 %. Niclosamide (NIC), originally an anthelmintic drug, has attracted attention for its potential in disrupting cancer cells through various intracellular signaling pathways. However, its effectiveness is hampered by limited solubility, reducing its bioavailability. This study investigates the efficacy of NIC against lung cancer using inhalable hybrid nano-assemblies with chitosan-functionalized Poly (ε-caprolactone) (PCL) as a carrier for pulmonary delivery. The evaluation encompasses various aspects such as aerodynamic and physicochemical properties, drug release kinetics, cellular uptake, biocompatibility, cell migration, autophagic flux, and apoptotic cell death in A549 lung cancer cells. Increasing NIC dosage correlates with enhanced inhibition of cell proliferation, showing a dose-dependent profile (approximately 75 % inhibition efficiency at 20 μg/mL of NIC). Optimization of inhaled dosage and efficacy is conducted in a murine model of NNK-induced tumor-bearing lung cancer. Following inhalation, NIC-CS-PCL-NA demonstrates significant lung deposition, retention, and metabolic stability. Inhalable nano-assemblies promote autophagy flux and induce apoptotic cell death. Preclinical trials reveal substantial tumor regression with minimal adverse effects, underscoring the potential of inhalable NIC-based nano-formulation as a potent therapeutic approach for NSCLC, offering effective tumor targeting and killing capabilities.
肺癌，特别是非小细胞肺癌（NSCLC），是导致癌症相关死亡的主要原因之一，死亡率约为 19%。尼氯苯甲酰胺（NIC）最初是一种驱虫药，因其能通过多种细胞内信号通路破坏癌细胞而受到关注。然而，由于溶解度有限，其生物利用度降低，从而限制了其疗效。本研究采用壳聚糖功能化聚（ε-己内酯）（PCL）作为载体的可吸入混合纳米组装体来研究 NIC 对肺癌的疗效。评估包括空气动力学和物理化学性质、药物释放动力学、细胞摄取、生物相容性、细胞迁移、自噬通量和 A549 肺癌细胞中的凋亡细胞死亡等各个方面。增加 NIC 剂量与增强抑制细胞增殖相关，呈现出剂量依赖性特征（在 20μg/mL 的 NIC 下，约有 75%的抑制效率）。在 NNK 诱导的荷瘤肺癌小鼠模型中进行了吸入剂量和疗效的优化。吸入后，NIC-CS-PCL-NA 表现出显著的肺部沉积、保留和代谢稳定性。可吸入纳米组装体促进自噬通量并诱导凋亡细胞死亡。临床前试验显示肿瘤明显消退，副作用极小，这突显了基于可吸入 NIC 的纳米制剂作为 NSCLC 有效治疗方法的潜力，具有有效的肿瘤靶向和杀伤能力。
