Tumor Microenvironment-Responsive Lipid Nanoparticle for Blocking Mitosis and Reducing Drug Resistance in NSCLC

• Published in: Journal of medicinal chemistry Vol. 68; no. 3; pp. 3814 - 3823
• Main Authors: Yang, Fengrui, Jiang, Xiao-Rou, Lei, Lingling, Fu, Jing-Hao, Chen, Zeng-Ping, Yu, Ru-Qin
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13.02.2025
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Deoxyglucose - pharmacology; Drug Resistance, Neoplasm - drug effects; Glycolysis - drug effects; Humans; Lipids - chemistry; Liposomes; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice; Mice, Nude; Mitosis - drug effects; Nanoparticles - chemistry; Polo-Like Kinase 1; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; RNA, Small Interfering; Tumor Microenvironment - drug effects
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c02960

Blocking mitosis is a promising strategy to induce tumor cell death. However, AMPK- and PFKFB3-mediated glycolysis can maintain ATP supply and help tumor cells overcome antimitotic drugs. Inhibiting glycolysis provides an opportunity to decrease the resistance of tumor cells to antimitotic drugs. Meanwhile, increased glutathione (GSH) expression in cancer cells due to glycolysis becomes a target for developing microenvironment-responsive drugs. Herein, a novel cationic lipid with disulfide bonds in hydrophobic tails was synthesized and used to prepare a GSH-triggered lipid nanoparticle named 2-DG@SLNP­(siR) encapsulating both Plk1 siRNA and 2-deoxyglucose (2-DG) for blocking mitosis and reducing drug resistance of nonsmall cell lung cancer (NSCLC) cells in vivo. Experimental results showed that the NSCLC cell cycle was arrested at the G2/M phase by Plk1 siRNA and glycolysis was effectively inhibited by 2-DG, demonstrating the potential of 2-DG@SLNP­(siR) as an efficient platform for blocking mitosis and reducing drug resistance of cancer cells.