A mitochondria-targeting self-assembled carrier-free lonidamine nanodrug for redox-activated drug release to enhance cancer chemotherapy

• Published in: Journal of materials chemistry. B, Materials for biology and medicine Materials for biology and medicine, 2023-05, Vol.11 (17), p.3951-3957
• Main Authors: Yang, Ting, Zhang, Xianfen, Yang, Xing, Li, Ying, Xiang, Jingjing, Xiang, Chunbai, Liu, Zhongke, Hai, Luo, Huang, Saipeng, Zhou, Lihua, Liang, Ruijing, Gong, Ping
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - therapeutic use; Apoptosis; Bcl-2 protein; Cancer; Cancer therapies; Chemotherapy; Cytochrome; Cytochrome c; Cytochromes; Drug Liberation; Hexokinase; Homeostasis; Humans; Laser radiation; Mitochondria; Mitochondria - metabolism; Nanoparticles; Nanoparticles - therapeutic use; Nanotechnology; Necrosis; Neoplasms - pathology; Oxidation-Reduction; Oxidative stress; Prodrugs; Prodrugs - metabolism; Radiation; Self-assembly; Tumor cells; Tumors
• ISSN: 2050-750X; 2050-7518
• DOI: 10.1039/d2tb02728c

Mitochondria play a vital role in maintaining cellular homeostasis. In recent years, studies have found that mitochondria have an important role in the occurrence and development of tumors, and targeting mitochondria has become a new strategy for tumor treatment. Lonidamine (LND), as a hexokinase inhibitor, can block the energy supply and destroy mitochondria. However, poor water solubility and low mitochondrial selectivity limit its clinical application. To overcome these obstacles, we report redox-activated self-assembled carrier-free nanoparticles (Cy-TK-LND NPs) based on a small molecule prodrug, in which photosensitizer IR780 (Cy) which targets mitochondria is conjugated to LND via a sensitive thioketal (TK) linker. Intracellular oxidative stress induced by laser radiation leads to the responsive cleavage of Cy-TK-LND NPs, facilitating the release of free LND into mitochondria. Subsequently, LND damages mitochondria, triggering the apoptosis pathway. The results show the effective killing effect of Cy-TK-LND NPs on cancer cells in vitro and in vivo . The IC 50 value of irradiated Cy-TK-LND NPs is 5-fold lower than that of free LND. Moreover, tumor tissue section staining results demonstrate that irradiated Cy-TK-LND NPs induce necrosis and apoptosis of tumor cells, upregulate cytochrome C and pro-apoptotic Bax, and downregulate anti-apoptotic Bcl-2. Generally, Cy-TK-LND NPs exhibit efficient mitochondria-targeted delivery to improve the medicinal availability of LND. Accordingly, such a carrier-free prodrug-based nanomedicine holds promise as an effective cancer chemotherapy strategy. Self-assembled carrier-free nanoparticles based on a prodrug enhance tumor chemotherapy through mitochondrial targeting, redox-activated drug release, and apoptotic pathway activation.