Overcoming the Heat Endurance of Tumor Cells by Interfering with the Anaerobic Glycolysis Metabolism for Improved Photothermal Therapy

• Published in: ACS nano Vol. 11; no. 2; pp. 1419 - 1431
• Main Authors: Chen, Wei-Hai, Luo, Guo-Feng, Lei, Qi, Hong, Sheng, Qiu, Wen-Xiu, Liu, Li-Han, Cheng, Si-Xue, Zhang, Xian-Zheng
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 28-02-2017
• Subjects: Anaerobiosis - drug effects; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Cercopithecus aethiops; COS Cells; Diclofenac - chemistry; Diclofenac - pharmacology; Drug Screening Assays, Antitumor; Glycolysis; Glycolysis - drug effects; Gold; Gold - chemistry; Gold - pharmacology; HeLa Cells; Hot Temperature; Humans; Hyaluronic Acid - chemistry; Hyaluronic Acid - pharmacology; Inhibition; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - pathology; MCF-7 Cells; Metabolism; Metal Nanoparticles - chemistry; Mice; Mice, Inbred BALB C; Nanorods; Nanostructure; Phototherapy; RAW 264.7 Cells; Therapy; Tumors; tumor targeting; anaerobic glycolysis; gold nanorod; photothermal therapy
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.6b06658

In this study, we developed a general method to decorate plasmonic gold nanorods (GNRs) with a CD44-targeting functional polymer, containing a hyaluronic acid (HA)-targeting moiety and a small molecule Glut1 inhibitor of diclofenac (DC), to obtain GNR/HA-DC. This nanosystem exhibited the superiority of selectively sensitizing tumor cells for photothermal therapy (PTT) by inhibiting anaerobic glycolysis. Upon specifically targeting CD44, sequentially time-dependent DC release could be achieved by the trigger of hyaluronidase (HAase), which abundantly existed in tumor tissues. The released DC depleted the Glut1 level in tumor cells and induced a cascade effect on cellular metabolism by inhibiting glucose uptake, blocking glycolysis, decreasing ATP levels, hampering heat shock protein (HSP) expression, and ultimately leaving malignant cells out from the protection of HSPs to stress (e.g., heat), and then tumor cells were more easy to kill. Owing to the sensitization effect of GNR/HA-DC, CD44 overexpressed tumor cells could be significantly damaged by PTT with an enhanced therapeutic efficiency in vitro and in vivo.