Theranostics 2018; 8(18):5059-5071. doi:10.7150/thno.28344 This issue Cite

Research Paper

Tumor-specific activated photodynamic therapy with an oxidation-regulated strategy for enhancing anti-tumor efficacy

Huan Liang1,2, Zhanwei Zhou3, Renjie Luo1, Mangmang Sang 1, Bowen Liu 4, Minjie Sun 3, Wei Qu 4, Feng Feng 4,5✉, Wenyuan Liu 1,2 ✉

1. Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China
2. Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University), Ministry of Education, Nanjing 210009, China
3. State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 210009, China
4. Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China
5. Jiangsu Food and Pharmaceutical Science College, Huaian 223003, China

Citation:
Liang H, Zhou Z, Luo R, Sang M, Liu B, Sun M, Qu W, Feng F, Liu W. Tumor-specific activated photodynamic therapy with an oxidation-regulated strategy for enhancing anti-tumor efficacy. Theranostics 2018; 8(18):5059-5071. doi:10.7150/thno.28344. https://www.thno.org/v08p5059.htm
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Abstract

Graphic abstract

Photodynamic therapy relies on photosensitizers to generate cytotoxic reactive oxygen species (ROS) resulting in the apoptois of tumor cells. However, there is an antioxidant system that impedes the elevation of oxidation levels in tumor cells. Thus, photodynamic therapy may exhibit insufficient curative effects due to ungenerous reactive oxygen species levels. Herein, we describe tumor-specific activated photodynamic therapy using an oxidation-regulating strategy.

Methods: We first synthesised a reactive oxygen species-sensitive amphipathic prodrug of gambogic acid-grafted hyaluronic acid (HA-GA). The hydrophobic photosensitizer chlorin e6 (Ce6) was then loaded into HA-GA by hydrophobic interactions between GA and Ce6, forming amphipathic nanomicelles (HA-GA@Ce6). The ROS-responsive behavior, cytotoxicity, cell uptake, tumor cell killing, in vivo biodistribution and in vivo anti-tumor efficacy of HA-GA@Ce6 were investigated. The in vitro and in vivo experiments were performed on 4T1 murine breast cancer cells and 4T1 tumor model.

Results: We validated that the micelles of HA-GA@Ce6 showed stronger cell uptake in 4T1 tumor cells and lower cytotoxicity in normal cells compared with free Ce6 and GA, which exhibited the benefits of nanomicelles on enhancing the tumor cell acumulation and reducing the side effects on normal cells synchronously. Additionally, the cytotoxic free radicals of photodynamic therapy were generated after irradiation and the high oxidation levels activated the ROS-sensitive GA prodrug efficiently, which killed the tumor cells and depleted intracellular glutathione (GSH), thereby impairing antioxidant levels and enhancing photodynamic therapy.

Conclusion: With the successfully eradicated tumor growth in vivo. Our work represents a new photodynamic therapy concept, achieving superior anti-tumor efficacy by reducing intracellular antioxidant levels.

Keywords: chlorin e6, gambogic acid, photodynamic therapy, ROS-sensitive, GSH depletion


Citation styles

APA
Liang, H., Zhou, Z., Luo, R., Sang, M., Liu, B., Sun, M., Qu, W., Feng, F., Liu, W. (2018). Tumor-specific activated photodynamic therapy with an oxidation-regulated strategy for enhancing anti-tumor efficacy. Theranostics, 8(18), 5059-5071. https://doi.org/10.7150/thno.28344.

ACS
Liang, H.; Zhou, Z.; Luo, R.; Sang, M.; Liu, B.; Sun, M.; Qu, W.; Feng, F.; Liu, W. Tumor-specific activated photodynamic therapy with an oxidation-regulated strategy for enhancing anti-tumor efficacy. Theranostics 2018, 8 (18), 5059-5071. DOI: 10.7150/thno.28344.

NLM
Liang H, Zhou Z, Luo R, Sang M, Liu B, Sun M, Qu W, Feng F, Liu W. Tumor-specific activated photodynamic therapy with an oxidation-regulated strategy for enhancing anti-tumor efficacy. Theranostics 2018; 8(18):5059-5071. doi:10.7150/thno.28344. https://www.thno.org/v08p5059.htm

CSE
Liang H, Zhou Z, Luo R, Sang M, Liu B, Sun M, Qu W, Feng F, Liu W. 2018. Tumor-specific activated photodynamic therapy with an oxidation-regulated strategy for enhancing anti-tumor efficacy. Theranostics. 8(18):5059-5071.

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