Theranostics 2020; 10(17):7710-7729. doi:10.7150/thno.45858

Research Paper

Fructose-coated Angstrom silver inhibits osteosarcoma growth and metastasis via promoting ROS-dependent apoptosis through the alteration of glucose metabolism by inhibiting PDK

Xiong-Ke Hu1,2, Shan-Shan Rao2,4, Yi-Juan Tan1,2, Hao Yin1,2, Ming-Jie Luo4, Zhen-Xing Wang1,2,3, Jin-Hua Zhou5, Chun-Gu Hong2, Zhong-Wei Luo1,2, Wei Du1,6, Ben Wu1,2, Zi-Qi Yan1,2, Ze-Hui He1,2, Zheng-Zhao Liu1,2,7,12, Jia Cao1,2, Yang Wang3,8, Wei-Yi Situ3, Hao-Ming Liu1,2, Jie Huang1,2, Yi-Yi Wang1,2, Kun Xia1,2, Yu-Xuan Qian1,2, Yan Zhang2,7, Tao Yue1,2, Yi-Wei Liu2,7, Hong-Qi Zhang9, Si-Yuan Tang4, Chun-Yuan Chen1,2,3✉, Hui Xie1,2,3,7,10,11,12,13✉

1. Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
2. Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
3. Xiangya Hospital of Central South University - Amcan Pharmaceutical Biotechnology Co. Ltd. Joint Research Center, Changsha, Hunan 410008, China.
4. Xiangya School of Nursing, Central South University, Changsha, Hunan 410013, China.
5. Department of Orthopedics, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan 410005, China.
6. Department of Rehabilitation, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
7. Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
8. Institute of Integrative Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
9. Department of Spine Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
10. Hunan Key Laboratory of Organ Injury, Aging and Regenerative Medicine, Changsha, Hunan 410008, China.
11. Hunan Key Laboratory of Bone Joint Degeneration and Injury, Changsha, Hunan 410008, China.
12. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
13. Key Laboratory of Biological Nanotechnology of National Health Commission, Changsha, Hunan 410008, China.

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Citation:
Hu XK, Rao SS, Tan YJ, Yin H, Luo MJ, Wang ZX, Zhou JH, Hong CG, Luo ZW, Du W, Wu B, Yan ZQ, He ZH, Liu ZZ, Cao J, Wang Y, Situ WY, Liu HM, Huang J, Wang YY, Xia K, Qian YX, Zhang Y, Yue T, Liu YW, Zhang HQ, Tang SY, Chen CY, Xie H. Fructose-coated Angstrom silver inhibits osteosarcoma growth and metastasis via promoting ROS-dependent apoptosis through the alteration of glucose metabolism by inhibiting PDK. Theranostics 2020; 10(17):7710-7729. doi:10.7150/thno.45858. Available from http://www.thno.org/v10p7710.htm

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Abstract

Osteosarcoma is a common malignant bone cancer easily to metastasize. Much safer and more efficient strategies are still needed to suppress osteosarcoma growth and lung metastasis. We recently presented a pure physical method to fabricate Ångstrom-scale silver particles (AgÅPs) and determined the anti-tumor efficacy of fructose-coated AgÅPs (F-AgÅPs) against lung and pancreatic cancer. Our study utilized an optimized method to obtain smaller F-AgÅPs and aimed to assess whether F-AgÅPs can be used as an efficient and safe agent for osteosarcoma therapy. We also investigated whether the induction of apoptosis by altering glucose metabolic phenotype contributes to the F-AgÅPs-induced anti-osteosarcoma effects.

Methods: A modified method was developed to prepare smaller F-AgÅPs. The anti-tumor, anti-metastatic and pro-survival efficacy of F-AgÅPs and their toxicities on healthy tissues were compared with that of cisplatin (a first-line chemotherapeutic drug for osteosarcoma therapy) in subcutaneous or orthotopic osteosarcoma-bearing nude mice. The pharmacokinetics, biodistribution and excretion of F-AgÅPs were evaluated by testing the levels of silver in serum, tissues, urine and feces of mice. A series of assays in vitro were conducted to assess whether the induction of apoptosis mediates the killing effects of F-AgÅPs on osteosarcoma cells and whether the alteration of glucose metabolic phenotype contributes to F-AgÅPs-induced apoptosis.

Results: The newly obtained F-AgÅPs (9.38 ± 4.11 nm) had good stability in different biological media or aqueous solutions and were more effective than cisplatin in inhibiting tumor growth, improving survival, attenuating osteolysis and preventing lung metastasis in osteosarcoma-bearing nude mice after intravenous injection, but were well tolerated in normal tissues. One week after injection, about 68% of F-AgÅPs were excreted through feces. F-AgÅPs induced reactive oxygen species (ROS)-dependent apoptosis of osteosarcoma cells but not normal cells, owing to their ability to selectively shift glucose metabolism of osteosarcoma cells from glycolysis to mitochondrial oxidation by inhibiting pyruvate dehydrogenase kinase (PDK).

Conclusion: Our study suggests the promising prospect of F-AgÅPs as a powerful selective anticancer agent for osteosarcoma therapy.

Keywords: Ångstrom-scale silver particles, osteosarcoma, reactive oxygen species, glucose metabolism, pyruvate dehydrogenase kinase