A Selective Reduction of Osteosarcoma by Mitochondrial Apoptosis Using Hydroxyapatite Nanoparticles

Abstract

Hongfeng Wu,1,2 Shuo Liu,1,2 Siyu Chen,1,2 Yuchen Hua,1,2 Xiangfeng Li,1,2 Qin Zeng,1– 3 Yong Zhou,4 Xiao Yang,1,2 Xiangdong Zhu,1,2 Chongqi Tu,4 Xingdong Zhang1– 3 1National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, 610064, People’s Republic of China; 2College of Biomedical Engineering, Sichuan University, Chengdu, 610064, People’s Republic of China; 3NMPA Key Laboratory for Quality Research and Control of Tissue Regenerative Biomaterials & Institute of Regulatory Science for Medical Devices & NMPA Research Base of Regulatory Science for Medical Devices, Sichuan University, Chengdu, 610064, People’s Republic of China; 4Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of ChinaCorrespondence: Qin Zeng; Xiangdong Zhu, National Engineering Research Center for Biomaterials, Sichuan University, NO. 29 Wangjiang Road, Chengdu, 610064, People’s Republic of China, Email [email protected]; [email protected]: In recent years, using hydroxyapatite nanoparticles (HANPs) for tumor therapy attracted increasing attention because HANPs were found to selectively suppress the growth of tumor cells but exhibit ignorable toxicity to normal cells.Purpose: This study aimed to investigate the capacities of HANPs with different morphologies and particle sizes against two kinds of osteosarcoma (OS) cells, human OS 143B cells and rat OS UMR106 cells.Methods: Six kinds of HANPs with different morphologies and particle sizes were prepared by wet chemical method. Then, the antitumor effect of these nanoparticles was characterized by means of in vitro cell experiments and in vivo tumor-bearing mice model. The underlying antitumor mechanism involving mitochondrial apoptosis was also investigated by analysis of intracellular calcium, expression of apoptosis-related genes, reactive oxygen species (ROS), and the endocytosis efficiency of the particles in tumor cells.Results: Both in vitro cell experiments and in vivo mice model evaluation revealed the anti-OS performance of HANPs depended on the concentration, morphology, and particle size of the nanoparticles, as well as the OS cell lines. Among the six HANPs, rod-like HANPs (R-HANPs) showed the best inhibitory activity on 143B cells, while needle-like HANPs (N-HANPs) inhibited the growth of UMR106 cells most efficiently. We further demonstrated that HANPs induced mitochondrial apoptosis by selectively raising intracellular Ca2+ and the gene expression levels of mitochondrial apoptosis-related molecules, and depolarizing mitochondrial membrane potential in tumor cells but not in MC3T3-E1, a mouse pre-osteoblast line. Additionally, the anti-OS activity of HANPs also linked with the endocytosis efficiency of the particles in the tumor cells, and their ability to drive oxidative damage and immunogenic cell death (ICD).Conclusion: The current study provides an effective strategy for OS therapy where the effectiveness was associated with the particle morphology and cell line.Keywords: hydroxyapatite nanoparticles, osteosarcoma, material features, cell line, mitochondrial apoptosis

Keywords

• hydroxyapatite nanoparticles
• osteosarcoma
• material features
• cell line
• mitochondrial apoptosis