Abstract
The vicious cycle between tumor cell proliferation and bone resorption remarkably elevates the progression and metastasis of bone tumors. Here, we fabricated polyethylene glycol-conjugated alendronate-functionalized and chloroquine (CQ)-loaded polydopamine nanoparticles (PPA/CQ) for efficient treatment of bone tumors via breaking the vicious cycle. The nanoparticles were efficiently accumulated to the bone tissues, especially the osteolytic lesions around tumors. CQ released from PPA/CQ inhibited osteoclastogenesis via preventing the degradation of tumor necrosis factor (TNF) receptor-associated receptor 3 to attenuate the osteolysis in bone tumors. On the other hand, CQ blocked the autophagy in cancer cells, resulting in improved photothermal killing of cancer cells. Finally, the in vivo experiment revealed that PPA/CQ-associated treatment efficiently inhibited both tumor growth and osteolysis. This work suggests that autophagy inhibition-associated photothermal therapy could be a promising strategy for treating malignant bone tumors.
摘要
肿瘤细胞增殖与骨吸收之间的恶性循环加剧了骨肿瘤的进展和转移风险. 为此, 我们设计并制备了聚乙二醇-阿仑膦酸钠修饰的聚多巴胺(PPA)纳米粒子, 并在其表面负载自噬抑制剂氯喹(CQ), 期望利用该治疗载体(PPA/CQ)打破肿瘤细胞增殖与骨吸收之间的恶性循环, 从而有效地治疗骨肿瘤. 实验证明, PPA/CQ可以有效地富集到骨组织, 尤其是肿瘤周围的溶骨性病变组织. PPA/CQ释放的CQ, 一方面通过抑制肿瘤坏死因子受体相关受体-3的降解, 抑制破骨细胞的生成, 进而减轻骨肿瘤中的骨溶蚀病变; 另一方面, CQ可以抑制肿瘤细胞的自噬, 从而提高光热治疗对肿瘤细胞的杀伤效力. 动物实验证明, PPA/CQ介导的联合治疗能有效抑制肿瘤的生长和骨溶蚀的发生. 该项研究表明, 自噬抑制联合光热疗法可能成为一种治疗恶性骨肿瘤的有效策略.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (21725402, 31871010, 81971735, 81871470 and 81901867), Shanghai Municipal Science and Technology Commission (17XD1401600), the Fok Ying Tong Education Foundation (151036), and Guangdong Innovative and Entrepreneurial Research Team Program (2016ZT06C322). The authors acknowledge the East China Normal University (ECNU) Electron Microscopy Center for the nanoparticle characterization and the ECNU Multifunctional Platform for Innovation (011) for the animal experiments.
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Author contributions Wang Y, Zhang Q and Cheng Y designed the research; Wang Y, Chen H and Ying T performed the experiments; Huang Q, Cai X and Xiao J constructed the animal model; Wang Y, Lin K, Xiao J, Zhang Q and Cheng Y analyzed the data; Wang Y, Zhang Q and Cheng Y wrote the paper. All authors contributed to the general discussion.
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Yitong Wang received his PhD degree from the East China Normal University in 2018. He is currently working as a postdoctoral fellow at Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine. His research interests mainly focus on nanoparticlemediated bone tumor treatment.
Qiang Zhang is a full professor at the School of Life Sciences, East China Normal University. He received his BS and PhD degrees from the University of Science and Technology of China, and was a postdoctoral fellow at Georgia Institute of Technology. His research interests focus on the syntheses of photothermal nanomaterials and their applications in biomedical area.
Yiyun Cheng is a full professor at the School of Life Sciences, East China Normal University. He received his PhD degree from the University of Science and Technology of China and was a postdoctoral fellow at Washington University in St. Louis, MO. His research interests focus on the rational design of polymers for the delivery of biomacromolecules such as DNA, RNA, proteins and peptides.
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Breaking the Vicious Cycle between Tumor Cell Proliferation and Bone Resorption by Chloroquine-loaded and Bone-targeted Polydopamine Nanoparticles
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Wang, Y., Chen, H., Lin, K. et al. Breaking the vicious cycle between tumor cell proliferation and bone resorption by chloroquine-loaded and bone-targeted polydopamine nanoparticles. Sci. China Mater. 64, 474–487 (2021). https://doi.org/10.1007/s40843-020-1405-8
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DOI: https://doi.org/10.1007/s40843-020-1405-8