Jia Fei, Ruan Lifo, Du Chuanchao, Liu Yu, Cai Xiaomeng, Dou Rui, Zhang Jiayu, Liu Xiaoguang, Chen Jun, Zhang Xingcai, Chai Zhifang, Hu Yi
Department of Orthopedics, Peking University Third Hospital, Beijing, 100191, PR China; Beijing Key Laboratory of Spinal Diseases, Beijing, 100191, PR China; Engineering Research Center of Bone and Joint Precision Medicine, Beijing, 100191, PR China.
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics and University of Chinese Academy of Sciences (UCAS), Chinese Academy of Sciences (CAS), Beijing, 100049, PR China.
Biomaterials. 2023 May;296:122059. doi: 10.1016/j.biomaterials.2023.122059. Epub 2023 Feb 17.
Osteoporosis is known as an imbalance in bone catabolism and anabolism. Overactive bone resorption causes bone mass loss and increased incidence of fragility fractures. Antiresorptive drugs are widely used for osteoporosis treatment, and their inhibitory effects on osteoclasts (OCs) have been well established. However, due to the lack of selectivity, their off-target and side effects often bring suffering to patients. Herein, an OCs' microenvironment-responsive nanoplatform HA-MC/CaCO/ZOL@PBAE-SA (HMCZP) is developed, consisting of succinic anhydride (SA)-modified poly(β-amino ester) (PBAE) micelle, calcium carbonate shell, minocycline-modified hyaluronic acid (HA-MC) and zoledronic acid (ZOL). Results indicate that HMCZP, as compared with the first-line therapy, could more effectively inhibit the activity of mature OCs and significantly reverse the systemic bone mass loss in ovariectomized mice. In addition, the OCs-targeted capacity of HMCZP makes it therapeutically efficient at sites of severe bone mass loss and allows it to reduce the adverse effects of ZOL, such as acute phase reaction. High-throughput RNA sequencing (RNA-seq) reveals that HMCZP could down-regulate a critical osteoporotic target, tartrate-resistant acid phosphatase (TRAP), as well as other potential therapeutical targets for osteoporosis. These results suggest that an intelligent nanoplatform targeting OCs is a promising strategy for osteoporosis therapy.
骨质疏松症被认为是骨分解代谢和合成代谢的失衡。过度活跃的骨吸收会导致骨量流失和脆性骨折发生率增加。抗吸收药物被广泛用于骨质疏松症的治疗，其对破骨细胞（OCs）的抑制作用已得到充分证实。然而，由于缺乏选择性，它们的脱靶效应和副作用常常给患者带来痛苦。在此，开发了一种OCs微环境响应纳米平台HA-MC/CaCO/ZOL@PBAE-SA（HMCZP），它由琥珀酸酐（SA）修饰的聚（β-氨基酯）（PBAE）胶束、碳酸钙壳、米诺环素修饰的透明质酸（HA-MC）和唑来膦酸（ZOL）组成。结果表明，与一线治疗相比，HMCZP能更有效地抑制成熟OCs的活性，并显著逆转去卵巢小鼠的全身骨量流失。此外，HMCZP对OCs的靶向能力使其在严重骨量流失部位具有治疗效果，并能减少ZOL的不良反应，如急性期反应。高通量RNA测序（RNA-seq）显示，HMCZP可下调一个关键的骨质疏松靶点——抗酒石酸酸性磷酸酶（TRAP），以及其他潜在的骨质疏松治疗靶点。这些结果表明，靶向OCs的智能纳米平台是一种有前景的骨质疏松治疗策略。
