A nanodrug combining CD47 and sonodynamic therapy efficiently inhibits osteosarcoma deterioration
A nanodrug combining CD47 and sonodynamic therapy efficiently inhibits osteosarcoma deterioration
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结合 CD47 和声动力疗法的纳米药物可有效抑制骨肉瘤恶化。
DOI：
10.1016/j.jconrel.2023.01.038
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发表时间：
2023-02-02
影响因子：
10.8
通讯作者：
Wang, Jin
中科院分区：
文献类型：
--
作者：
Gong, Ming;Huang, Yufeng;Wang, Jin
骨肉瘤肺转移的治疗已成为治疗的瓶颈，存活率高达10-20%。肿瘤相关巨噬细胞(TAMs)的抑制和CD47的过度表达是导致治疗失败的主要原因。声动力疗法(SonoDynamic Treatment，SDT)可产生穿透肿瘤深度的ROS诱导肿瘤细胞凋亡，据报道可进一步诱导M1巨噬细胞极化。CD47抑制联合SDT协同调节TAMS对OS的治疗效果更佳。在这项工作中，首次将IR780(声敏剂)和RRx-001(CD47抑制剂)负载到聚乙二醇PCL纳米胶束中，然后包覆OS细胞膜，制备了一种名为MPIRx的仿生纳米微球。超声激活后，纳米粒显著抑制OS细胞的增殖和迁移，诱导OS细胞的凋亡和免疫原性细胞死亡。此外，MPIRx还可引导巨噬细胞向肿瘤细胞迁移，促进M1型极化，同时增强巨噬细胞对OS细胞的吞噬活性。最终，MPIRx在体内表现出良好的肿瘤蓄积，并成功地抑制了皮下OS和原位肿瘤，并检测了肺转移。总之，通过创造局部氧化微环境和调节肿瘤组织中的TAMS/CD47，MPIRx纳米片为巨噬细胞相关免疫治疗提供了一种新的策略，成功地消除了OS并抑制了难治性肺转移。
Treatments for osteosarcoma (OS) with pulmonary metastases reach a bottleneck with a survival rate of 10-20%. The suppressive tumor associated macrophages(TAMs) and CD47 over-expression greatly lead to the treatment failure. Sonodynamic therapy (SDT) can generate ROS with deep tumor penetration to induce tumor cell apoptosis, which is reported to further induce M1 macrophage polarization. CD47 inhibition combined with SDT to synergistically modulate TAMs may induce superior effects for OS treatment. In this work, for the first time, a biomimetic nanodrug named MPIRx was deveploped by loading IR780 (a sonosensitizer) and RRx-001 (a CD47 inhibitor) in PEG-PCL nanomicelles and then coating with OS cell membranes. After ultrasound activation, the nanodrug significantly inhibited OS proliferation and migration, induced apoptosis and immunogenic cell death in OS cells. Furthermore, MPIRx could guide macrophage migrating towards tumor cells and promote M1-type polarization while increasing the phagocytosis activity of macrophages on OS cells. Ultimately, MPIRx showed good tumor accumulation in vivo and successfully inhibited subcutaneous OS and orthotopic tumor with dete-rioration of pulmonary metastasis. Overall, by creating a local oxidative microenvironment and modulating the TAMs/CD47 in tumor tissue, the MPIRx nanodrug presents a novel strategy for macrophage-related immuno-therapy to successfully eliminate OS and inhibit the intractable pulmonary metastasis.