Metal-Organic Framework Nanoparticles for Ameliorating Breast Cancer-Associated Osteolysis
Metal-Organic Framework Nanoparticles for Ameliorating Breast Cancer-Associated Osteolysis
复制标题
金属有机框架纳米粒子用于改善乳腺癌相关的骨溶解
DOI：
10.1021/acs.nanolett.9b02916
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发表时间：
2020-02-01
期刊：
影响因子：
10.8
通讯作者：
Qin, An
中科院分区：
文献类型：
--
作者：
Pang, Yichuan;Fu, Yao;Qin, An
乳腺癌骨转移给治疗策略的管理带来了重大挑战。骨微环境、转移性肿瘤细胞、破骨细胞和肿瘤相关巨噬细胞（TAM）在为转移性肿瘤的增殖、进展和存活创造有利环境方面都发挥着至关重要的协同作用，这反过来又诱导破骨细胞介导的骨破坏。在这项研究中，我们功能化免疫刺激胞嘧啶-磷酸-鸟苷（CpG）负载的金属有机框架（MOF）纳米粒子的骨靶向能力，通过表面修饰与FDA批准的抗再吸收双膦酸盐，唑来膦酸（ZOL）。功能化骨靶向免疫刺激性MOF（BT-isMOF）纳米颗粒在体外表现出与磷酸钙的强结合，并且在体内表现出在骨组织中的特异性靶向和积累。体外细胞和生物化学分析表明，BT-isMOF纳米颗粒可以有效地抑制破骨细胞的形成，并伴随诱导巨噬细胞向M1促炎表型极化。最后，使用乳腺癌骨转移的胫骨内小鼠模型，我们表明BT-isMOF纳米颗粒的施用显著抑制破骨细胞介导的骨破坏，并增强肿瘤驻留巨噬细胞向M1表型的极化。总之，我们的数据为BT-isMOF纳米颗粒在治疗乳腺癌骨转移中的潜在治疗应用提供了有希望的证据。
Breast cancer metastases to bone poses a significant challenge for the administration of treatment strategies. The bone microenvironment, metastatic tumor cells, osteoclasts, and tumor-associated macrophages (TAMs) all play crucial and synergistic roles in creating a favorable environment for the proliferation, progression, and survival of the metastatic tumor, which in turn induces osteoclast-mediated bone destruction. In this study, we functionalized immunostimulatory cytosine-phosphate-guanosine (CpG)-loaded metal-organic framework (MOF) nanoparticles with bone targeting capabilities by surface modification with FDA approved antiresorptive bisphosphonate, zoledronic acid (ZOL). The functionalized bone targeting immunostimulatory MOF (BT-isMOF) nanoparticles demonstrates strong binding to calcium phosphate in vitro and exhibits specific targeting and accumulation in bone tissues in vivo. In vitro cellular and biochemical analyses demonstrated that the BT-isMOF nanoparticles could potently inhibit osteoclast formation and concomitantly induce macrophages polarization toward the M1 pro-inflammatory phenotype. Finally, using the intratibial murine model of breast cancer bone metastasis, we showed that the administration of BT-isMOF nanoparticles significantly suppressed osteoclast-mediated bone destruction and enhanced polarization of tumor-resident macrophages to M1 phenotype. Together, our data provides promising evidence for the potential therapeutic application of the BT-isMOF nanoparticles in the treatment of breast cancer bone metastases.