A light-triggered self-reinforced nanoagent for targeted chemo-photodynamic therapy of breast cancer bone metastases via ER stress and mitochondria mediated apoptotic pathways
A light-triggered self-reinforced nanoagent for targeted chemo-photodynamic therapy of breast cancer bone metastases via ER stress and mitochondria mediated apoptotic pathways
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DOI：
10.1016/j.jconrel.2019.12.043
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发表时间：
2020-03-10
影响因子：
10.8
通讯作者：
Zhao, Chunshun
中科院分区：
文献类型：
--
作者：
Huang, Yanjuan;Xiao, Zhanghong;Zhao, Chunshun
目前治疗骨转移的治疗策略常常因缺乏选择性、严重的全身毒性和疗效欠佳而受到限制。纳米医学介导的化学光动力疗法为增强癌症治疗提供了有前景的治疗机会。在此，我们构建了一种阿仑膦酸钠（ALN）功能化的骨寻道纳米剂（BTZ@ZnPc-ALN）来共同递送蛋白酶体抑制剂硼替佐米（BTZ）和光敏剂酞菁锌（ZnPc），用于骨转移的协同化学光动力治疗。结果表明，BTZ@ZnPc-ALN 在体外和体内均具有良好的骨亲和力，并且能够以 pH 响应方式释放药物。在辐照下，BTZ@ZnPc-ALN可产生活性氧（ROS）引起线粒体损伤，并增加胞浆Ca2+水平和GRP78蛋白表达，诱导过度内质网（ER）应激，从而协同抑制细胞增殖。更重要的是，BTZ@ZnPc-ALN可以延长血液循环时间并优先导航到骨受影响部位。结果，骨靶向化学光动力疗法显着抑制了肿瘤生长，与PBS组相比，肿瘤体积缩小了85%，且骨骼未受损。此外，BTZ的全身毒性也显着降低。因此，多功能纳米剂有望成为一个有前途的纳米平台，用于关注多种细胞内应激，以实现骨转移的显着协同化学光动力治疗。
Current therapeutic strategies for the treatment of bone metastases are often limited by the lack of selectivity, severe systemic toxicity and suboptimal efficacy. Nanomedicine meditated chemo-photodynamic therapy provides a promising therapeutic opportunity for enhanced cancer therapy. Herein, we constructed an alendronate (ALN)-functionalized bone-seeking nanoagent (BTZ@ZnPc-ALN) to co-deliver the proteasome inhibitor bortezomib (BTZ) and the photosensitizer Zinc phthalocyanine (ZnPc) for synergistic chemo-photodynamic therapy of bone metastases. Results showed that BTZ@ZnPc-ALN possessed favorable bone affinity both in vitro and in vivo and could release drug in a pH-responsive manner. Under irradiation, BTZ@ZnPc-ALN could generate reactive oxygen species (ROS) to cause mitochondrial damage, and increase the cytosolic Ca2+ levels and the expression of GRP78 protein to induce excessive endoplasmic reticulum (ER) stress, thereby synergistically inhibiting cell proliferation. More importantly, BTZ@ZnPc-ALN could prolong blood circulation time and preferentially navigate to the bone affected site. As a result, tumor growth was significantly inhibited by bone targeted chemo-photodynamic therapy, with tumor volume cut down by 85% compared with PBS group and bone remained undamaged. Besides, the systemic toxicity of BTZ was significantly reduced. Therefore, the versatile nanoagent is expected to be a promising nanoplatform to concern multiple intracellular stress for remarkable synergistic chemo-photodynamic therapy of bone metastases.