Alendronate-functionalized hypoxia-responsive polymeric micelles for targeted therapy of bone metastatic prostate cancer
Alendronate-functionalized hypoxia-responsive polymeric micelles for targeted therapy of bone metastatic prostate cancer
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DOI：
10.1016/j.jconrel.2021.04.035
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发表时间：
2021-05-03
影响因子：
10.8
通讯作者：
Chen, Zhongping
中科院分区：
文献类型：
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作者：
Long, Mengmeng;Liu, Xuemeng;Chen, Zhongping
骨转移是癌症相关死亡的主要原因之一，尽管付出了巨大努力，但仍然无法治愈。骨靶向纳米药物载体可以克服将治疗药物递送到转移性骨的困难，并赋予它们刺激响应性特征以用于可控药物释放，可以进一步最大化其治疗效果。针对骨转移瘤的缺氧微环境，本文报道了一种骨靶向和缺氧响应的聚合物胶束系统，用于有效治疗骨转移性前列腺癌。胶束自组装从聚乙二醇和聚-L-赖氨酸为基础的共聚物使用阿仑膦酸钠作为骨靶向部分和偶氮苯作为缺氧响应连接器，显示出高亲和力转移骨和高敏感性，在体外响应缺氧。体内研究进一步表明，在转移性骨中选择性积聚后，胶束可以响应于缺氧骨转移而快速释放药物至有效治疗剂量。结果表明，该胶束可通过抑制破骨细胞活性和促进成骨细胞活性，抑制骨肿瘤的生长和骨破坏，从而改善治疗效果，减轻骨痛，延长生存时间。因此，骨靶向和低氧响应性纳米载体代表了治疗骨转移的有希望的进展。据我们所知，这可能是缺氧响应性纳米载体在治疗骨转移中的第一个应用实例。
Bone metastasis is one of the leading causes of cancer-related death and remains incurable in spite of great efforts. Bone-targeted nanoparticle-based drug carriers can overcome the difficulties in delivering therapeutic agents to metastatic bone and endowing them with a stimuli-responsive feature for controllable drug release can further maximize their therapeutic outcome. In light of hypoxic microenvironment of bone metastasis, we herein reported a bone-targeted and hypoxia-responsive polymeric micelle system for effective treatment of bone metastatic prostate cancer. The micelles were self-assembled from a polyethylene glycol and poly-L-lysine based copolymer using alendronate as a bone-targeted moiety and azobenzene as a hypoxia-responsive linker, showing a high affinity to metastatic bone and a high sensitivity in responding to hypoxia in vitro. In vivo studies further showed that after a selective accumulation in metastatic bone, the micelles could respond to hypoxic bone metastasis for rapid drug release to an effective therapeutic dosage. As a result, the micelles could suppress tumor growth in bone and inhibit bone destruction by inhibiting osteoclast activity and promoting osteoblast activity, achieving an enhanced therapeutic outcome with relieved bone pain and prolonged survival time. Bone-targeted and hypoxia-responsive nanocarriers therefore represent a promising advancement for treating bone metastasis. To our best knowledge, it might be the first example of the application of hypoxia-responsive nanocarriers in treating bone metastasis.