Self-assembling mertansine prodrug improves tolerability and efficacy of chemotherapy against metastatic triple-negative breast cancer
Self-assembling mertansine prodrug improves tolerability and efficacy of chemotherapy against metastatic triple-negative breast cancer
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自组装美坦辛前药可改善转移性三阴性乳腺癌化疗的耐受性和疗效
DOI：
10.1016/j.jconrel.2019.12.027
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发表时间：
2020-02-01
影响因子：
10.8
通讯作者：
Zhang, Pengcheng
中科院分区：
文献类型：
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作者：
Ran, Wei;Liu, Xiaoyu;Zhang, Pengcheng
转移性三阴性乳腺癌是最具破坏性的癌症类型之一。全身化疗是必要的，但其临床效果在很大程度上受到严重副作用的限制。在此，我们报道了一种mermeransine前药，它可以在水中自组装成球形纳米颗粒，并且在谷胱甘肽存在下很容易转化为活性mermeransine。自组装的mertansine前药（SAMPDs）通过小泡介导的途径进入癌细胞并表现出强大的细胞毒性。自释sampd不引起溶血，更重要的是通过减少大多数主要器官的游离mermeransine暴露，将mermeransine的最大耐受剂量（MTD）提高了8倍。sampd改善了肿瘤内药物暴露，并显示出剂量依赖性的抗肿瘤活性。在MTD给药时，sampd对原发肿瘤生长和肺转移的抑制作用分别为80%和95%，而MTD给药时，mertansine仅对原发肿瘤生长和转移的抑制作用分别< 50%和60%。我们的研究结果揭示了自组装前药的体内生物转化机制，并突出了自组装前药策略在提高化疗疗效和安全性方面的独特优势。
Metastatic triple-negative breast cancer is one of the most devastating cancer types. Systemic chemotherapy is necessary, but its clinical performance is largely limited by severe side effects. Herein, we report a mertansine prodrug, which could self-assemble into spherical nanoparticles in water and readily convert into active mertansine at the presence of glutathione. The self-assembling mertansine prodrugs (SAMPDs) entered cancer cells via a caveolae-mediated pathway and exhibited potent cytotoxicity. The self-delivering SAMPDs did not cause hemolysis, and more importantly increased maximum tolerated dose (MTD) of mertansine by 8 folds via reducing free mertansine exposure in most of the major organs. SAMPDs improved intratumoral drug exposure and showed dose-dependent antitumor activity. When dosed at MTD, SAMPDs inhibited primary tumor growth and pulmonary metastasis by 80% and 95%, while mertansine dosed at MTD only reduced primary tumor growth and metastasis by < 50% and 60%, respectively. Our results reveal the mechanism of in vivo biotransformation of self-assembling prodrug and highlight the unique advantages of self-assembling prodrug strategy in improving the efficacy and safety of chemotherapy.