Combretastatin A4 Nanodrug-Induced MMP9 Amplification Boosts Tumor-Selective Release of Doxorubicin Prodrug
Combretastatin A4 Nanodrug-Induced MMP9 Amplification Boosts Tumor-Selective Release of Doxorubicin Prodrug
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Combretastatin A4纳米药物诱导的MMP9扩增促进阿霉素前药的肿瘤选择性释放
DOI：
10.1002/adma.201904278
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发表时间：
2019-09-24
影响因子：
29.4
通讯作者：
Chen, Xuesi
中科院分区：
文献类型：
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作者：
Jiang, Jian;Shen, Na;Chen, Xuesi
肿瘤相关酶激活的前药有可能提高化疗药物的选择性。然而，对前药激活至关重要的肿瘤相关酶的缺乏通常限制了抗肿瘤效力。一种利用考布他汀A4纳米药物（CA4 - NPs）和基质金属蛋白酶9（MMP9）激活的阿霉素前药（MMP9 - DOX - NPs）的协同策略被开发出来。CA4是一种典型的血管破坏剂，它能选择性地破坏未成熟的肿瘤血管并加剧肿瘤的缺氧状态。用CA4 - NPs治疗后，在治疗的肿瘤中MMP9的表达可显著提高5.6倍，这在原位4T1乳腺腺癌小鼠模型中进一步使MMP9 - DOX - NPs的肿瘤选择性活性药物释放提高3.7倍。与非协同对照组相比，CA4 - NPs和MMP9 - DOX - NPs的顺序给药显示出增强的抗肿瘤功效且全身毒性降低。
Tumor-associated enzyme-activated prodrugs can potentially improve the selectivity of chemotherapeutics. However, the paucity of tumor-associated enzymes which are essential for prodrug activation usually limits the antitumor potency. A cooperative strategy that utilizes combretastatin A4 nanodrug (CA4-NPs) and matrix metalloproteinase 9 (MMP9)-activated doxorubicin prodrug (MMP9-DOX-NPs) is developed. CA4 is a typical vascular disrupting agent that can selectively disrupt immature tumor blood vessels and exacerbate the tumor hypoxia state. After treatment with CA4-NPs, MMP9 expression can be significantly enhanced by 5.6-fold in treated tumors, which further boosts tumor-selective active drug release of MMP9-DOX-NPs by 3.7-fold in an orthotopic 4T1 mammary adenocarcinoma mouse model. The sequential delivery of CA4-NPs and MMP9-DOX-NPs exhibits enhanced antitumor efficacy with reduced systemic toxicity compared with the noncooperative controls.