Selectively Potentiating Hypoxia Levels by Combretastatin A4 Nanomedicine: Toward Highly Enhanced Hypoxia-Activated Prodrug Tirapazamine Therapy for Metastatic Tumors
Selectively Potentiating Hypoxia Levels by Combretastatin A4 Nanomedicine: Toward Highly Enhanced Hypoxia-Activated Prodrug Tirapazamine Therapy for Metastatic Tumors
复制标题
通过康布他汀 A4 纳米药物选择性增强缺氧水平：高度增强缺氧激活前药替拉扎明治疗转移性肿瘤
DOI：
10.1002/adma.201805955
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发表时间：
2019-03-15
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：
Yang, Shengcai;Tang, Zhaohui;Chen, Xuesi
缺氧激活的前药（HAP）具有选择性杀死缺氧细胞并将肿瘤缺氧从问题转化为选择性治疗优势的潜力。然而，HAP在大多数临床试验中是不成功的，这是由于所治疗的肿瘤内缺氧不足，如II期临床试验的进一步子研究所暗示的。在这里，开发了一种新的策略，用于有效的实体瘤治疗的HAP加血管破坏剂（VDA）纳米药物的组合。制备了一种有效的聚（L-谷氨酸）-接枝-甲氧基聚（乙二醇）/考布他汀A4（CA 4-NPs）的VDA纳米药物，其可以选择性地增强肿瘤缺氧并促进典型的HAP替拉扎明（TPZ）治疗转移性4 T1乳腺肿瘤。在用TPZ加CA 4-NP的组合治疗后，在4 T1异种移植小鼠中观察到完全的肿瘤缩小（初始肿瘤体积为180 mm 3（3）），并且在初始体积为500 mm 3的挑战性大肿瘤中观察到显著的肿瘤缩小和抗转移作用（3）。该报告强调了在实体瘤治疗中使用HAP + VDA纳米药物组合的潜力。
Hypoxia-activated prodrugs (HAPs) have the potential to selectively kill hypoxic cells and convert tumor hypoxia from a problem to a selective treatment advantage. However, HAPs are unsuccessful in most clinical trials owing to inadequate hypoxia within the treated tumors, as implied by a further substudy of a phase II clinical trial. Here, a novel strategy for the combination of HAPs plus vascular disrupting agent (VDA) nanomedicine for efficacious solid tumor therapy is developed. An effective VDA nanomedicine of poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4 (CA4-NPs) is prepared and can selectively enhance tumor hypoxia and boost a typical HAP tirapazamine (TPZ) therapy against metastatic 4T1 breast tumors. After treatment with the combination of TPZ plus CA4-NPs, complete tumor reduction is observed in 4T1 xenograft mice (initial tumor volume is 180 mm (3) ), and significant tumor shrinkage and antimetastatic effects are observed in challenging large tumors with initial volume of 500 mm(3) . The report here highlights the potential of using a combination of HAPs plus VDA nanomedicine in solid tumor therapy.