Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China.
College of Chemistry, Jilin University, Changchun, 130012, P. R. China.
Adv Mater. 2019 Mar;31(11):e1805955. doi: 10.1002/adma.201805955. Epub 2019 Jan 24.
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 ), and significant tumor shrinkage and antimetastatic effects are observed in challenging large tumors with initial volume of 500 mm . The report here highlights the potential of using a combination of HAPs plus VDA nanomedicine in solid tumor therapy.
缺氧激活前药（HAPs）有可能选择性地杀死缺氧细胞，并将肿瘤缺氧从问题转化为选择性治疗优势。然而，由于治疗肿瘤内的缺氧不足，HAP 在大多数临床试验中都不成功，这是 II 期临床试验的进一步子研究所暗示的。在这里，开发了一种将 HAP 与血管破坏剂（VDA）纳米药物联合用于有效治疗实体瘤的新策略。制备了有效的 VDA 纳米药物聚（L-谷氨酸）-接枝-甲氧基聚（乙二醇）/康普瑞汀 A4（CA4-NPs），可选择性增强肿瘤缺氧，并增强典型的 HAP 替拉扎胺（TPZ）治疗转移性 4T1 乳腺癌。用 TPZ 加 CA4-NPs 的联合治疗后，在 4T1 异种移植小鼠中观察到完全肿瘤消退（初始肿瘤体积为 180mm ），并且在具有初始体积为 500mm 的挑战性大肿瘤中观察到明显的肿瘤缩小和抗转移作用。本报告强调了将 HAP 与 VDA 纳米药物联合用于实体瘤治疗的潜力。
