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首页> 外文期刊>Biomaterials Science >Tumor regression and potentiation of polymeric vascular disrupting therapy through reprogramming of a hypoxia microenvironment with temsirolimus
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Tumor regression and potentiation of polymeric vascular disrupting therapy through reprogramming of a hypoxia microenvironment with temsirolimus

机译：肿瘤回归和聚合物血管破坏治疗的抑制与Temsirolimus的缺氧微环境重新编程

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摘要

Although the polymeric vascular disrupting agent (poly(l-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4) nanoparticles (CA4-NPs) has great potential to inhibit cancer growth, it is still a challenge to avert tumor recurrence and metastasis after treatment. It is mainly tightly associated with hypoxia induced by CA4-NPs, which can activate many downstream genes regulating tumor growth and metastasis. Herein, to relieve a tumor hypoxia microenvironment, the mTOR inhibitor temsirolimus was employed to modulate the tumor microenvironment when treated with CA4-NPs. In vitro MTT experiments strongly verified that the combination of temsirolimus with polymeric CA4-NPs exhibited an additive toxicity to 4T1 cells. An in vivo study with the 4T1 mammary adenocarcinoma model revealed that consistent with the proposed scenario, combination therapy with CA4-NPs plus temsirolimus suppressed tumor growth significantly more strongly compared to either CA4-NPs or temsirolimus monotherapy, and the inhibition rate to 4T1 tumor with a volume of 300 mm(3) was 71%. The mechanism underling combination treatment was confirmed by western blotting and immunofluorescence staining, and the results demonstrated that temsirolimus could inhibit HIF1 alpha expression. Thus, this work provides a mechanistic rationale for the use of VDAs in combination with the mTOR inhibitor to enhance anticancer efficacy, delaying tumor recurrence and inhibiting tumor metastasis.
机译：虽然聚合物血管破坏剂（聚（L-谷氨酸） - 甲氧基聚（乙二醇）/组合A4）纳米颗粒（CA4-NPS）具有巨大的抑制癌症生长的潜力，但避免肿瘤复发仍然是一项挑战治疗后转移。它主要与CA4-NPS诱导的缺氧相关，这可以激活许多调节肿瘤生长和转移的下游基因。在此，为了缓解肿瘤缺氧微环境，使用MTOR抑制剂Temsirolimus在用Ca 4-NPS处理时调节肿瘤微环境。体外MTT实验强烈验证，具有聚合物Ca4-NPS的Temsirolimus的组合表现出对4T1细胞的添加剂毒性。具有4T1乳腺癌模型的体内研究表明，与所提出的情况一致，与CA4-NPS加温血症的联合治疗抑制肿瘤生长明显更强烈，与CA4-NPS或Temsirolimus单疗法相比，与4T1肿瘤的抑制率更强300毫米（3）的体积为71％。通过蛋白质印迹和免疫荧光染色证实了内部组合处理的机制，结果表明Temsirolimus可以抑制HIF1α表达。因此，这项工作提供了用于使用VDA的机械理由，与MTOR抑制剂组合以增强抗癌功​​效，延迟肿瘤复发和抑制肿瘤转移。

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  • 来源
    《Biomaterials Science》 |2020年第1期|共8页
  • 作者

    Yu Haiyang; Shen Na; Bao Yanli; Chen Li; Tang Zhaohui;

  • 作者单位

    Northeast Normal Univ Dept Chem 5268 Renmin St Changchun 130024 Peoples R China;

    Chinese Acad Sci Changchun Inst Appl Chem Key Lab Polymer Ecomat 5625 Renmin St Changchun 130022 Peoples R China;

    Northeast Normal Univ Dept Chem 5268 Renmin St Changchun 130024 Peoples R China;

    Northeast Normal Univ Dept Chem 5268 Renmin St Changchun 130024 Peoples R China;

    Chinese Acad Sci Changchun Inst Appl Chem Key Lab Polymer Ecomat 5625 Renmin St Changchun 130022 Peoples R China;

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  • 正文语种 eng
  • 中图分类 分子生物学;
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