Fibrinolytic tissue plasminogen activator installed redox-active nanoparticles (t-PA@iRNP) for cancer therapy
Fibrinolytic tissue plasminogen activator installed redox-active nanoparticles (t-PA@iRNP) for cancer therapy
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DOI：
10.1016/j.biomaterials.2020.120290
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发表时间：
2020-11-01
期刊：
影响因子：
14
通讯作者：
Nagasaki, Yukio
中科院分区：
文献类型：
--
作者：
Mei, Ting;Shashni, Babita;Nagasaki, Yukio
实体瘤内良好的血流已成为药物输送的主要策略。溶栓药物如组织纤溶酶原激活剂（t-PA）与其他药物或药物载体联合使用，可通过纤维蛋白降解和血流恢复增加实体瘤附近的药物递送，从而提高其治疗效果。因此，我们设计了t- pa安装的氧化还原活性纳米颗粒（t-PA@iRNP），通过纤维蛋白降解来减压肿瘤血管，以改善抗氧化纳米颗粒在肿瘤中的灌注。此外，抗氧化剂iRNP通过降低肿瘤中严重升高的活性氧（ROS）水平来抑制肿瘤。当给药于结肠癌模型时，t-PA@iRNP可降解沉积的纤维蛋白，并通过恢复的血流提高iRNP和免疫细胞在肿瘤组织中的渗透，从而更有效地抑制肿瘤生长。iRNP的抗肿瘤作用归因于ros减少介导的关键转录因子NF-kappa b的下调。最后，本研究为增强纳米治疗药物进入实体瘤的递送提供了一种新的策略。
Favorable blood flow within solid tumors has become the principal strategy for drug delivery. The use of thrombolytic drugs, such as tissue plasminogen activator (t-PA), in combination with other drugs or drug carriers may increase their therapeutic effect by increasing drug delivery near the solid tumor through fibrin degradation and blood flow restoration. We, therefore, designed t-PA-installed redox-active nanoparticles (t-PA@iRNP) to improve the perfusion of antioxidant nanoparticles in tumors, via fibrin degradation to decompress tumor vessels. Additionally, antioxidant iRNP was developed for tumor inhibition by reduction of critically elevated levels of reactive oxygen species (ROS) in tumors. The t-PA@iRNP, when administered to a colon cancer model, degraded the deposited fibrin and improved the iRNP and immune cells penetration in tumor tissues via the restored blood flow, thus more effectively inhibited tumor growth. The anti-tumor effect of iRNP was attributed to ROS-reduction mediated downregulation of crucial a transcriptional factor, NF-kappa B. Conclusively, this study provides a new strategy to enhance the delivery of nanotherapeutics into solid tumors.