Mei Ting, Shashni Babita, Maeda Hiroshi, Nagasaki Yukio
Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki, 305-8573, Japan; Present Address: School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China.
Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba, Ibaraki, 305-8573, Japan.
Biomaterials. 2020 Nov;259:120290. doi: 10.1016/j.biomaterials.2020.120290. Epub 2020 Aug 14.
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-κB. Conclusively, this study provides a new strategy to enhance the delivery of nanotherapeutics into solid tumors.
实体肿瘤内良好的血流已成为药物递送的主要策略。使用溶栓药物，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，可能通过纤维蛋白降解和血流恢复来增加实体肿瘤附近的药物递送，从而提高其治疗效果。因此，我们设计了安装有t-PA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，从而改善抗氧化纳米颗粒在肿瘤中的灌注。此外，还开发了抗氧化iRNP，通过降低肿瘤中关键升高的活性氧（ROS）水平来抑制肿瘤。当将t-PA@iRNP应用于结肠癌模型时，它降解沉积的纤维蛋白，并通过恢复的血流改善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-κB的下调。总之，本研究提供了一种增强纳米治疗药物向实体肿瘤递送的新策略。
