Synergy of Tumor Microenvironment Remodeling and Autophagy Inhibition to Sensitize Radiation for Bladder Cancer Treatment
Synergy of Tumor Microenvironment Remodeling and Autophagy Inhibition to Sensitize Radiation for Bladder Cancer Treatment
复制标题
肿瘤微环境重塑和自噬抑制的协同作用使膀胱癌治疗的放射敏感
DOI：
10.7150/thno.45358
复制
发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Guo, Hongqian
中科院分区：
文献类型：
--
作者：
Lin, Tingsheng;Zhang, Qing;Guo, Hongqian
肿瘤缺氧、酸中毒、活性氧（ROS）过多是膀胱肿瘤微环境（TME）的主要特征，TME异常导致自噬激活，促进癌细胞增殖。TME异常也可能影响自噬抑制剂的治疗效果。为了解决这些问题，我们提出了一种利用二氧化锰（MnO2）纳米颗粒优化异常TME和活化自噬抑制剂的新策略，氧合和自噬抑制都可能使肿瘤细胞对放射治疗敏感。方法：利用带负电荷的MnO2和带正电荷的氯喹（CQ）之间的强亲和力，将MnO2和CQ整合到人血清白蛋白（HSA）纳米平台（HSA-MnO2-CQ NPs）中制备纳米颗粒。结果：HSA-MnO2-CQ NPs NPs在体外与H+/H2O2反应后能有效生成O2，提高pH值，并以H+/H2O2浓度依赖性释放包被的CQ。NPs通过增加氯喹在细胞内的摄取，恢复了氯喹在酸性条件下的自噬抑制活性，并显著阻断了缺氧诱导的自噬通量。体内研究表明，NPs改善了氯喹的药代动力学行为，并有效地在肿瘤组织中积累。NPs显著降低肿瘤缺氧面积，增加肿瘤pH，对膀胱肿瘤具有显著的自噬抑制作用。最后，通过增强自噬抑制和辐射致敏来实现显著的抗肿瘤作用。结论：HSA-MnO2-CQ NPs协同调节异常TME，抑制自噬通量，有效增敏放疗治疗膀胱癌。
Tumor hypoxia, acidosis, and excessive reactive oxygen species (ROS) were the main characteristics of the bladder tumor microenvironment (TME), and abnormal TME led to autophagy activation, which facilitated cancer cell proliferation. The therapeutic efficacy of autophagy inhibitors might also be impeded by abnormal TME. To address these issues, we proposed a new strategy that utilized manganese dioxide (MnO2) nanoparticles to optimize the abnormal TME and revitalize autophagy inhibitors, and both oxygenation and autophagy inhibition may sensitize the tumor cells to radiation therapy. Methods: By taking advantage of the strong affinity between negatively charged MnO2 and positively charged chloroquine (CQ), the nanoparticles were fabricated by integrating MnO2 and CQ in human serum albumin (HSA)-based nanoplatform (HSA-MnO2-CQ NPs). Results: HSA-MnO2-CQ NPs NPs efficiently generated O2 and increased pH in vitro after reaction with H+/H2O2 and then released the encapsulated CQ in a H+/H2O2 concentration-dependent manner. The NPs restored the autophagy-inhibiting activity of chloroquine in acidic conditions by increasing its intracellular uptake, and markedly blocked hypoxia-induced autophagic flux. In vivo studies showed the NPs improved pharmacokinetic behavior of chloroquine and effectively accumulated in tumor tissues. The NPs exhibited significantly decreased tumor hypoxia areas and increased tumor pH, and had remarkable autophagy inhibition efficacy on bladder tumors. Finally, a significant anti-tumor effect achieved by the enhanced autophagy inhibition and radiation sensitization. Conclusions: HSA-MnO2-CQ NPs synergistically regulated the abnormal TME and inhibited autophagic flux, and effectively sensitized radiation therapy to treat bladder cancers.