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./nMethods: 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)./nResults: 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./nConclusions: HSA-MnO₂-CQ NPs synergistically regulated the abnormal TME and inhibited autophagic flux, and effectively sensitized radiation therapy to treat bladder cancers.

中文翻译：

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肿瘤微环境重塑和自噬抑制增敏放射治疗膀胱癌的协同作用。

肿瘤缺氧，酸中毒和过量的活性氧（ROS）是膀胱肿瘤微环境（TME）的主要特征，而异常的TME导致自噬激活，从而促进了癌细胞的增殖。自噬抑制剂的治疗功效也可能受到异常TME的阻碍。为了解决这些问题，提出了一种新的策略，使用二氧化锰（MnO的₂）纳米粒子以优化异常TME和振兴自噬抑制剂，并且两个氧化和自噬抑制可敏化肿瘤细胞对辐射therapy./n方法：通过取带负电的MnO ₂之间的强亲和力的优点和带正电荷的氯喹（CQ），通过将MnO ₂和CQ整合到基于人血清白蛋白（HSA）的纳米平台（HSA-MnO ₂ -CQ NPs）中来制备纳米颗粒。/n结果： HSA-MnO ₂ -CQ NPs NPs与H ⁺ / H ₂ O ₂反应后，在体外有效产生O ₂并提高pH值，然后在H ⁺ / H ₂ O _2中释放封装的CQ浓度依赖性的方式。在酸性条件下，NPs通过增加其细胞内摄取恢复了氯喹的自噬抑制活性，并显着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，并有效地积累在肿瘤组织中。NPs表现出明显减少的肿瘤缺氧面积和增加的肿瘤pH，并且对膀胱肿瘤具有显着的自噬抑制功效。最后，通过增强自噬抑制作用和放射增敏作用，可以获得显着的抗肿瘤作用。/n结论： HSA-MnO ₂-CQ NP协同调节异常TME并抑制自噬通量，并有效地使放射疗法敏化以治疗膀胱癌。