Department of Urology, Drum Tower Hospital, Medical school of Nanjing University, Institute of Urology, Nanjing University, Nanjing 210008, Jiangsu, China.
State Key Laboratory of Pharmaceutical Biotechnology, Medical School of Nanjing University, Nanjing 210093, Jiangsu, China.
Theranostics. 2020 Jun 19;10(17):7683-7696. doi: 10.7150/thno.45358. eCollection 2020.
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 (MnO) nanoparticles to optimize the abnormal TME and revitalize autophagy inhibitors, and both oxygenation and autophagy inhibition may sensitize the tumor cells to radiation therapy. By taking advantage of the strong affinity between negatively charged MnO and positively charged chloroquine (CQ), the nanoparticles were fabricated by integrating MnO and CQ in human serum albumin (HSA)-based nanoplatform (HSA-MnO-CQ NPs). HSA-MnO-CQ NPs NPs efficiently generated O and increased pH after reaction with H/HO and then released the encapsulated CQ in a H/HO 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. 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. HSA-MnO-CQ NPs synergistically regulated the abnormal TME and inhibited autophagic flux, and effectively sensitized radiation therapy to treat bladder cancers.
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，异常的 TME 导致自噬激活，从而促进癌细胞增殖。自噬抑制剂的治疗效果也可能受到异常 TME 的阻碍。为了解决这些问题，我们提出了一种新的策略，即利用二氧化锰（MnO）纳米粒子来优化异常的 TME 并使自噬抑制剂恢复活力，氧合和自噬抑制都可能使肿瘤细胞对放射治疗更敏感。 通过利用带负电荷的 MnO 与带正电荷的氯喹（CQ）之间的强亲和力，将 MnO 和 CQ 整合到人血清白蛋白（HSA）基纳米平台（HSA-MnO-CQ NPs）中制备纳米粒子。 HSA-MnO-CQ NPs 与 H/HO 反应后，可有效产生 O 和提高 pH 值，然后以 H/HO 浓度依赖的方式释放包裹的 CQ。纳米粒子通过增加其细胞内摄取来恢复 CQ 在酸性条件下的自噬抑制活性，并显著阻断缺氧诱导的自噬流。 研究表明，纳米粒子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。纳米粒子显示出明显减少肿瘤缺氧区域和增加肿瘤 pH 值的作用，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增敏作用实现了显著的抗肿瘤效果。 HSA-MnO-CQ NPs 协同调节异常的 TME 并抑制自噬流，有效增强了放射治疗治疗膀胱癌的效果。
