Department of Biomedical Sciences and BioMedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Gwangju 61469, Republic of Korea.
Center for Global Future Biomedical Scientists at Chonnam National University, Chonnam National University Medical School, Hwasun 58128, Republic of Korea.
Biomater Sci. 2023 Sep 12;11(18):6177-6192. doi: 10.1039/d3bm00618b.
Radiation therapy (RT) is a mainstream clinical approach in cancer treatment. However, the therapeutic efficacy of RT is greatly hindered by the presence of excessive hydrogen peroxide (HO) in the hypoxic region of the solid tumor, thus leading to tumor recurrence and metastasis. Herein, a thioketal-linked amphiphilic nano-assembly (MTS) loaded with hydrophobic manganese oxide (HMO) nanoparticles (MTS@HMO) is examined as a promising multi-purpose reactive oxygen species (ROS)-catalytic nanozyme for transforming an RT-resistant hypoxic tumor microenvironment (TME) into an RT-susceptible one by scavenging ROS in the hypoxic core of the solid tumor. After intravenous injection, the MTS@HMO nano-assembly was able to sense and be degraded by the abundant ROS in the hypoxic TME, thereby releasing HMO particles for subsequent scavenging of HO. The oxygen generated during peroxide scavenging then relieved the hypoxic TME, thereby resulting in an increased sensitivity of the hypoxic tumor tissue towards RT. Moreover, the hypoxic status was monitored the 1-enhanced magnetic resonance (MR) imaging of the Mn ions generated by the ROS-mediated degradation of HMO. The results demonstrated a significant HO elimination and enhanced oxygen generation after the treatment of the MTS@HMO nano-assembly with tumor cells under hypoxic conditions, compared to the control MTS group. In addition, the combination of RT and pre-treatment with MTS@HMO nano-assembly significantly amplified the permanent DNA strand breaks in tumor cells compared to the control RT group. More importantly, the results proved that the systemic injection of the MTS@HMO nano-assembly prior to RT irradiation enhanced the RT-mediated tumor suppression and down-regulated the hypoxic marker of HIF-1α in the solid tumor compared to the control RT group. Overall, the present work demonstrates the great potential of the versatile ROS-catalytic hypoxia modulating strategy using the MTS@HMO nano-assembly to enhance the RT-induced antitumor efficacy in hypoxic solid tumors.
放射治疗（RT）是癌症治疗的一种主流临床方法。然而，由于实体瘤缺氧区域中存在过量的过氧化氢（HO），RT 的治疗效果受到了极大的阻碍，从而导致肿瘤复发和转移。在此，研究了一种硫代缩醛连接的两亲性纳米组装体（MTS）负载疏水性氧化锰（HMO）纳米颗粒（MTS@HMO），作为一种有前途的多用途活性氧（ROS）催化纳米酶，通过清除实体瘤缺氧核心中的 ROS，将 RT 抵抗性缺氧肿瘤微环境（TME）转化为 RT 敏感型。静脉注射后，MTS@HMO 纳米组装体能够被缺氧 TME 中的丰富 ROS 感应和降解，从而释放 HMO 颗粒以随后清除 HO。而过氧化物清除过程中产生的氧气缓解了缺氧 TME，从而使缺氧肿瘤组织对 RT 的敏感性增加。此外，通过 ROS 介导的 HMO 降解产生的 Mn 离子的 1 增强磁共振（MR）成像监测缺氧状态。结果表明，与对照组 MTS 相比，在缺氧条件下用 MTS@HMO 纳米组装体处理肿瘤细胞后，HO 的消除和氧气的生成显著增加。此外，与对照组 RT 相比，RT 联合 MTS@HMO 纳米组装体预处理显著放大了肿瘤细胞中的永久性 DNA 链断裂。更重要的是，结果证明，与对照组 RT 相比，在 RT 照射前系统注射 MTS@HMO 纳米组装体增强了 RT 介导的肿瘤抑制作用，并下调了实体瘤中缺氧标志物 HIF-1α。总体而言，本工作证明了使用 MTS@HMO 纳米组装体进行多功能 ROS 催化缺氧调节策略的巨大潜力，可增强 RT 诱导的缺氧实体瘤抗肿瘤疗效。
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