College of Materials Science and Engineering, Jilin Institute of Chemical Technology, Jilin City 132022, Jilin Province, China.
Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine and Center for Molecular and Cellular Imaging, Samsung Biomedical Research Institute, Seoul 06351, the Republic of Korea.
J Colloid Interface Sci. 2024 Jul;665:188-203. doi: 10.1016/j.jcis.2024.03.133. Epub 2024 Mar 23.
Anti-tumor therapies reliant on reactive oxygen species (ROS) as primary therapeutic agents face challenges due to a limited oxygen substrate. Photodynamic therapy (PDT) is particularly hindered by inherent hypoxia, while chemodynamic therapy (CDT) encounters obstacles from insufficient endogenous hydrogen peroxide (HO) levels. In this study, we engineered biodegradable tumor microenvironment (TME)-activated hollow mesoporous MnO-based nanotheranostic agents, designated as HAMnOA. This construct entails loading artemisinin (ART) into the cavity and surface modification with a mussel-inspired polymer ligand, namely hyaluronic acid-linked poly(ethylene glycol)-diethylenetriamine-conjugated (3,4-dihydroxyphenyl) acetic acid, and the photosensitizer Chlorin e6 (mPEG-HA-Dien-(Dhpa/Ce6)), facilitating dual-modal imaging-guided PDT/CDT synergistic therapy. In vitro experimentation revealed that HAMnOA exhibited ideal physiological stability and enhanced cellular uptake capability via CD44-mediated endocytosis. Additionally, it was demonstrated that accelerated endo-lysosomal escape through the pH-dependent protonation of Dien. Within the acidic and highly glutathione (GSH)-rich TME, the active component of HAMnOA, MnO, underwent decomposition, liberating oxygen and releasing both Mn and ART. This process alleviates hypoxia within the tumor region and initiates a Fenton-like reaction through the combination of ART and Mn, thereby enhancing the effectiveness of PDT and CDT by generating increased singlet oxygen (O) and hydroxyl radicals (•OH). Moreover, the presence of Mn ions enabled the activation of T-weighted magnetic resonance imaging. In vivo findings further validated that HAMnOA displayed meaningful tumor-targeting capabilities, prolonged circulation time in the bloodstream, and outstanding efficacy in restraining tumor growth while inducing minimal damage to normal tissues. Hence, this nanoplatform serves as an efficient all-in-one solution by facilitating the integration of multiple functions, ultimately enhancing the effectiveness of tumor theranostics.
基于活性氧 (ROS) 的抗肿瘤疗法作为主要治疗药物，由于氧气底物有限而面临挑战。光动力疗法 (PDT) 特别受到固有缺氧的限制，而化学动力学疗法 (CDT) 则受到内源性过氧化氢 (HO) 水平不足的阻碍。在这项研究中，我们设计了可生物降解的肿瘤微环境 (TME) 激活的中空介孔 Mn 基纳米治疗剂，命名为 HAMnOA。该结构包括将青蒿素 (ART) 装载到空腔中，并通过贻贝启发的聚合物配体（即透明质酸连接的聚乙二醇-二亚乙基三胺偶联（3,4-二羟基苯基）乙酸）和光敏剂 Chlorin e6（mPEG-HA-Dien-（Dhpa/Ce6））进行表面修饰，便于双模式成像引导的 PDT/CDT 协同治疗。体外实验表明，HAMnOA 表现出理想的生理稳定性和通过 CD44 介导的内吞作用增强的细胞摄取能力。此外，通过 Dien 的 pH 依赖性质子化证明了加速内体 - 溶酶体逃逸。在酸性和富含谷胱甘肽 (GSH) 的 TME 中，HAMnOA 的活性成分 MnO 分解，释放氧气并释放 Mn 和 ART。这一过程缓解了肿瘤区域的缺氧，并通过 ART 和 Mn 的结合引发类 Fenton 反应，从而通过产生更多的单线态氧 (O) 和羟基自由基 (•OH) 来增强 PDT 和 CDT 的效果。此外，Mn 离子的存在使 T 加权磁共振成像得以激活。体内研究结果进一步验证了 HAMnOA 具有有意义的肿瘤靶向能力、延长在血液中的循环时间以及在抑制肿瘤生长的同时对正常组织造成最小损伤的出色功效。因此，这种纳米平台通过促进多种功能的整合，成为一种有效的一体化解决方案，最终增强肿瘤治疗效果。
