Key Laboratory of Polyoxometalate and Reticular Material Chemistry of Ministry of Education, National & Local United Engineering Laboratory for Power Batteries, Key Laboratory of Nanobiosensing and Nanobioanalysis at Universities of Jilin Province, Analysis and Testing Center, Department of Chemistry, Northeast Normal University, Changchun, Jilin Province 130024, China.
Key Laboratory of Polyoxometalate and Reticular Material Chemistry of Ministry of Education, National & Local United Engineering Laboratory for Power Batteries, Key Laboratory of Nanobiosensing and Nanobioanalysis at Universities of Jilin Province, Analysis and Testing Center, Department of Chemistry, Northeast Normal University, Changchun, Jilin Province 130024, China.
Acta Biomater. 2021 Nov;135:617-627. doi: 10.1016/j.actbio.2021.08.015. Epub 2021 Aug 15.
Reactive oxygen species (ROS)-mediated antitumor modalities that induced oxidative damage of cancer cells have recently acquired increasing attention on account of their noninvasiveness, low systemic toxicity, and high specificity. However, their clinical efficacy was often constrained by complex and various tumor microenvironment (TME), especially hypoxia characteristic and antioxidation effect of glutathione (GSH). Herein, we constructed a multinanozyme system based on hyaluronic acid (HA)-stabilized CuMnO nanoparticles (CMOH) loaded with indocyanine green (ICG) with high-efficient ROS generation, O self-evolving function, GSH depletion ability and hyperthermia effect for achieving hypoxic tumor therapy. The CMOH nanozymes exhibited peroxidase-like and oxidase-like activities, which could efficiently catalyze HO or O to generate hydroxyl radicals (•OH) or superoxide radicals (•O) in acidic tumor microenvironment (TME), elevating oxidative stress of tumor. Indocyanine green (ICG) was further loaded into HA-CuMnO to form HA-CuMnO@ICG nanocomposites (CMOI NCs), which can effectively generate singlet oxygen (O) and local hyperthermia under light irradiation. The hyperthermia generated by CMOI NCs further enhances the catalytic activities of nanozymes for ROS generation. Meanwhile, the CMOI with catalase-like activity could catalyze HO into O for relieving tumor hypoxia and elevate O-dependent ROS generation. Notably, CMOI can consume endogenous GSH, thereby impairing tumor antioxidant system and enhancing ROS-based therapy efficacy. After modified with HA, CMOI NCs with tumor targeting ability realized synergistic PTT-enhanced tumor oxidation therapy based on their multimodal properties. Thus, this work contributes to design high-performance therapeutic reagent to overcome the limitation of hypoxia and high antioxidant defense of tumor. STATEMENT OF SIGNIFICANCE: Reactive oxygen species (ROS)-mediated antitumor modalities were often constrained by complex and various tumor microenvironment (TME), especially hypoxia characteristic and antioxidation effect of glutathione (GSH). In this work, a multinanozyme system based on hyaluronic acid (HA)-stabilized CuMnO nanoparticles (CMOH) loaded with indocyanine green (ICG) was designed to realize PTT-enhanced multiple catalysis tumor therapy. Although antitumor modalities based on multienzyme catalysis have been developed. Here, we highlighted the responsive catalysis of multienzyme system on tumor microenvironment (TME) and the promoting effect of photothermal effect on ROS production. Both in vitro and in vivo manifested that the enhanced anticancer efficacy of CMOI NCs due to their thermally amplified catalytic activity and TME regulation ability.
活性氧（ROS）介导的抗肿瘤方式通过诱导癌细胞发生氧化损伤而受到越来越多的关注，因为它们具有非侵入性、全身毒性低和特异性高的特点。然而，其临床疗效常常受到复杂多样的肿瘤微环境（TME）的限制，尤其是谷胱甘肽（GSH）的缺氧特征和抗氧化作用。在此，我们构建了一种基于透明质酸（HA）稳定的载有吲哚菁绿（ICG）的 CuMnO 纳米粒子（CMOH）的多酶纳米体系，该体系具有高效 ROS 生成、O 自衍生功能、GSH 耗竭能力和高热效应，可实现缺氧肿瘤治疗。CMOH 纳米酶具有过氧化物酶和氧化酶样活性，可在酸性肿瘤微环境（TME）中高效催化 HO 或 O 生成羟基自由基（•OH）或超氧自由基（•O），从而提高肿瘤的氧化应激。吲哚菁绿（ICG）进一步负载到 HA-CuMnO 中形成 HA-CuMnO@ICG 纳米复合物（CMOI NCs），在光照射下可有效生成单线态氧（O）和局部热疗。CMOI NCs 产生的热疗进一步增强了纳米酶生成 ROS 的催化活性。同时，具有过氧化氢酶样活性的 CMOI 可以将 HO 催化为 O，从而缓解肿瘤缺氧并提高 O 依赖性 ROS 生成。值得注意的是，CMOI 可以消耗内源性 GSH，从而破坏肿瘤抗氧化系统并增强基于 ROS 的治疗效果。经 HA 修饰后，具有肿瘤靶向能力的 CMOI NCs 基于其多模态特性实现了协同 PTT 增强肿瘤氧化治疗。因此，这项工作有助于设计高性能治疗试剂以克服肿瘤缺氧和高抗氧化防御的限制。
ROS 介导的抗肿瘤方式常受到复杂多样的肿瘤微环境（TME）的限制，尤其是谷胱甘肽（GSH）的缺氧特征和抗氧化作用。在这项工作中，设计了一种基于透明质酸（HA）稳定的载有吲哚菁绿（ICG）的 CuMnO 纳米粒子（CMOH）的多酶纳米体系，以实现 PTT 增强的多种催化肿瘤治疗。尽管已经开发了基于多酶催化的抗肿瘤方法，但在这里，我们强调了多酶系统对肿瘤微环境（TME）的响应性催化以及光热效应对 ROS 生成的促进作用。体外和体内实验均表明，由于其热放大催化活性和 TME 调节能力，CMOI NCs 的抗癌效果得到增强。
