Tumor microenvironment-responsive fenton nanocatalysts for intensified anticancer treatment

(2022) 20:69 Wang et al. Journal of Nanobiotechnology https://doi.org/10.1186/s12951-022-01278-z Journal of Nanobiotechnology Open Access REVIEW Tumor microenvironment‑responsive fenton nanocatalysts for intensified anticancer treatment Yandong Wang1, Fucheng Gao1, Xiaofeng Li1, Guiming Niu1, Yufei Yang1, Hui Li1* and Yanyan Jiang1,2* Abstract Chemodynamic therapy (CDT) based on Fenton or Fenton-like reactions is an emerging cancer treatment that can both effectively fight cancer and reduce side effects on normal cells and tissues, and it has made important progress in cancer treatment. The catalytic efficiency of Fenton nanocatalysts(F-NCs) directly determines the anticancer effect of CDT. To learn more about this new type of therapy, this review summarizes the recent development of F-NCs that are responsive to tumor microenvironment (TME), and detailedly introduces their material design and action mechanism. Based on the deficiencies of them, some effective strategies to significantly improve the anticancer efficacy of F-NCs are highlighted, which mainly includes increasing the temperature and hydrogen peroxide concentration, reducing the pH, glutathione (GSH) content, and the dependence of F-NCs on acidic environment in the TME. It also discusses the differences between the effect of multi-mode therapy with external energy (light and ultrasound) and the single-mode therapy of CDT. Finally, the challenges encountered in the treatment process, the future development direction of F-NCs, and some suggestions are analyzed to promote CDT to enter the clinical stage in the near future. Keywords: Nanocatalyst, Fenton reaction, Tumor microenvironment, Multi-mode therapy, Cancer treatment *Correspondence: ; 1 Key Laboratory for Liquid‑Solid Structural Evolution & Processing of Materials (Ministry of Education), School of Materials Science and Engineering, Shandong University, Jinan, Shandong 250061, People’s Republic of China Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wang et al. Journal of Nanobiotechnology (2022) 20:69 Page 2 of 33 Graphical Abstract Introduction Malignant tumor is one of the main causes of death in the world. It has become a major disease that seriously endangers human life and health and restricts social and economic development [1, 2]. Traditional methods of cancer treatment mainly include surgical resection, radiotherapy, and chemotherapy [3, 4]. However, conventional treatments have many limitations (such as low selectivity, easy recurrence, large side effects, and so on) [5]. Fortunately, nanotechnology shows great potentials to improve the anticancer effect and reduce the side effects, and various nanomedicines are widely applied to different new therapeutic methods, including hyperthermia therapy, sonodynamic therapy (SDT), immunotherapy, and chemodyanic therapy (CDT) [6]. Among them, CDT has attracted much attention in recent years due to its strong oxidative lethality to cells and specific suborganelles [7]. CDT is an emerging and minimally invasive cancer treatment, it is defined as the transformation of endogenous H2O2 through Fenton or Fenton-like reactions into highly harmful hydroxyl radical (•OH), which is known as the most oxidizing reactive oxygen species (ROS), and can induce massive apoptosis of tumor cells by damaging DNA and inactivating proteins [8]. Compared with normal cells, cancer cells have a unique way of proliferation, metabolic activity, and mitochondrial dysfunction so that the tumor tissue has a unique structure and physical properties. Especially, the content of hydrogen peroxide (H2O2) in tumor tissues is far higher than that of normal tissues [9]. CDT relies on the higher expression of H2O2 in tumors, so this method is highly selective and Wang et al. Journal of Nanobiotechnology (2022) 20:69 can reduce the damage to normal tissues [10, 11]. However, the low efficiency of CDT limits its potential clinical applications. Fenton and Fenton-like reactions are the basis of CDT, which determine the efficiency of this treatment, the equation of Fenton reaction is shown in Fig. 1a [8]. The discovery of Fenton reaction comes from the British scientist H. J. H. Fenton. In 1983, he first proved that H 2O2 in acidic environment has the ability to oxidize various organic substances under the catalysis of iron ions, and this technology has widely applied to the field of wastewater treatment [12]. Inspired by this technology, various metals with Fenton-like effect have been developed and applied to cancer treatment, such as Au [13], Ag [14], Cu [15], Mn [16], and so on. However, the tumor is not the best place for Fenton reaction, which greatly reduces the efficiency of CDT. To improve the therapeutic effect of chemical kinetics, three conditions must be met to produce sufficient hydroxyl radicals (•OH). First, sufficient hydrogen peroxide concentration. The concentration of H 2O2 in the tumor microenvironment (TME) is not enough to continuously produce •OH [17]. Therefore, increasing the level of H 2O2 in the TME is the main method to solve this problem. Second, the generation rate of •OH must be fast enough to produce strong oxidation to the tumor in a short time, so as to avoid the resurrection of cancer cells. The generation rate of •OH can be adjusted by changing the reaction conditions (such as temperature and pH) and optimizing the structure and composition of F-NCs [18, 19]. Third, •OH produced by Fenton or Fenton-like reactions should attack cancer cells Page 3 of 33 directly as much as possible, rather than being captured by reducing substances in the TME, such as (GSH) [20]. In addition to the above strategies, another direct way to improve the therapeutic effect of CDT is multi-mode therapy. For example, CDT combined with photothermal therapy (PTT), photodynamic therapy (PDT), or SDT. The combination of CDT and (...truncated)