[Reprint] Theranostics | Tumor microenvironment responsive platinum single-atom nanoenzyme is used for synergistic treatment of chemoradiation and chemotherapy
*The superscript and subscript cannot be displayed on the headlines today. For a better reading experience, please go to the WeChat official account.
* Go to the " Nanozymes" official account to learn the latest news about nanozymes!
*This article was first published on the "Nanozymes" public account. September 26, 2022
* Editor: Yu Jiyuan
The high incidence and mortality rate of malignant tumors have seriously threatened human health. Currently, the treatment methods for malignant tumors mainly include surgical resection, radiotherapy, chemotherapy and other means. To date, chemotherapy and radiation therapy remain the main methods of cancer treatment, however, repeated treatments are prone to drug resistance. In order to improve the efficacy of tumor treatment, cancer treatment has gradually developed from single treatment to combined treatment, striving to achieve the therapeutic effect of "1+12". However, the serious side effects of combination therapy greatly limit its widespread clinical application, such as multidrug resistance, inefficient uptake or non-specific distribution. Therefore, it is of great significance to continuously improve the level of cancer treatment and to rationally design and develop highly efficient and low-toxic chemotherapy sensitizers.
Recently, Associate Researcher Team of Southwest University for Nationalities Yong Yuan reported a single-atom platinum nanoenzyme (PtN4C-SAzyme) prodrug, which has the characteristics of many catalytic active sites, high activity of diverse enzymes, strong surface charge density and X-ray absorption. It can achieve the effective reversal of the regulation of the tumor microenvironment and the multidrug resistance and radiation resistance, and is expected to transform into clinical practice.
As a new type of nanoenzyme, the development and application of single-atom nanoenzyme (SAzyme) has aroused the interest of more and more researchers. SAzyme combines the characteristics of nanomaterials and enzymes, with uniformly distributed atom active center and precise coordination structure, providing 100% atom utilization efficiency and active site density for efficient enzyme catalytic treatment, improving nanoenzyme technology to the atomic level and having excellent catalytic activity 10~100 times higher than traditional nanoenzymes. In this study, the researchers used cisplatin prodrug as raw material and synthesized a single-atom platinum nanoenzyme (PtN4C-SAzyme) prodrug using oxidative polymerization. PtN4C-SAzyme exhibits a diverse enzyme-like catalytic activity by mimicking catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD). This single-atom nanoenzyme with excellent catalytic activity and radiosensitization ability can effectively generate cytotoxic reactive oxygen species (ROS) and hydroxyl radicals (∙OH) using overexpressed H2O2 in the tumor microenvironment to eliminate cancer cells. At the same time, its SOD enzyme-like activity can allow H2O2 to accumulate cyclically and achieve a cascade reaction. Furthermore, PtN4C-SAzyme prodrug can continuously consume GSH in situ and release Pt2+ by changing the autocirculation of Pt(IV) and Pt(II) , thereby counteracting antioxidant effects and alleviating drug resistance of hypoxic tumors.
Figure 1. Schematic diagram of PtN4C-SAzyme for chemoradiation and chemotherapy collaborative treatment
1. Construction and characterization of PtN4C-SAzyme prodrug
PtN4C-SAzyme prodrug is used as raw material for cisplatin prodrug, further with 3, The synthetic PtN4C-SAzyme obtained by oxidative polymerization of 4-diaminopyridine (DAP) has uniform size and spherical morphology, and has atomically dispersed Pt-N-C site structure.
Figure 2. Structural characterization of PtN4C-SAzyme
2. The enzyme-like catalytic activity detection of PtN4C-SAzyme prodrug and DFT simulation calculation
in vitro simulation environment, the system The diversified enzyme-like activities and tumor microenvironment regulation performance of PtN4C-SAzyme prodrug in cascade reactions were discussed. The results showed that PtN4C-SAzyme prodrug has excellent catalytic activities of SOD, POD and CAT, and its microenvironment responsive multi-environment versatile enzyme-like activity has great potential in the collaborative treatment of chemoradiotherapy.
Figure 3. The diverse enzyme activity detection of PtN4C-SAzyme
3. The synergistic anti-tumor effect of PtN4C-SAzyme prodrug at the cell level
evaluated the "catalytic radiation" effect of PtN4C-SAzyme prodrug in vitro and at the cell level. The results showed that after X-ray treatment, the PtN4C-SAzyme prodrug produced a large amount of cytotoxic reactive oxygen species substances, and by depleting the reducing substance GSH in TME, the sensitivity of tumor cells to external X-rays is increased, and then the tumor is killed. This shows that PtN4C-SAzyme prodrug has a good radiosensitization effect, can consume endogenous GSH, and release Pt2+ at the same time, enhancing the efficiency of radiotherapy and chemotherapy. These results suggest that PtN4C-SAzyme prodrug has the potential to synergistic CDT and chemoradiotherapy treatment.
Figure 4. Detection of the diversified enzyme activity of PtN4C-SAzyme
IV. Anti-tumor effect and biosafety evaluation of PtN4C-SAzyme prodrug at the living level
According to the above results of the catalytic treatment experiments of PtN4C-SAzyme prodrug in vitro, we further studied its efficacy in vitro synergistic chemotherapy. Taking the 4T1 tumor transplantation of BALB/c nude mice as a model, its synergistic anti-tumor effect in vivo was studied. Experimental results show that PtN4C-SAzyme prodrug has significant effects in overcoming drug resistance and inhibiting tumor growth. Subsequently, the PtN4C-SAzyme prodrug was analyzed for toxicology to ensure its safe biological application. The biosafety of tumor cells and tumor-bearing mice at different nanometer drug doses was evaluated. At the same time, after 3 weeks and 3 months of the tail vein administration, the main organs or tissues and blood of the heart, liver, spleen, lungs, and kidneys of each group of mice were collected respectively, and used for pathological sections , blood routine and blood biochemical analysis. Experimental results show that PtN4C-SAzyme prodrug has high biosafety.
Figure 5. PtN4C-SAzyme In vivo Anti-tumor Research
5. Summary
This study introduced the X-ray-responsive PtN4C-SAzyme prodrug system into the treatment of breast cancer , resulting in new rules and new phenomena different from traditional chemotherapy or radiotherapy drugs for tumor treatment, providing a new perspective for SAzyme's rational design. In addition, PtN4C-SAzyme showed good biocompatibility, providing favorable conditions for its in vivo application and clinical transformation. This work not only helps to fully explain key data such as radiotherapy sensitization mechanism and biosafety of nanomaterials, but also helps to further understand the structural effect relationship between nanomaterials and radiotherapy sensitization, providing a new strategy for tumor treatment that combines multicatalytic therapy.
This research result was recently titled in the first district of biomedical journal "Theranostics" (2021 IF: 11.600) (DOI: 10.7150/thno.73039), the associate researcher of Yong Yuan from the School of Chemistry and Environment of Southwest University for Nationalities is the corresponding author of of the article, and the members of the research group Xu Qiqi and Zhang Yuetong are the tiered first authors of the article.
References:
Qiqi Xu, Yuetong Zhang, Zulu Yang, Guohui Jiang, Mingzhu Lv, Huan Wang, Chenghui Liu, Jiani Xie, Chengyan Wang, Kun Guo, Zhanjun Gu, Yuan Yong. Tumor microenvironment-activated single-atom platinum nanozyme with H2O2 self-supplement and O2-evolving for tumor-specific cascade catalysis chemodynamic and chemicalotherapy. Theranostics. 2022. 12 (11): 5155-5171.
Original link:
https://www.thno.org/v12p5155.html
Author profile:
Yong Yuan, currently a teacher at the School of Chemistry and Environmental Protection Engineering, Southwest University for Nationalities.PhD, associate researcher, graduated from the Institute of High Energy Physics, Chinese Academy of Sciences. He teaches courses such as inorganic chemistry, material chemistry, inorganic non-metallic materials. More than 20 papers have been published in high-level journals such as ACS NANO, NPG Asia Materials, Theranostics, ACS Applied Materials & Interfaces, Nanoscale and other high-level journals. The research results have attracted widespread attention. SCI cited more than 900 times, and 4 papers were selected as ESI high-cited papers, and were selected as cover articles and reported as research highlights by technology websites such as X-MOL.
