On December 13, 2019, a new enzyme-loaded magnetic nanogel came out, which was jointly developed by the teams of CHENG Yu, professor from TUSM and Affiliated East Hospital and WANG Qigang, from Tongji University School of Chemical Science and Engineering, can be used to efficiently kill cancer cells. The results were published online in Angew. Chem. Int. Ed. (DOI: 10.1002 / anie.201915118.).

Cheng Yu introduced that it is our dream to completely cure tumors. However, cancer cells have three characteristics different from normal cells: infinite proliferation, transformability and easy metastasis. In addition to uncontrolled division, cancer also invade surrounding tissues and even metastasize to other parts via circulatory system or lymphatic system. Scientists and doctors have been fighting for nearly a century to find the golden key to defeat cancer.

Wang Qigang believes that tumor cells rely on their own antioxidant defense system to maintain reactive oxygen species (ROS) level to reach oxidation-reduction balance for normal physiological activities. Can anti-tumor treatment be achieved by up-regulating the ROS level in tumor area, breaking its fragile redox balance, making them dysfunctional, even apoptosis and necrosis? At present, physical factors such as radiation and laser are generally applied to produce exogenous ROS to kill tumor cells, among which radiotherapy and photodynamic therapy are representative.

Aerobic respiration and metabolic processes from mitochondria produce endogenous ROS and whether it’s possible to increase ROS by exerting external physical control forces on specific catalytic activity of biological enzymes in the body? WANG Qigang's team and CHENG Yu's team hit it off and decided to adopt an "ignition" method to explore new anti-tumor methods.

They used magnetic nanomaterials as a medium to "ignite" tumors, triggering the "explosion" of endogenous ROS through efficient biocatalysis of enzymes, and developed a new type of enzyme-loaded magnetic nanogels (MNP-CPO @ Nanogels) as a programmable neutrophil mimic. The nanogels can control the singlet oxygen (1O2), who possesses the strongest oxidaive activity, combining magnetic with enzyme therapy (METT). It is reported that the magnetic nanogel uses zinc-doped magnetic iron oxide trioxide (Fe3O4) nanoparticles as the core, and coated with small molecule oligopeptide as a layer of gel, which is induced by acid phosphatase. At the same time, with the help of non-covalent bond, chloroperoxidase (CPO) is loaded, so the nanomaterial is stabilized and acquires catalytic activity. At the cellular level, this new type of enzyme-loaded magnetic nanogel-mediated magnetic enzyme combination therapy can regulate intracellular 1O2 sequentially. Magnetothermal (43 ℃) can trigger hydrogen peroxide (H2O2) product, which is then catalyzed by chloroperoxidase to produce more toxic 1O2, forcing 80% of tumor cells to apoptosis.

Diagram of METT

The results showed that in situ glioma model, METT could prolong the survival of tumor mice by 30%. In addition, in subcutaneous breast cancer, the new nanogel via tail vein administration could be enriched in tumor site after magnetic guidance, and showed significant inhibitory effect. In intratumoral administration group, METT made the tumors disappeared completely. Besides, there is no significant damage to normal tissues.

According to Prof. CHENG, the results show that METT can achieve spatiotemporal control of thermal and biochemical signals as well as the penetration depth of tissue through external magnetic field, effectively and safely, providing a new method of physical and biochemical co-therapy for deep tumor eradication.

The co-first authors of this paper are ZHANG Qi, PhD candidate from WANG Qigang’s team, WU Jiaojiao, PhD candidate and WANG Jingjing, research assistant from CHENG Yu’s team. The co-corresponding authors are Prof. Wang, and Prof. Cheng. This project is strongly supported by the National Key Research and Development Plan, Special Development Fund of Zhangjiang National Independent Innovation Demonstration Zone, the National Natural Science Fund, Major Innovation Projects of Scientific Research Innovation Plan of Shanghai Education Commission, Shanghai Science and Technology Commission and the Central University Fund.

It is understood that the two teams will continue to deepen the METT mechanism research，actively promote the clinical transformation, and provide a more efficient and safe "fire" for anti-tumor cause.