Recently, Junwei Zhao's team from the College of Chemistry and Molecular Sciences in Henan University has made new progress in the preparation of giant polyoxometalate clusters and the study on the anti-tumor activity. The related progress entitled "A Giant Heterometallic Polyoxometalate Nanocluster for Enhanced Brain-Targeted Glioma Therapy” has been published in Angew. Chem. Int. Ed. 2024, 63, e202319700.

Brain tumors have a special blood-brain barrier (BBB), which blocks almost all drugs from entering the brain. At the same time, existing drugs have poor tumor targeting and low drug activity, making glioma still lack effective treatment drugs. Giant polyoxometalates (POMs) clusters have a very promising brain-targeted glioma nanodrug with advantages of precise atomic structures, flexible adjustment and abundant active sites. However, due to the huge synthetic challenges, current giant brain-targeted POM drugs are almost vacant in orthotopic brain tumor therapy.

Figure 1. The structure of the giant POM cluster {[Ce₁₀Ag₆(DMEA)(H₂O)₂₇W₂₂O₇₀][B-α-TeW₉O₃₃]₉}₂^88–.

To address this issue, Zhao et al. designed and synthesized a giant POM cluster {[Ce₁₀Ag₆(DMEA)(H₂O)₂₇W₂₂O₇₀][B-α-TeW₉O₃₃]₉}₂^88– via synergistic coordination between two geometry-unrestricted Ce³⁺ and Ag⁺ linkers with tungsten-oxo cluster fragments (Figure 1). This cluster with 238 metal centers (3.0 nm × 6.0 nm) represents the largest and longest transition-metal–lanthanide co-encapsulated POM cluster. The huge metal space sites of this cluster simultaneously accommodate anticancer centers of Ag and luminescence centers. After ball-milling operation, this POM cluster was further combined with brain-targeted peptide to prepare a brain-targeted nanodrug that exhibits excellent anti-glioma cell activity. The in vivo anti-glioma results reveal the nanodrug could efficiently traverse BBB and target glioma cells, and greatly prolong the survival of orthotopic glioma-bearing mice (Figure 2). Our brain-targeted POM nanodrug has the merit of brain-targeted and high-selectivity anticancer activity, effectively filling the gap in the current lack of effective anti-glioma drugs, and provides potential therapeutic possibility for giant POM clusters in other brain diseases, e.g. neurodegenerative Parkinson’s disease (PD) and Alzheimer’s disease (AD).

Figure 2. a) Schematic route of the in vivo therapy of Ang-Te-Ag-Ce NPs in an orthotopic glioma model. b) The bioluminescence images of the tumor growth as a function of time (n = 5). c) H&E staining images of ex vivo brains from the mice after finishing various treatments. d) The corresponding quantified levels of bioluminescence. e) Immunofluorescence photographs of TUNEL and CD31 and immunohistochemical photographs of  C-Cas3 and Ki67 of various groups. f) Body weight change of all mice during the therapy process. g) Survival monitoring of all mice (n = 5).

Nizi Song and Mengya Lu, Jiancai Liu from Henan University are the co-first authors, while Associate Professor Jiefei Wang and Professor Junwei Zhao are the co-corresponding authors. The research work is supported by the National Natural Science Foundation of China, the Joint Training Fund for Science & Technology R&D of Henan Province, and the Program for Science & Technology Innovation Talents in Universities of Henan Province.

In recent years, Zhao's team has been focusing on the synthesis strategy, structural regulation and property development of giant polyoxometalate clusters, and has achieved innovative research results. For example, the team proposed a new idea that rare earth ions and heteroatoms cooperatively bridge tungsten-oxygen fragments to construct metal-functionalized tungsten-oxygen clusters and prepared the largest tungsten-oxygen nanocluster functionalized by cerium-oxygen clusters and bismuth-oxygen clusters, and investigated its low-temperature proton conductivity for the first time (Angew. Chem. Int. Ed. 2018, 57, 8416–8420). Also, the team proposed another synthetic strategy by combining the geometry-restricted organotin cations and geometry-unrestricted lanthanide cations with tungsten-oxygen fragments and prepared the largest organotin-lanthanide functionalized tungsten-oxygen nanoclusters and evaluated its antitumor activity (Angew. Chem. Int. Ed. 2021, 60, 11153–11157).

Junwei Zhao is the doctoral supervisor, the second-level professor, the provincial distinguished  professor and the Fellow of the Royal Society of Chemistry. His research interests are focused on polyoxometalate-based materials and their optoelectronic devices and drug activity. He has published more than 180 academic papers in J. Am. Chem. Soc., Angew. Chem. Int. Ed. ect, with a total of more than 9000 citations. He presided over five projects of the National Natural Science China and fifteen other projects such as the Foundation of Henan Province Outstanding Youth, the Program of Scientific and Technological Innovation Talents of Universities in Henan Province, received twelve authorized patents and won two ministerial and provincial-level science and technology awards.

Linker: https://onlinelibrary.wiley.com/doi/10.1002/anie.202319700