Reactive oxygen species switcher via MnO2-coated Prussian blue loaded hyaluronic acid methacrylate hydrogel microspheres for local anti-tumor treatment

Huijie Han; Shiqi Wang; Mohammad-Ali Shahbazi; Inge S Zuhorn; Zhengwei Cai; Jie Chen; Jiachen Li; Yu Chen; Yawei Du; Raquel Bártolo; Liang Chen; Hélder A Santos; Wenguo Cui

doi:10.1016/j.jconrel.2024.12.036

Reactive oxygen species switcher via MnO₂-coated Prussian blue loaded hyaluronic acid methacrylate hydrogel microspheres for local anti-tumor treatment

J Control Release. 2024 Dec 19:378:350-364. doi: 10.1016/j.jconrel.2024.12.036. Online ahead of print.

Authors

Huijie Han¹, Shiqi Wang², Mohammad-Ali Shahbazi³, Inge S Zuhorn³, Zhengwei Cai⁴, Jie Chen⁴, Jiachen Li³, Yu Chen⁴, Yawei Du⁴, Raquel Bártolo³, Liang Chen⁴, Hélder A Santos⁵, Wenguo Cui⁶

Affiliations

¹ Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China; Department of Biomaterials and Biomedical Technology, The Personalized Medicine Research Institute (PRECISION), University Medical Center Groningen, University of Groningen, 9713 AV Groningen, the Netherlands; Department of Biology, College of Chemistry and Life Science, Beijing University of Technology, Beijing, 100124 P. R. China.
² Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
³ Department of Biomaterials and Biomedical Technology, The Personalized Medicine Research Institute (PRECISION), University Medical Center Groningen, University of Groningen, 9713 AV Groningen, the Netherlands.
⁴ Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
⁵ Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China; Department of Biomaterials and Biomedical Technology, The Personalized Medicine Research Institute (PRECISION), University Medical Center Groningen, University of Groningen, 9713 AV Groningen, the Netherlands; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland. Electronic address: h.a.santos@umcg.nl.
⁶ Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. Electronic address: wgcui@sjtu.edu.cn.

PMID: 39701450
DOI: 10.1016/j.jconrel.2024.12.036

Abstract

ROS-induced therapy can eradicate breast tumors when combined with thermal ablation, but excessive ROS also threatens peritumoral tissue with inflammation. To eradicate tumors and avoid inflammatory sequela, it is necessary to generate ROS in treatment stage and scavenge ROS in prognostic stage. However, it is a great challenge to reverse ROS in different stages. Herein, the "ROS switcher" of MnO₂-coated Prussian blue (PM) is loaded in hyaluronic acid methacrylate (HAMA) hydrogel microspheres, combining ROS generation by Mn-mediated Fenton-like reaction, and ROS scavenging by Fe^3+/2+ electron transfer. Firstly, it is ROS generator that oxidatively damages biomacromolecules in residual tumors, then it is ROS scavenger that reduces pro-inflammatory cytokines and oxidation stress in peritumoral skin_. Glucose oxidase is immobilized in HAMA microspheres to enhance ROS supply by catalyzing glucose into H₂O₂, degrading MnO₂ into Mn²⁺, and providing H₂O₂ for a Fenton-like reaction. After MnO₂ degradation, Prussian blue is gradually exposed and scavenges ROS, thus defending oxidative skin damage and alleviating ROS-stimulated inflammation. In vitro results indicate that the microsphere supplied sustained ROS for up to 5 days, and H₂O₂-degraded PM (0.2 mg mL^-1) scavenged 500 μM H₂O₂. In vivo results confirm that 4/6 breast tumors were eradicated while pro-inflammatory cytokines were significantly reduced with ROS level in peri-tumoral skin. In summary, ROS switcher is developed by Mn-mediated nano-shell peeling and achieves tumor eradication and post-operative skin repair after thermal ablation of the breast tumor.

Keywords: Anti-inflammatory; Anti-tumor; MnO(2); Prussian blue; Reactive oxygen species switcher.