Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 231300, China
Department of General Surgery, The Second Affiliated Hospital of Zhejiang University Medical College, Hangzhou 310027, China
State Key Laboratory of Silicon Materials, School of Materials Science and Engineering, Zhejiang University, Hangzhou 310027, China
Jiangsu Key Laboratory of Biological Cancer, Cancer institute, Xuzhou Medical University, Xuzhou 221002, China
Department of surgery, the People’s Hospital of Hanshan County, Ma’anshan 238101, China
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We constructed the mesothelin targeting membrane via fusion protein by gene recombination, and realized accurate drug delivery nano-system to cancer cells. Two mechanisms of lactate depletion generated more H2O2 to enhance chemodynamic therapy (CDT) and created hypoxia circumstance for tirapazamine (TPZ) therapy. The lactate consumption, enhanced CDT, and activated TPZ occur intracellularly in a synergistic manner to enable considerable proliferation and metastasis inhibition both in vitro and in vivo.
Abstract
The enhanced permeability and retention (EPR) effect alone is not enough for nanoparticles to reach the target. Combination of active and passive targeting may be an effective drug delivery route. Hollow ferric-tannic acid complex nanocapsules (HFe-TA) may effectively degrade and release Fe2+ ions, and Fe2+ ions induce the production of ·OH, however, the fenton reaction needs amount of H2O2 to enhance chemodynamic therapy. Due to their deficiencies, such nanoparticles cannot realize intravenous drug delivery. Here, the mesothelin-targeted membrane (MTM) was constructed to realize accurate delivery nano-system, and mesothelin antibody was expressed on the 293T cell membrane to prepare a MTM. Lactate oxidase (Lox) was loaded on HFe-TA to obtain Lox@HFe-TA. Lox@HFe-TA was coated with MTM to develop the MTM nanosystem. Tirapazamine (TPZ) therapy also requires hypoxia circumstance. The MTM nanosystem combined with TPZ can significantly kill tumour cells and inhibit metastasis in vivo and in vitro. We also tested the biological safety of the treatment. In this study, we overcame the EPR defects via the MTM nanosystem, which can realize acute targeted delivery to the tumour site, lactate depletion, promoted reactive oxygen species (ROS) induction, and enhanced the effect of TPZ, demonstrating a potential synergistic combination of cancer therapy with better efficacy and biosafety.
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