Biodegradable Biomimic Copper/Manganese Silicate Nanospheres for Chemodynamic/Photodynamic Synergistic Therapy with Simultaneous Glutathione Depletion and Hypoxia Relief.

The integration of reactive oxygen species (ROS)-involved photodynamic therapy (PDT) and chemodynamic therapy (CDT) holds great promise for enhanced anticancer effects. Herein, we report biodegradable cancer cell membrane-coated mesoporous copper/manganese silicate nanospheres (mCMSNs) with homotypic targeting ability to the cancer cell lines and enhanced ROS generation through singlet oxygen (1O2) production and glutathione (GSH)-activated Fenton reaction, showing excellent CDT/PDT synergistic therapeutic effects. We demonstrate that mCMSNs are able to relieve the tumor hypoxia microenvironment by catalytic decomposition of endogenous H2O2 to O2 and further react with O2 to produce toxic 1O2 with a 635 nm laser irradiation. GSH-triggered mCMSNs biodegradation can simultaneously generate Fenton-like Cu+ and Mn2+ ions and deplete GSH for efficient hydroxyl radical (•OH) production. The specific recognition and homotypic targeting ability to the cancer cells were also revealed. Notably, relieving hypoxia and GSH depletion disrupts the tumor microenvironment (TME) and cellular antioxidant defense system, achieving exceptional cancer-targeting therapeutic effects in vitro and in vivo. The cancer cells growth was significantly inhibited. Moreover, the released Mn2+ can also act as an advanced contrast agent for cancer magnetic resonance imaging (MRI). Thus, together with photosensitizers, Fenton agent provider and MRI contrast effects along with the modulating of the TME allow mCMSNs to realize MRI-monitored enhanced CDT/PDT synergistic therapy. It provides a paradigm to rationally design TME-responsive and ROS-involved therapeutic strategies based on a single polymetallic silicate nanomaterial with enhanced anticancer effects.

[1]  Zhuang Liu,et al.  Bimetallic Oxide MnMoOX Nanorods for in Vivo Photoacoustic Imaging of GSH and Tumor-Specific Photothermal Therapy. , 2018, Nano letters.

[2]  K. Soo,et al.  Nanoparticles in photodynamic therapy. , 2015, Chemical reviews.

[3]  D. Zheng,et al.  Preferential Cancer Cell Self-Recognition and Tumor Self-Targeting by Coating Nanoparticles with Homotypic Cancer Cell Membranes. , 2016, Nano letters.

[4]  Liangzhu Feng,et al.  Theranostic Liposomes with Hypoxia-Activated Prodrug to Effectively Destruct Hypoxic Tumors Post-Photodynamic Therapy. , 2017, ACS nano.

[5]  Zhuang Liu,et al.  Hollow MnO2 as a tumor-microenvironment-responsive biodegradable nano-platform for combination therapy favoring antitumor immune responses , 2017, Nature Communications.

[6]  Junjie Zhu,et al.  One-Dimensional Fe2 P Acts as a Fenton Agent in Response to NIR II Light and Ultrasound for Deep Tumor Synergetic Theranostics. , 2019, Angewandte Chemie.

[7]  Angel Ortega,et al.  Glutathione in Cancer Biology and Therapy , 2006, Critical reviews in clinical laboratory sciences.

[8]  W. Cai,et al.  Chemical-template synthesis of micro/nanoscale magnesium silicate hollow spheres for waste-water treatment. , 2010, Chemistry.

[9]  Zhiguang Wu,et al.  Cell‐Membrane‐Coated Synthetic Nanomotors for Effective Biodetoxification , 2015 .

[10]  Ronnie H. Fang,et al.  Nanoparticulate Delivery of Cancer Cell Membrane Elicits Multiantigenic Antitumor Immunity , 2017, Advanced materials.

[11]  Feng Liu,et al.  Self-Assembled Copper-Amino Acid Nanoparticles for in Situ Glutathione "AND" H2O2 Sequentially Triggered Chemodynamic Therapy. , 2018, Journal of the American Chemical Society.

[12]  Hong Cheng,et al.  Cancer Cell Membrane Camouflaged Cascade Bioreactor for Cancer Targeted Starvation and Photodynamic Therapy. , 2017, ACS nano.

[13]  Tao Yang,et al.  Bifunctional Tellurium Nanodots for Photo-Induced Synergistic Cancer Therapy. , 2017, ACS nano.

[14]  T. Hyeon,et al.  Continuous O2-Evolving MnFe2O4 Nanoparticle-Anchored Mesoporous Silica Nanoparticles for Efficient Photodynamic Therapy in Hypoxic Cancer. , 2017, Journal of the American Chemical Society.

[15]  Xiaoyuan Chen,et al.  Nanotechnology for Multimodal Synergistic Cancer Therapy. , 2017, Chemical reviews.

[16]  W. Cai,et al.  One-pot synthesis of nanotube-based hierarchical copper silicate hollow spheres. , 2008, Chemical communications.

[17]  Liangzhu Feng,et al.  Amplification of Tumor Oxidative Stresses with Liposomal Fenton Catalyst and Glutathione Inhibitor for Enhanced Cancer Chemotherapy and Radiotherapy. , 2018, Nano letters.

[18]  Shuang‐Shuang Wan,et al.  An Adenosine Triphosphate-Responsive Autocatalytic Fenton Nanoparticle for Tumor Ablation with Self-Supplied H2O2 and Acceleration of Fe(III)/Fe(II) Conversion. , 2018, Nano letters.

[19]  Zhiguang Wu,et al.  Stem-Cell-Membrane Camouflaging on Near-Infrared Photoactivated Upconversion Nanoarchitectures for in Vivo Remote-Controlled Photodynamic Therapy. , 2016, ACS applied materials & interfaces.

[20]  Irving L. Weissman,et al.  Association of reactive oxygen species levels and radioresistance in cancer stem cells , 2009, Nature.

[21]  Yu Cao,et al.  Three-dimensional Nitrogen-Doped Graphene Supported Molybdenum Disulfide Nanoparticles as an Advanced Catalyst for Hydrogen Evolution Reaction , 2015, Scientific Reports.

[22]  Zhengfang Yi,et al.  Copper Silicate Hollow Microspheres-Incorporated Scaffolds for Chemo-Photothermal Therapy of Melanoma and Tissue Healing. , 2018, ACS nano.

[23]  Yongsheng Chen,et al.  Mechanism of photogenerated reactive oxygen species and correlation with the antibacterial properties of engineered metal-oxide nanoparticles. , 2012, ACS nano.

[24]  K. Lam,et al.  Facile synthesis of size controllable dendritic mesoporous silica nanoparticles. , 2014, ACS applied materials & interfaces.

[25]  Haifeng Dong,et al.  Erythrocyte-Cancer Hybrid Membrane Camouflaged Hollow Copper Sulfide Nanoparticles for Prolonged Circulation Life and Homotypic-Targeting Photothermal/Chemotherapy of Melanoma. , 2018, ACS nano.

[26]  W. Bu,et al.  Chemodynamic Therapy: Tumour Microenvironment-Mediated Fenton and Fenton-like Reactions. , 2018, Angewandte Chemie.

[27]  G. Qiao,et al.  Cancer Treatment through Nanoparticle-Facilitated Fenton Reaction. , 2018, ACS nano.

[28]  P. Prasad,et al.  Nanochemistry and Nanomedicine for Nanoparticle-based Diagnostics and Therapy. , 2016, Chemical reviews.

[29]  Jun Lin,et al.  Assembly of Au Plasmonic Photothermal Agent and Iron Oxide Nanoparticles on Ultrathin Black Phosphorus for Targeted Photothermal and Photodynamic Cancer Therapy , 2017 .

[30]  Zunyao Wang,et al.  Bicarbonate enhanced removal of triclosan by copper(II) catalyzed Fenton-like reaction in aqueous solution , 2016 .

[31]  Ping Gong,et al.  Cancer Cell Membrane-Biomimetic Nanoparticles for Homologous-Targeting Dual-Modal Imaging and Photothermal Therapy. , 2016, ACS nano.

[32]  R. Bauer,et al.  The photo-Fenton reaction — an effective photochemical wastewater treatment process , 1993 .

[33]  Sungjin Jung,et al.  DNA‐Au Nanomachine Equipped with i‐Motif and G‐Quadruplex for Triple Combinatorial Anti‐Tumor Therapy , 2018 .

[34]  Xian‐Zheng Zhang,et al.  Switching Apoptosis to Ferroptosis: Metal-Organic Network for High-Efficiency Anticancer Therapy. , 2017, Nano letters.

[35]  Heliang Yao,et al.  Synthesis of Iron Nanometallic Glasses and Their Application in Cancer Therapy by a Localized Fenton Reaction. , 2016, Angewandte Chemie.

[36]  Qiang He,et al.  Stem Cell Membrane-Coated Nanogels for Highly Efficient In Vivo Tumor Targeted Drug Delivery. , 2016, Small.

[37]  Xiaohan Liu,et al.  Mesoporous manganese silicate coated silica nanoparticles as multi-stimuli-responsive T1-MRI contrast agents and drug delivery carriers. , 2016, Acta biomaterialia.

[38]  Ronnie H. Fang,et al.  Cancer Cell Membrane-Coated Nanoparticles for Anticancer Vaccination and Drug Delivery , 2014, Nano letters.

[39]  Yousheng Tao,et al.  Mesopore-modified zeolites: preparation, characterization, and applications. , 2006, Chemical reviews.

[40]  Xiaoyuan Chen,et al.  Tumor‐Specific Drug Release and Reactive Oxygen Species Generation for Cancer Chemo/Chemodynamic Combination Therapy , 2019, Advanced science.

[41]  Changha Lee,et al.  Chloride-enhanced oxidation of organic contaminants by Cu(II)-catalyzed Fenton-like reaction at neutral pH. , 2018, Journal of hazardous materials.

[42]  Z. Dai,et al.  Self-assembly of porphyrin-grafted lipid into nanoparticles encapsulating doxorubicin for synergistic chemo-photodynamic therapy and fluorescence imaging , 2018, Theranostics.

[43]  Xiaoyuan Chen,et al.  Organic Semiconducting Photoacoustic Nanodroplets for Laser-Activatable Ultrasound Imaging and Combinational Cancer Therapy. , 2018, ACS nano.

[44]  Xiaogang Qu,et al.  Copper(II)-Graphitic Carbon Nitride Triggered Synergy: Improved ROS Generation and Reduced Glutathione Levels for Enhanced Photodynamic Therapy. , 2016, Angewandte Chemie.

[45]  X. Lou,et al.  General Formation of MS (M = Ni, Cu, Mn) Box‐in‐Box Hollow Structures with Enhanced Pseudocapacitive Properties , 2014 .

[46]  Chulhun Kang,et al.  Disulfide-cleavage-triggered chemosensors and their biological applications. , 2013, Chemical reviews.

[47]  Jianlin Shi,et al.  Antiferromagnetic Pyrite as the Tumor Microenvironment‐Mediated Nanoplatform for Self‐Enhanced Tumor Imaging and Therapy , 2017, Advanced materials.

[48]  Jianlin Shi,et al.  "Manganese Extraction" Strategy Enables Tumor-Sensitive Biodegradability and Theranostics of Nanoparticles. , 2016, Journal of the American Chemical Society.

[49]  Guoying Sun,et al.  All-in-One Theranostic Nanoagent with Enhanced Reactive Oxygen Species Generation and Modulating Tumor Microenvironment Ability for Effective Tumor Eradication. , 2018, ACS nano.

[50]  Jun Lin,et al.  Magnetic Targeting, Tumor Microenvironment-Responsive Intelligent Nanocatalysts for Enhanced Tumor Ablation. , 2018, ACS nano.

[51]  Ronnie H. Fang,et al.  Cell Membrane Coating Nanotechnology , 2018, Advanced materials.

[52]  K. Lam,et al.  Facile large-scale synthesis of monodisperse mesoporous silica nanospheres with tunable pore structure. , 2013, Journal of the American Chemical Society.

[53]  Jianlin Shi,et al.  Near infrared-assisted Fenton reaction for tumor-specific and mitochondrial DNA-targeted photochemotherapy. , 2017, Biomaterials.

[54]  Peng Huang,et al.  Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? , 2009, Nature Reviews Drug Discovery.

[55]  Liangzhu Feng,et al.  Smart Nanoreactors for pH-Responsive Tumor Homing, Mitochondria-Targeting, and Enhanced Photodynamic-Immunotherapy of Cancer. , 2018, Nano letters.

[56]  Juan Li,et al.  Simultaneous Fenton-like Ion Delivery and Glutathione Depletion by MnO2 -Based Nanoagent to Enhance Chemodynamic Therapy. , 2018, Angewandte Chemie.