{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T17:19:27Z","timestamp":1789060767036,"version":"build-2803163510"},"reference-count":50,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T00:00:00Z","timestamp":1713398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the local funding project for scientific and technological development under the guidance of the central government","award":["GuiKe ZY21195012"],"award-info":[{"award-number":["GuiKe ZY21195012"]}]},{"name":"the local funding project for scientific and technological development under the guidance of the central government","award":["SSTLAB-2023-03"],"award-info":[{"award-number":["SSTLAB-2023-03"]}]},{"name":"the local funding project for scientific and technological development under the guidance of the central government","award":["2020023"],"award-info":[{"award-number":["2020023"]}]},{"name":"Shenzhen Key Laboratory of Southern Subtropical Plant Diversity","award":["GuiKe ZY21195012"],"award-info":[{"award-number":["GuiKe ZY21195012"]}]},{"name":"Shenzhen Key Laboratory of Southern Subtropical Plant Diversity","award":["SSTLAB-2023-03"],"award-info":[{"award-number":["SSTLAB-2023-03"]}]},{"name":"Shenzhen Key Laboratory of Southern Subtropical Plant Diversity","award":["2020023"],"award-info":[{"award-number":["2020023"]}]},{"name":"Foundation of Nanning Qingxiu District Key Research and Development Project","award":["GuiKe ZY21195012"],"award-info":[{"award-number":["GuiKe ZY21195012"]}]},{"name":"Foundation of Nanning Qingxiu District Key Research and Development Project","award":["SSTLAB-2023-03"],"award-info":[{"award-number":["SSTLAB-2023-03"]}]},{"name":"Foundation of Nanning Qingxiu District Key Research and Development Project","award":["2020023"],"award-info":[{"award-number":["2020023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The integration of a multidimensional treatment dominated by active ingredients of traditional Chinese medicine (TCM), including enhanced chemotherapy and synergistically amplification of oxidative damage, into a nanoplatform would be of great significance for furthering accurate and effective cancer treatment with the active ingredients of TCM. Herein, in this study, we designed and synthesized four matrine-proteolysis-targeting chimeras (PROTACs) (depending on different lengths of the chains named LST-1, LST-2, LST-3, and LST-4) based on PROTAC technology to overcome the limitations of matrine. LST-4, with better anti-tumor activity than matrine, still degrades p-Erk and p-Akt proteins. Moreover, LST-4 NPs formed via LST-4 self-assembly with stronger anti-tumor activity and glutathione (GSH) depletion ability could be enriched in lysosomes through their outstanding enhanced permeability and retention (EPR) effect. Then, we synthesized LST-4@ZnPc NPs with a low-pH-triggered drug release property that could release zinc(II) phthalocyanine (ZnPc) in tumor sites. LST-4@ZnPc NPs combine the application of chemotherapy and phototherapy, including both enhanced chemotherapy from LST-4 NPs and the synergistic amplification of oxidative damage, through increasing the reactive oxygen species (ROS) by photodynamic therapy (PDT), causing an GSH decrease via LST-4 mediation to effectively kill tumor cells. Therefore, multifunctional LST-4@ZnPc NPs are a promising method for killing cancer cells, which also provides a new paradigm for using natural products to kill tumors.<\/jats:p>","DOI":"10.3390\/molecules29081845","type":"journal-article","created":{"date-parts":[[2024,4,18]],"date-time":"2024-04-18T07:55:54Z","timestamp":1713426954000},"page":"1845","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Self-Assembled Matrine-PROTAC Encapsulating Zinc(II) Phthalocyanine with GSH-Depletion-Enhanced ROS Generation for Cancer Therapy"],"prefix":"10.3390","volume":"29","author":[{"given":"Sitong","family":"Lai","sequence":"first","affiliation":[{"name":"School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Wang","sequence":"additional","affiliation":[{"name":"NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Institute for Drug Control, Shenzhen 518057, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunhui","family":"Sun","sequence":"additional","affiliation":[{"name":"NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Institute for Drug Control, Shenzhen 518057, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2918-7369","authenticated-orcid":false,"given":"Xie-An","family":"Yu","sequence":"additional","affiliation":[{"name":"NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Institute for Drug Control, Shenzhen 518057, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihe","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise 533000, China"},{"name":"Shenzhen Key Laboratory of Southern Subtropical Plant Diversity, Fairylake Botanical Garden, Shenzhen & Chinese Academy of Science, Shenzhen 518004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisheng","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Medicine, Guangxi University, Nanning 530004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.jep.2019.02.045","article-title":"Antiviral activity of sophoridine against enterovirus 71 in vitro","volume":"236","author":"Ren","year":"2019","journal-title":"J. Ethnopharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"103698","DOI":"10.1016\/j.micpath.2019.103698","article-title":"Total alkaloids of Sophora alopecuroides and matrine inhibit auto-inducer 2 in the biofilms of Staphylococcus epidermidis","volume":"136","author":"Jia","year":"2019","journal-title":"Microb. Pathog."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1177\/1753425918800555","article-title":"Matrine induces apoptosis via targeting CCR7 and enhances the effect of anticancer drugs in non-small cell lung cancer in vitro","volume":"24","author":"Pu","year":"2018","journal-title":"Innate. Immun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.1021\/acs.jnatprod.8b00576","article-title":"Matrine-Type Alkaloids from the Roots of Sophora flavescens and Their Antiviral Activities against the Hepatitis B Virus","volume":"81","author":"Zhang","year":"2018","journal-title":"J. Nat. Prod."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1002\/cjoc.202100526","article-title":"Structurally diverse matrine-based alkaloids with anti-inflammatory effects from sophora alopecuroides","volume":"39","author":"Luo","year":"2021","journal-title":"Chin. J. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1055\/s-2007-969179","article-title":"Study of the antipyretic activity of matrine. A lupin alkaloid isolated from Sophora subprostrata","volume":"52","author":"Cho","year":"1986","journal-title":"Planta. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"844","DOI":"10.3109\/13880209.2013.767363","article-title":"Antinociceptive effects of matrine on neuropathic pain induced by chronic constriction injury","volume":"51","author":"Wang","year":"2013","journal-title":"Pharm. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"588","DOI":"10.3389\/fphar.2020.00588","article-title":"Matrine: A Promising Natural Product With Various Pharmacological Activities","volume":"11","author":"Zhang","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"867318","DOI":"10.3389\/fchem.2022.867318","article-title":"Research Advances on Matrine","volume":"10","author":"Sun","year":"2022","journal-title":"Front. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1045345","DOI":"10.1155\/2019\/1045345","article-title":"Matrine Exerts Hepatotoxic Effects via the ROS-Dependent Mitochondrial Apoptosis Pathway and Inhibition of Nrf2-Mediated Antioxidant Response","volume":"2019","author":"You","year":"2019","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"113682","DOI":"10.1016\/j.jep.2020.113682","article-title":"Matrine: A review of its pharmacology, pharmacokinetics, toxicity, clinical application and preparation researches","volume":"269","author":"Li","year":"2021","journal-title":"J. Ethnopharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1016\/j.jpba.2009.11.020","article-title":"Biopharmaceutical and pharmacokinetic characterization of matrine as determined by a sensitive and robust UPLC-MS\/MS method","volume":"51","author":"Yang","year":"2010","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.1021\/acscentsci.9b00713","article-title":"Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs","volume":"5","author":"Pfaff","year":"2019","journal-title":"ACS Cent. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/s41568-021-00365-x","article-title":"Advancing targeted protein degradation for cancer therapy","volume":"21","author":"Dale","year":"2021","journal-title":"Nat. Rev. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13045-020-00885-3","article-title":"Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy","volume":"13","author":"Li","year":"2020","journal-title":"J. Hematol. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Sincere, N.I., Anand, K., Ashique, S., Yang, J., and You, C. (2023). PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies. Molecules, 28.","DOI":"10.3390\/molecules28104014"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/nrc3599","article-title":"Cancer drug resistance: An evolving paradigm","volume":"13","author":"Holohan","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1146\/annurev-physiol-021119-034627","article-title":"The Acidic Tumor Microenvironment as a Driver of Cancer","volume":"82","author":"Boedtkjer","year":"2020","journal-title":"Annu. Rev. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"An, J., Hu, Y.G., Cheng, K., Li, C., Hou, X.L., Wang, G.L., Zhang, X.S., Liu, B., Zhao, Y.D., and Zhang, M.Z. (2020). ROS-augmented and tumor-microenvironment responsive biodegradable nanoplatform for enhancing chemo-sonodynamic therapy. Biomaterials., 234.","DOI":"10.1016\/j.biomaterials.2020.119761"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"13078","DOI":"10.1039\/C9NR03052B","article-title":"Enhancement of ultralow-intensity NIR light-triggered photodynamic therapy based on exo- and endogenous synergistic effects through combined glutathione-depletion chemotherapy","volume":"11","author":"Shi","year":"2019","journal-title":"Nanoscale"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.scib.2017.02.001","article-title":"A smart photodynamic therapy strategy: Depletion of glutathione in cancer cells","volume":"62","author":"Huang","year":"2017","journal-title":"Sci. Bull."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.biomaterials.2018.09.043","article-title":"Nitric oxide as an all-rounder for enhanced photodynamic therapy: Hypoxia relief, glutathione depletion and reactive nitrogen species generation","volume":"187","author":"Deng","year":"2018","journal-title":"Biomaterials"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1039\/C9TB02120E","article-title":"Enhanced photodynamic therapy based on an amphiphilic branched copolymer with pendant vinyl groups for simultaneous GSH depletion and Ce6 release","volume":"8","author":"Cao","year":"2020","journal-title":"J. Mater. Chem. B"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"127212","DOI":"10.1016\/j.cej.2020.127212","article-title":"Tumor-specific carrier-free nanodrugs with GSH depletion and enhanced ROS generation for endogenous synergistic anti-tumor by a chemotherapy-photodynamic therapy","volume":"407","author":"Lan","year":"2021","journal-title":"Chem. Eng. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.cbpa.2019.10.004","article-title":"Metal-based photosensitizers for photodynamic therapy: The future of multimodal oncology?","volume":"56","author":"McFarland","year":"2020","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Plekhova, N., Shevchenko, O., Korshunova, O., Stepanyugina, A., Tananaev, I., and Apanasevich, V. (2022). Development of Novel Tetrapyrrole Structure Photosensitizers for Cancer Photodynamic Therapy. Bioengineering, 9.","DOI":"10.3390\/bioengineering9020082"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1002\/cyto.a.23596","article-title":"Enhancing Type I Photochemistry in Photodynamic Therapy Under Near Infrared Light by Using Antennae-Fullerene Complexes","volume":"93","author":"Li","year":"2018","journal-title":"Cytom. A"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Correia, J.H., Rodrigues, J.A., Pimenta, S., Dong, T., and Yang, Z. (2021). Photodynamic Therapy Review: Principles, Photosensitizers, Applications, and Future Directions. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13091332"},{"key":"ref_29","first-page":"2357","article-title":"Therapeutic Polymersome Nanoreactors with Tumor-Specific Activable Cascade Reactions for Cooperative Cancer Therapy","volume":"13","author":"Ke","year":"2019","journal-title":"ACS Nano"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1002\/anie.201507634","article-title":"Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL","volume":"55","author":"Lai","year":"2016","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1021\/acs.jmedchem.7b00635","article-title":"Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1","volume":"61","author":"Crew","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"6827","DOI":"10.1021\/acsami.9b18443","article-title":"Exploration of the Natural Active Small-Molecule Drug-Loading Process and Highly Efficient Synergistic Antitumor Efficacy","volume":"12","author":"Wang","year":"2020","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1007\/s11426-021-1146-6","article-title":"Frontiers in circularly polarized luminescence: Molecular design, self-assembly, nanomaterials, and applications","volume":"64","author":"Gong","year":"2021","journal-title":"Sci. China Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/376599a0","article-title":"Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction","volume":"376","author":"Burgering","year":"1995","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7391","DOI":"10.1038\/sj.onc.1209100","article-title":"AKT signaling in normal and malignant cells","volume":"24","author":"Testa","year":"2005","journal-title":"Oncogene"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3279","DOI":"10.1038\/sj.onc.1210421","article-title":"MAP kinase signalling pathways in cancer","volume":"26","author":"Dhillon","year":"2007","journal-title":"Oncogene"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.bbamcr.2006.10.001","article-title":"Roles of the Raf\/MEK\/ERK pathway in cell growth, malignant transformation and drug resistance","volume":"1773","author":"McCubrey","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1007\/s12032-022-01762-4","article-title":"Matrine induces autophagy in human neuroblastoma cells via blocking the AKT-mTOR pathway","volume":"39","author":"Liu","year":"2022","journal-title":"Med. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"23212","DOI":"10.3390\/ijms141223212","article-title":"Blocking autophagic flux enhances matrine-induced apoptosis in human hepatoma cells","volume":"14","author":"Wang","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"82","DOI":"10.3892\/or.2021.8033","article-title":"Matrine inhibits ovarian cancer cell viability and promotes apoptosis by regulating the ERK\/JNK signaling pathway via p38MAPK","volume":"45","author":"Liang","year":"2021","journal-title":"Oncol. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e1800670","DOI":"10.1002\/adhm.201800670","article-title":"Self-Assembled Nanomedicines for Anticancer and Antibacterial Applications","volume":"7","author":"Zhou","year":"2018","journal-title":"Adv. Healthc. Mater."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.1039\/C9BM01912J","article-title":"In situ self-assembly of conjugated polyelectrolytes for cancer targeted imaging and photodynamic therapy","volume":"8","author":"Khatoon","year":"2020","journal-title":"Biomater. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"13002","DOI":"10.1002\/anie.201307346","article-title":"Biological imaging using nanoparticles of small organic molecules with fluorescence emission at wavelengths longer than 1000 nm","volume":"52","author":"Tao","year":"2013","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e1901492","DOI":"10.1002\/adhm.201901492","article-title":"Tailor-Made Polymer Nano-Assembly with Switchable Function and Amplified Anti-Tumor Therapy","volume":"9","author":"Guo","year":"2020","journal-title":"Adv. Healthc. Mater."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.addr.2010.04.009","article-title":"The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect","volume":"63","author":"Fang","year":"2011","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Zheng, M., Liu, Y., Wu, C., Yang, K., Wang, Q., Zhou, Y., Chen, L., and Li, H. (2021). Novel PROTACs for degradation of SHP2 protein. Bioorg. Chem., 110.","DOI":"10.1016\/j.bioorg.2021.104788"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"19695","DOI":"10.1021\/jacs.2c09804","article-title":"Total Synthesis of Matrine Alkaloids","volume":"144","author":"Magann","year":"2022","journal-title":"J. Am. Chem. Soc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7839","DOI":"10.1021\/acs.jmedchem.1c00649","article-title":"Rational Design and Synthesis of Novel Dual PROTACs for Simultaneous Degradation of EGFR and PARP","volume":"64","author":"Zheng","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1021\/acs.bioconjchem.9b00819","article-title":"Self-Assembled Naphthalimide Conjugated Porphyrin Nanomaterials with D-A Structure for PDT\/PTT Synergistic Therapy","volume":"31","author":"Yang","year":"2020","journal-title":"Bioconjug. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.jphotobiol.2016.04.018","article-title":"Preparation and characterization of new zinc(II) phthalocyanine-Containing poly(l-lactide)-b-poly(ethylene glycol) copolymer micelles for photodynamic therapy","volume":"160","author":"Lamch","year":"2016","journal-title":"J. Photochem. Photobiol. 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