{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T18:02:00Z","timestamp":1789495320765,"version":"build-2803163510"},"reference-count":36,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Centre, Poland","award":["2022\/45\/B\/NZ7\/01056"],"award-info":[{"award-number":["2022\/45\/B\/NZ7\/01056"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Polymers"],"abstract":"<jats:p>(1) Background: Glioblastoma is the most common and aggressive primary brain tumor in adults, with a median survival time for patients treated with standard chemotherapy often of less than 1 year. Potential anticancer activity against glioblastoma is demonstrated by flavonoids, including fisetin (FIS). Although, its clinical application is limited by poor solubility and chemical instability. This study aimed to conduct a preliminary evaluation of fisetin\u2019s suitability for intravenous delivery by developing and characterizing FIS-loaded poly(lactic-co-glycolic acid) nanoparticles (FIS-PLGA-NPs) and assessing their in vitro cytotoxic potential against glioblastoma. (2) Methods: Six FIS-PLGA nanoparticle formulations were prepared via the emulsification\u2013solvent evaporation method and evaluated for key physicochemical properties. The biological activity of fisetin was examined through cell cycle analysis and apoptosis assays, and the most promising formulation was further assessed using an MTT assay in U-138 MG glioblastoma cells. In parallel, pure fisetin was exposed to ionizing radiation, including the standard sterilization dose of 25 kGy, to evaluate its structural stability and suitability for terminal sterilization approaches. (3) Results: The selected formulation (NP4) exhibited a mean particle size of approximately 330 nm, a zeta potential of \u22127.2 mV, a polydispersity index of 0.25, and high encapsulation efficiency and drug loading of 83.58% and 13.93%, respectively. Despite its preliminary nature, this formulation retained cytotoxic activity in vitro. Moreover, pure fisetin maintained its structural and chemical integrity following radiation exposure, supporting the feasibility of radiation sterilization prior to nanoparticle incorporation. (4) Conclusions: These findings confirm the feasibility of combining radiosterilizable fisetin with PLGA-based nanoencapsulation and provide an initial foundation for the development of an injectable fisetin delivery system for glioblastoma treatment. Further optimization, particularly surface modification, will be required to enhance colloidal stability and systemic performance.<\/jats:p>","DOI":"10.3390\/polym17223074","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T09:44:53Z","timestamp":1763631893000},"page":"3074","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Anticancer Potential of Fisetin Against Glioblastoma: In Vitro Evaluation, Radiostability Assessment, and Preliminary PLGA Encapsulation"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8651-4560","authenticated-orcid":false,"given":"Agnieszka","family":"Sobczak","sequence":"first","affiliation":[{"name":"Poznan University of Medical Sciences, Chair and Department of Pharmaceutical Chemistry, 3 Rokietnicka, 60-802 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Dominiak","sequence":"additional","affiliation":[{"name":"Poznan University of Medical Sciences, Chair and Department of Pharmaceutical Chemistry, 3 Rokietnicka, 60-802 Pozna\u0144, Poland"},{"name":"Poznan University of Medical Sciences, Doctoral School, 70 Bukowska, 60-812 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart\u0142omiej","family":"Sztenc","sequence":"additional","affiliation":[{"name":"Poznan University of Medical Sciences, Chair and Department of Pharmaceutical Chemistry, 3 Rokietnicka, 60-802 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5222-4557","authenticated-orcid":false,"given":"Barbara","family":"Jadach","sequence":"additional","affiliation":[{"name":"Poznan University of Medical Sciences, Chair and Department of Pharmaceutical Technology, 3 Rokietnicka, 60-802 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aneta","family":"Wo\u017aniak-Braszak","sequence":"additional","affiliation":[{"name":"Adam Mickiewicz University, Functional Materials Physics Division, Faculty of Physics and Astronomy, 2 Uniwersytetu Pozna\u0144skiego, 61-614 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miko\u0142aj","family":"Baranowski","sequence":"additional","affiliation":[{"name":"Adam Mickiewicz University, Functional Materials Physics Division, Faculty of Physics and Astronomy, 2 Uniwersytetu Pozna\u0144skiego, 61-614 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawe\u0142","family":"Bilski","sequence":"additional","affiliation":[{"name":"Adam Mickiewicz University, Department of Experimental Physics of Condensed Phase, Faculty of Physics and Astronomy, 2 Uniwersytetu Pozna\u0144skiego, 61-614 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2872-8875","authenticated-orcid":false,"given":"Aleksandra","family":"Majchrzak-Celi\u0144ska","sequence":"additional","affiliation":[{"name":"Poznan University of Medical Sciences, Chair and Department of Pharmaceutical Biochemistry, 3 Rokietnicka, 60-802 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7275-0298","authenticated-orcid":false,"given":"Violetta","family":"Krajka-Ku\u017aniak","sequence":"additional","affiliation":[{"name":"Poznan University of Medical Sciences, Chair and Department of Pharmaceutical Biochemistry, 3 Rokietnicka, 60-802 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Jeli\u0144ska","sequence":"additional","affiliation":[{"name":"Poznan University of Medical Sciences, Chair and Department of Pharmaceutical Chemistry, 3 Rokietnicka, 60-802 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5106-5937","authenticated-orcid":false,"given":"Maciej","family":"Stawny","sequence":"additional","affiliation":[{"name":"Poznan University of Medical Sciences, Chair and Department of Pharmaceutical Chemistry, 3 Rokietnicka, 60-802 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3401-9503","authenticated-orcid":false,"given":"Aleksandra","family":"Gosty\u0144ska-Stawna","sequence":"additional","affiliation":[{"name":"Poznan University of Medical Sciences, Chair and Department of Pharmaceutical Chemistry, 3 Rokietnicka, 60-802 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kumar, R.M., Kumar, H., Bhatt, T., Jain, R., Panchal, K., Chaurasiya, A., and Jain, V. (2023). Fisetin in Cancer: Attributes, Developmental Aspects, and Nanotherapeutics. Pharmaceuticals, 16.","DOI":"10.3390\/ph16020196"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1186\/s40001-023-01271-8","article-title":"Biological Effects and Mechanisms of Fisetin in Cancer: A Promising Anti-Cancer Agent","volume":"28","author":"Zhou","year":"2023","journal-title":"Eur. J. Med. Res."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kubina, R., Krzykawski, K., Kaba\u0142a-Dzik, A., Wojtyczka, R.D., Chodurek, E., and Dziedzic, A. (2022). Fisetin, a Potent Anticancer Flavonol Exhibiting Cytotoxic Activity Against Neoplastic Malignant Cells and Cancerous Conditions: A Scoping, Comprehensive Review. Nutrients, 14.","DOI":"10.3390\/nu14132604"},{"key":"ref_4","unstructured":"Ferah, S., \u00c7aml\u0131bel, M., Er\u00e7elik, M., Tekin, \u00c7., Bekar, A., Kocaeli, H., Ta\u015fkap\u0131l\u0131o\u011flu, \u00d6.M., and Tunca, B. (2022, January 23\u201325). Investigation of the Effects of Fisetin with the Combination of Chemotherapy Drug Te-609 Mozolomide to the Biological Behaviour of Glioblastoma Cells. Proceedings of the 5th Inter-610 National Eurasian Conference on Biological and Chemical Sciences (EurasianBioChem 2022), Antalya, Turkey."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1515\/znc-2019-0098","article-title":"Fisetin Effects on Cell Proliferation and Apoptosis in Glioma Cells","volume":"74","author":"Pak","year":"2019","journal-title":"Z. F\u00fcr Naturforsch. C"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/j.biopha.2017.10.164","article-title":"A Review on the Chemotherapeutic Potential of Fisetin: In Vitro Evidences","volume":"97","author":"Sundarraj","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3407","DOI":"10.1007\/s13277-014-2975-9","article-title":"Fisetin Suppresses ADAM9 Expression and Inhibits Invasion of Glioma Cancer Cells through Increased Phosphorylation of ERK1\/2","volume":"36","author":"Chen","year":"2015","journal-title":"Tumor Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"901","DOI":"10.21873\/anticanres.16884","article-title":"Genotoxic and Cytotoxic Activity of Fisetin on Glioblastoma Cells","volume":"44","author":"Beltzig","year":"2024","journal-title":"Anticancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Joma, N., Zhang, I., Righetto, G.L., McKay, L., Gran, E.R., Kakkar, A., and Maysinger, D. (2023). Flavonoids Regulate Redox-Responsive Transcription Factors in Glioblastoma and Microglia. Cells, 12.","DOI":"10.3390\/cells12242821"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Renault-Mahieux, M., Vieillard, V., Seguin, J., Espeau, P., Le, D.T., Lai-Kuen, R., Mignet, N., Paul, M., and Andrieux, K. (2021). Co-Encapsulation of Fisetin and Cisplatin into Liposomes for Glioma Therapy: From Formulation to Cell Evaluation. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13070970"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1039\/D3NR05195A","article-title":"Sensitizing Chemotherapy for Glioma with Fisetin Mediated by Microenvironment-Responsive Nano-Drug Delivery System","volume":"16","author":"Wang","year":"2023","journal-title":"Nanoscale"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3964","DOI":"10.1002\/ptr.7855","article-title":"Fisetin Attenuates Doxorubicin-induced Cardiotoxicity by Inhibiting the Insulin-like Growth Factor","volume":"37","author":"Lin","year":"2023","journal-title":"Phytother. Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Grzegorzewski, J., Michalak, M., Wo\u0142oszczuk, M., Bulicz, M., and Majchrzak-Celi\u0144ska, A. (2025). Nanotherapy of Glioblastoma\u2014Where Hope Grows. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26051814"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.ijpharm.2013.01.050","article-title":"Liposomal Encapsulation of the Natural Flavonoid Fisetin Improves Bioavailability and Antitumor Efficacy","volume":"444","author":"Seguin","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ku\u017ami\u0144ska, J., Sobczak, A., Majchrzak-Celi\u0144ska, A., \u017b\u00f3\u0142nowska, I., Gosty\u0144ska, A., Jadach, B., Krajka-Ku\u017aniak, V., Jeli\u0144ska, A., and Stawny, M. (2023). Etoricoxib-Cannabidiol Combo: Potential Role in Glioblastoma Treatment and Development of PLGA-Based Nanoparticles. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15082104"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2776","DOI":"10.1021\/acs.jpcb.7b01090","article-title":"Molecular and Vibrational Dynamics in the Cholesterol-Lowering Agent Lovastatin: Solid-State NMR, Inelastic Neutron Scattering, and Periodic DFT Study","volume":"121","author":"Bilski","year":"2017","journal-title":"J. Phys. Chem. B"},{"key":"ref_17","unstructured":"International Council for Harmonisation (2023). ICH Q2(R2) Guideline on Validation of Analytical Procedures\u2014Step 5, International Council for Harmonisation."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.jneuroim.2016.11.012","article-title":"Natural Product HTP Screening for Attenuation of Cytokine-Induced Neutrophil Chemo Attractants (CINCs) and NO2\u2014In LPS\/IFN\u03b3 Activated Glioma Cells","volume":"302","author":"Mazzio","year":"2017","journal-title":"J. Neuroimmunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.ijbiomac.2022.08.210","article-title":"Brain Targeted Delivery of Carmustine Using Chitosan Coated Nanoparticles via Nasal Route for Glioblastoma Treatment","volume":"221","author":"Ahmad","year":"2022","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5397","DOI":"10.1039\/D0CS01127D","article-title":"Understanding Nanoparticle Endocytosis to Improve Targeting Strategies in Nanomedicine","volume":"50","author":"Susnik","year":"2021","journal-title":"Chem. Soc. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Messina, S., Zuchegna, C., and Bruzzi, M. (2025). Chemotherapeutic Nanoparticles for Glioblastoma. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1641752"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.ijpharm.2005.11.040","article-title":"Influence of Particle Size on Transport of Methotrexate across Blood Brain Barrier by Polysorbate 80-Coated Polybutylcyanoacrylate Nanoparticles","volume":"310","author":"Gao","year":"2006","journal-title":"Int. J. Pharm."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Dalle Carbonare, L., Bertacco, J., Gaglio, S.C., Minoia, A., Cominacini, M., Cheri, S., Deiana, M., Marchetto, G., Bisognin, A., and Gandini, A. (2022). Fisetin: An Integrated Approach to Identify a Strategy Promoting Osteogenesis. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.890693"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Liu, W.-Y., Lin, C.-C., Hsieh, Y.-S., and Wu, Y.-T. (2021). Nanoformulation Development to Improve the Biopharmaceutical Properties of Fisetin Using Design of Experiment Approach. Molecules, 26.","DOI":"10.3390\/molecules26103031"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1080\/10717544.2016.1245366","article-title":"Enhanced Oral Bioavailability and Anticancer Efficacy of Fisetin by Encapsulating as Inclusion Complex with HP\u03b2CD in Polymeric Nanoparticles","volume":"24","author":"Kadari","year":"2017","journal-title":"Drug Deliv."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/j.msec.2016.06.042","article-title":"Nanoencapsulation of Dietary Flavonoid Fisetin: Formulation and In Vitro Antioxidant and \u03b1-Glucosidase Inhibition Activities","volume":"68","author":"Sechi","year":"2016","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1111\/j.2042-7158.2012.01482.x","article-title":"Accelerated in-vitro release testing methods for extended-release parenteral dosage forms","volume":"64","author":"Shen","year":"2012","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.ejpb.2021.05.008","article-title":"Accelerated in vitro release testing method for a long-acting peptide-PLGA formulation","volume":"165","author":"Goel","year":"2021","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1007\/s10973-005-7545-3","article-title":"Theeffect of ionizing radiation on chloramphenicol","volume":"84","author":"Marciniec","year":"2006","journal-title":"J. Therm. Anal. Calorim."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Sakiroff, L.-M., Chennell, P., Yessaad, M., Pereira, B., Bouattour, Y., and Sautou, V. (2022). Evaluation of Color Changes During Stability Studies Using Spectrophotometric Chromaticity Measurements Versus Visual Examination. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-13025-3"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.freeradbiomed.2020.03.018","article-title":"Multiharmonic Electron Paramagnetic Resonance Imaging as an Innovative Approach for In Vivo Studies","volume":"152","author":"Gonet","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1143\/JPSJ.9.888","article-title":"A General Theory of Magnetic Resonance Absorption","volume":"9","author":"Kubo","year":"1954","journal-title":"J. Phys. Soc. Jpn."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1103\/PhysRev.73.679","article-title":"Relaxation Effects in Nuclear Magnetic Resonance Absorption","volume":"73","author":"Bloembergen","year":"1948","journal-title":"Phys. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Dominiak, K., Gosty\u0144ska-Stawna, A., Sobczak, A., Paluszczak, J., Wo\u017aniak-Braszak, A., Baranowski, M., Bilski, P., Wicher, B., Tykarska, E., and Jeli\u0144ska, A. (2025). Formulation of Honokiol- and Magnolol-Loaded Nanoemulsions for Head and Neck Cancer Adjuvant Therapy: Evaluation of Radiation Sterilization Effects on Active Substance Properties. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26168032"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"121780","DOI":"10.1016\/j.ijpharm.2022.121780","article-title":"Interaction of Surfactant Coated PLGA Nanoparticles with In Vitro Human Brain-Like Endothelial Cells","volume":"621","author":"Moya","year":"2022","journal-title":"Int. J. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"106680","DOI":"10.1016\/j.jddst.2025.106680","article-title":"Regional Brain Distribution of PLGA Nanoparticles Functionalized with Glutathione or Phenylalanine Dipeptide","volume":"105","author":"Alonso","year":"2025","journal-title":"J. Drug Deliv. Sci. Technol."}],"container-title":["Polymers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4360\/17\/22\/3074\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T05:16:20Z","timestamp":1763788580000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4360\/17\/22\/3074"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,20]]},"references-count":36,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["polym17223074"],"URL":"https:\/\/doi.org\/10.3390\/polym17223074","relation":{},"ISSN":["2073-4360"],"issn-type":[{"value":"2073-4360","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,20]]}}}